the rationale of intradialytic amino acid supplementation

The Rationale of Intradialytic Amino Acid

Supplementation

dr Iyan Darmawan

Unavoidable nitrogen loss (FAO/WHO)

*:0.054(g) ×7.5* × 60(kg) × 1.3**=31.6(g)*: When nitrogen is converted to the amino acid volume (6.25 × 1.2)**: Usually 30% increase in consideration of individual differenceFAO: Food and Agricultural Organization

Roles of amino acidsmgN/kg/day Total

Urine 37 54 mg/kg/day

Stool 12Skin 3Other 2

When converted amino acids

(Human weighing 60 kg)31.6 g/day*

Materials for protein synthesis

Improvement of nitrogen accountability

Improvement of protein metabolism

Prevention of postoperative complications Improvement of treatment performance

Significance of administering amino acids

編集／必須アミノ酸研究委員会：エネルギー・蛋白質の必要性，医歯薬出版 1989：p46‐48

Presenter

Presentation Notes

Amino acids from which visceral proteins, enzymes, hormones and other proteins essential for maintenance of life need to be supplemented constantly by a certain amount. The improvement of nitrogen accountability and protein metabolism using amino acids is important to prevent postoperative complications and improve treatment performance and in principle necessary in the patients with renal impairment. Let’s discuss the minimum necessary amount of amino acids per day. According to the FAO/WHO report, healthy persons have loss of about 54 mg/kg/day of nitrogen from the urine, feces or skin. This is called unavoidable nitrogen loss and equivalent to about 32 g of amino acids in a person weighing 60 kg. Body protein is destroyed without the intake of at least this amount of amino acids. Under fasting or surgical invasion, people have hypercatabolism of muscular and body protein and increased loss of protein. Therefore, it is necessary to administer an adequate dose of amino acids under fasting or after surgery when oral intake is insufficient. [Supplemental explanations] *: Conversion of nitrogen to amino acid dose (6.25×1.2) Protein molecules are hydrolyzed into amino acids. In other words, 1.2 g of mixed amino acids are produced from 1 g of protein and 0.2 g of water. Therefore, the nitrogen coefficient is 1.2 times higher. 　　　　　　　　Nitrogen coefficient 6.25 gN1.2 = 7.5 gN 　　Protein 　　　　　　　　　　　　　Amino acids Takao Wada: Version 3, Program Training, Basic Information about Infusion, Iyaku Shuppan 1997:p.124-125 **: 30% increase in consideration of individual difference The individual safety rate is estimated to be 30% for the variation coefficient of 15% for inter-individual dispersion in nitrogen metabolism. Meiji Watanabe: Hepatic Disease and Therapeutic Nutrition, Daiichi Shuppan, 1992:p95-98

Ruptured suture/gastrointestinal fistula 170 to 2301)

Neonate/babies 230 to 2502)

After thoracic surgery 150 to 2003)

Cardiac cachexia 120 to 1904)

Heat burn 100 to 1205)

Multiple organ failure 150 to 2006)

Concomitant renal failure 200 to 3006)

Renal failure CRF Around 3007)

ARF 500 or over8)

General non-invasive disease 150 to2009)

Mildly invasive disease 150 to 2009)

Moderately invasive disease 100 to 1509)

Mildly invasive disease 80 to 1009)

Disease-specific NPC/N ratio

1）加固紀夫,他:日本臨牀静脈・経腸栄養 2001;59(Suppl.5):558-5622) 山内健,矢加部茂:実践静脈栄養と経腸栄養,エルゼビア・ジャパン;2005:p1233）幕内晴朗:日本臨牀静脈・経腸栄養 2001;59(Suppl.5):442-4454）福井康三,他:日本臨牀静脈・経腸栄養 2001;59(Suppl.5):438-4415）池田弘人,小林国男:日本臨牀静脈・経腸栄養 2001;59(Suppl.5):706-7096）貞広智仁,他:日本臨牀静脈・経腸栄養 2001;59(Suppl.5):693-6967）本渡幾久子,他:日本臨牀静脈・経腸栄養 2001;59(Suppl.5):663-6668）大貫隆子,他:日本臨牀静脈・経腸栄養 2001;59(Suppl.5):659-6629）標葉隆三郎:日本臨牀静脈・経腸栄養 2001;59(Suppl.5):136-140

Presenter

Presentation Notes

This slide presents the disease-specific NPC/N ratio. The desirable NPC/N ratio after the general surgery is 150 to 200, but in the patients with chronic renal failure, it should be about 300 to maintain good N balance and protein synthesis. In the patients with hypercatabolism associated with acute renal failure, the desirable NPC/N ratio is considered to be 500 or over.

Appropriate nitrogen source

Adequate calorie

Glucose, lipid

Prevention of body protein destruction due to hypercatabolismPrevention the accumulation of nitrogenous metabolites

Prevent the accumulation of nitrogenous metabolites and maintain nitrogen balance!

Problems in the administration of amino acids in the patients with renal failure

寺岡慧,太田和夫：救急医学 1993；17：1557-1562

Presenter

Presentation Notes

It is necessary to administer amino acids to prevent the accumulation of nitrogenous metabolites and body protein destruction due to hypercatabolism and maintain the nitrogen balance to the patients with renal failure. To realize such contradicting requirements, it is necessary to administer a proper amount of nitrogen source and adequate non-protein calorie in a good balance. KIDMIN is the infusion solution containing amino acids for renal failure as the appropriate nitrogen source.

Essential and Non-essential Amino Acids

EssentialAmino acids

Non-essentialAmino acids

+ Energy

Expired Air

BreakBody proteins Energy + Urea + H2O + CO2

Down

15 – 20 g protein/day in diet

Nitrogen equilibrium or positivenitrogen balance is achieved andUrea levels are allowed

Urine

Synthesis

Synthesis

Composition of EAA sol Administration of a small amount of essential amino acids in high-calorie low-protein diet prevents catabolism and the amino acids as well as produced non-essential amino acids are used for protein synthesis.

Azotemia and uremic symptoms are alleviated by the reuse of endogenous urea.

Ammonium produced from the urea in the intestinal tract is reabsorbed and used for the synthesis of non-essential amino acids in the liver.

At present, urea is reused by not more than a few percent and it is considered impossible to maintain the nitrogen balance at this dose.

Essential amino acid therapy (Endogenous urea reuse hypothesis)

菅英育,他：消化器外科 1992；15：637‐645

Naw/v%

g/dL

mEq/L+

Composition EAA SOl

1125720820820

11251125515255

---------13

7.060.911.637.7

560

w/w%

Am

ino

acid

s

L-LeucineL-IsoleucineL-ValineL-LysineL-MethionineL-PhenylalanineL-ThreonineL-Tryptophan L-HistidineL-ArginineL-Asparaginic acidL-Glutamic acidL-AlanineL-CysteineAmino acetateL-ProlineL-SerineL-Tyrosine

Concentration of total free amino acids N level E/N ratio BCAA content

Presenter

Presentation Notes

AMIYU was the first infusion solution for renal failure. The infusion solution was based on the idea of essential amino acid therapy. AMIYU contains 8 essential amino acids and histidine. Patients with renal failure, who have special amino acid metabolism, have decreased essential amino acids and BCAA in association with hypercatabolism and declined protein synthesis. Patients with renal failure develop abnormality of metabolism of amino acids and an increase in BUN along with the progression of the disease. Giordano reported in 1963 that the administration of a small amount of essential amino acids and adequate energy alleviated uremia. Giovanetti reported that the administration of high-calorie low-protein diet and a small amount of essential amino acids inhibited catabolism and alleviated azotemia and uremia. The mechanism of the so-called essential amino acid therapy is explained by the reabsorption of ammonium produced from the intestinal decomposition of urea and re-synthesis to non-essential amino acids and use of the amino acids in combination with EAA for protein synthesis. Based on the hypothesis, AMIYU, the infusion solution containing Rose’s essential amino acid formula and histidine considered essential for renal failure, was developed and used for the treatment of the patients with chronic renal failure treated by preservative dialysis, as the amino acid therapy for patients undergoing dialysis or TPN for the patients with renal failure. However, cases of consciousness disorder, fatty liver, and metabolic acidosis associated with hyperammonemia were reported from patients undergoing TPN using AMIYU.

Reason to add NEAA to EAA

EAA pada dosis diatas 0.5 g/kg/hari memiliki risiko lebih tinggi untuk terjadinya hiperamonemia dan ensefalopati metabolik, karena arginin, ornitin, dan sitrulin tidak dipasok. Ketiga asam amino non-esensial ini dibutuhkan untuk detoksifikasi amonia dalam sikuls Urea . Akibatnya larutan yang mengandung campuran asam amino esensial dan non-esensial dianjurkan

Kalista-Richards Nutrition in Clinical Practice Volume 26 Number 2April 2011 143-150

AmmoniumATP

Bicarbonate

ADP

Ornithine carbamyl transferase

Urea Arginase

Argininosuccinase

Carbamyl phosphate

Carbamyl phosphate synthetase

CitrullineOrnithine

Ornithine Citrulline

Arginine Argininosuccinic acidOrotic acid

Carbamyl phosphate

Carbamyl Asparaginic acid

Fatty liver

Dysfunction of urea circuit

Accumulation of carbamyl

phosphate

Accumulation of ammonium

Neutral fat, VLDLDisturbance of transportation

Increase of orotic acid

Consciousness disorder

Coma

Mitochondria

Cytoplasma

Argininosuccinic acidSynthetic enzyme

Decrease in arginine concentration

Mechanism of action of hyperammonemia and fatty liver

菅英育,他：消化器外科 1992；15：637‐645

Presenter

Presentation Notes

This slide explains the mechanism of action of hyperammonemia. Ammonium is metabolized to non-toxic urea by the uric cycle (circuit) but the administration of AMIYU not containing arginine causes relative arginine deficiency. This is considered to cause the dysfunction of the uric cycle inside the cytoplasm and accumulation of ammonium. However, the experiment using rats revealed the absence of decrease in the arginine concentration in the hepatic tissues than in healthy rats and the marked increase in the hepatocellular lysine concentration which acts antagonistically against arginase, the enzyme acting to convert arginine to ornithine. This suggested the involvement of the increase in the lysine concentration in hepatic tissues and the decrease in the arginine/lysine ratio in the dysfunction of the uric cycle. Since bicarbonate ion was considered essential for the metabolic cycle in the uric cycle, metabolic acidosis was considered to contribute to the dysfunction. As the mechanism of fatty liver, it was revealed that the increase in the orotic acid concentration would disturb the conversion of TG to VLDL in hepatic tissues and transportation of TG out of the cells. This result in the accumulation of hepatocellular TG and decrease in serum TG/VLDL. Rose’s formula was proposed as the daily minimum amount of essential amino acids required in healthy young males and it was not reasonable to apply the formula to the patients with renal failure having various abnormality of metabolism of amino acids. The clinical significance of “endogenous urea reuse hypothesis” is skeptical today and it is not reasonable to use the decrease in urea as one of the parameters for assessing the efficacy of EAA therapy. The decease in BUN associated with EAA substantiates the disturbance of conversion from ammonium to urea as a result of the dysfunction of the uric cycle and does not necessarily mean body protein synthesis of urea.

Benefits

Removal of uremic toxinβ2-microglobulin, intermediate-molecular substances, etc.

Removal of nitrogenous metabolites Urea, uric acid, creatinine, etc.Increase of protein intake

Demerits o HDLoss of amino acidsLoss of water-soluble vitamins and substances necessary for protein/amino acid metabolismSecretion of invasive hormones under stress Cortisol, catecholamine, glucagon, etc.Decrease in blood circulation in tissues Extracorporeal circulation, blood pressure decreaseDisturbance of cellular metabolism Rapid change of intracellular water content and osmotic pressureHypercatabolism caused by hemodialysis itself

Effects on protein/amino acid metabolism during hemodialysis

申性孝ほか：日本臨牀,50（増刊号）,536,1992

◎

◎

◎

◎

◎

◎

◎

◎

◎

0.3

0.2

0.1

0

EAA/TAA0.15

0.10

0.05

0

BCAA/TAA1.5

1.0

0.5

0

Val/Gly1.0

0.5

0

Ser/Gly1.5

1.0

0.5

0

Tyr/Phe*

* *

**

*:p<0.05(Mean±S.D.)Healthy people (n=20)

Patients under dialysis (n=15)

Abnormality of plasma amino acid metabolism in the patients under long dialysis

鈴木正司：胃と透析，33（臨時増刊号），566，1992

A.S.P.E.N. Clinical Guidelines: Nutrition Support in Adult Acute and Chronic Renal Failure

• Intradialytic parenteral nutrition should not be used as a nutritional supplement in malnourished chronic kidney disease-V hemodialysis patients.(Grade: C)

• The recommended protein intake for patients who receive maintenance HD is 1.2 g/kg/d and for those who receive CAPD... 1.3 g/kg/d

• Stage III or IV CKD have partial renal function and may require restrictions in protein intake to as low as 0.3–0.6 g/kg/d to delay the progression of renal disease

Brown RO, Compher C. JPEN Vol 34,No.4, July 2010

AA Loss during Dialysis

Membrane AA Loss

Low-flux cuprophane 7,2 + 2,6 g(Terumo T150)Low-flux polymethyl- 6,1 + 1,5 gmethacrylate (Toray B2)High-flux polysulfone 8,0 + 2,8 g(Fresenius F80)

Rully Rusli. 2nd xpert Meeting on Clinical Nutrition

Author Membrane Length of HD

session(hr)

Amino acid loss

Navarro polyacrylonitrile 3 6 g (membrane

0.9 m2)

Tepper T, Ikizler,

GomeZ P

Cellulose 4 4 -13 g

Izikler polyacrylonitrile 4 12 g

(membrane 1.7

m2)

Ikizler polysulfone 4 8 + 2.8 g

Ikizler polymethylmethacrylate 4 6.1 + 1.5 g

AA Loss during Dialysis

Navarro ,et al. Am J Clin Nutr2000;71:765–73

AMINO ACID REMOVAL DURING HEMODIALYSIS OF PATI-ENTS WHO HAD UNDERGONE INTRADIALYTIC

PARENTERAL NUTRITION

• 200 ml of 7.2% amino acid solution(KidminTM),• 200 ml of 50 % glucose, and 20% of lipid

emulsion as IDPN fluid

Norio Hanafusa, et al. Kidney Res Clin Pract 31(2012)A16–A96

Amino acid removal 9.1 + 1.4 g

Decreased BCAA in patients undergoing HD > 2 years

Fisher ratio in HD Patients in relation to duration of HD treatment and Nutritional Status

HD Patients

< 2 years

>2 years

Well-nourished

Malnourished

Control Subjects

BCAA 258.7 296.8 237.2 268.3 242.3 323

AAA 95.6 101.4 92.2 94.9 96.7 105.4

Fisher ratio

2.7 2.9 2.5 2.8 2.5 3.0

Margozewicz S. Journal of Renal Nutrition,Vol 18 No.2 (March) 2008 : pp239-247

BCAA in CRF

• s

Cano et al. J. Nutr.136:299S-307S.2006

Take Home Message

• Balanced Amino Acids. EAA/NEAA ratio 2.6 is required to prevent hyperammonemia

• Replaces amino acid loss during dialysis• High BCAA to improve the amino acid profile• IDPN containing protein,CHO dan Lipid should not

routinely used...but the administration of Balanced AA alone is justified

Thanks

the rationale of intradialytic amino acid supplementation

Healthcare

g of amino acids

amino acidshuman

g of mixed amino acids

g of protein

nitrogen coefficient

adequate dose of amino

amino acid dose

nitrogen metabolism