Intensive Care Medicine

, Volume 41, Issue 7, pp 1197–1208 | Cite as

Intravenous amino acid therapy for kidney function in critically ill patients: a randomized controlled trial

  • Gordon S. DoigEmail author
  • Fiona Simpson
  • Rinaldo Bellomo
  • Philippa T. Heighes
  • Elizabeth A. Sweetman
  • Douglas Chesher
  • Carol Pollock
  • Andrew Davies
  • John Botha
  • Peter Harrigan
  • Michael C. Reade
Seven-Day Profile Publication



Acute kidney injury (AKI) is characterized by severe loss of glomerular filtration rate (GFR) and is associated with a prolonged intensive care unit (ICU) stay and increased risk of death. No interventions have yet been shown to prevent AKI or preserve GFR in critically ill patients. Evidence from mammalian physiology and small clinical trials suggests higher amino acid intake may protect the kidney from ischemic insults and thus may preserve GFR during critical illness.


To determine whether amino acid therapy, achieved through daily intravenous (IV) supplementation with standard amino acids, preserves kidney function in critically ill patients.

Design, setting, and participants

Multicenter, phase II, randomized clinical trial conducted between December 2010 and February 2013 in the ICUs of 16 community and tertiary hospitals in Australia and New Zealand. Participants were adult critically ill patients expected to remain in the study ICU for longer than 2 days.


Random allocation to receive a daily supplement of up to 100 g of IV amino acids or standard care.

Main outcomes and measures

Duration of renal dysfunction (primary outcome); estimated GFR (eGFR) derived from creatinine; eGFR derived from cystatin C; urinary output; renal replacement therapy (RRT) use; fluid balance and other measures of renal function.


474 patients were enrolled and randomized (235 to standard care, 239 to IV amino acid therapy). At time of enrollment, patients allocated to receive amino acid therapy had higher APACHE II scores (20.2 ± 6.8 vs. 21.7 ± 7.6, P = 0.02) and more patients had pre-existing renal dysfunction (29/235 vs. 44/239, P = 0.07). Duration of renal dysfunction after enrollment did not differ between groups (mean difference 0.21 AKI days per 10 patient ICU days, 95 % CI −0.27 to 1.04, P = 0.45). Amino acid therapy significantly improved eGFR (treatment group × time interaction, P = 0.004), with an early peak difference of 7.7 mL/min/1.73 m2 (95 % CI 1.0–14.5 mL/min/1.73 m2, P = 0.02) on study day 4. Daily urine output was also significantly increased (+300 mL/day, 95 % CI 145–455 mL, P = 0.0002). There was a trend towards increased RRT use in patients receiving amino acid therapy (13/235 vs. 25/239, P = 0.062); however, this trend was not present after controlling for baseline imbalance (P = 0.21).

Conclusion and relevance

Treatment with a daily IV supplement of standard amino acids did not alter our primary outcome, duration of renal dysfunction.

Trial registration Identifier: ACTRN12609001015235.


Clinical trial Protein Acute kidney injury Amino acids Nutrition 



Dr. Doig reported receiving academic research grants from Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd and speakers’ honoraria from Fresenius Kabi Deutschland GmbH, Baxter Healthcare Australia, Pty Ltd and Nestle Healthcare, Vevy, Switzerland. Ms. Simpson reported receiving academic research grants from Fresenius Kabi Deutschland GmbH and Baxter Healthcare Australia Pty Ltd and speakers’ honoraria from Fresenius Kabi Pty Ltd and Baxter Healthcare Australia Pty Ltd. Dr. Harrigan has no potential conflicts to declare. No other authors reported disclosures.


This work was supported by a peer-reviewed academic grant from the Australian National Health and Medical Research Council (NH&MRC). Baxter Healthcare Pty Ltd supplied the study amino acids.

Role of the sponsors

As a peer review funding body, the NH&MRC provided constructive comments on the study design. Baxter Healthcare Pty Ltd played no role in the design or conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. Although participating sites were compensated for the costs of conducting the trial, site investigators did not receive financial compensation for their contributions.

Supplementary material

134_2015_3827_MOESM1_ESM.pdf (1.4 mb)
Supplementary material 1 (PDF 1427 kb)
134_2015_3827_MOESM2_ESM.pdf (668 kb)
Supplementary material 2 (PDF 667 kb)


  1. 1.
    Bagshaw SM, George C, Dinu I, Bellomo R (2008) A multi-centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients. Nephrol Dial Transpl 23:1203–1210CrossRefGoogle Scholar
  2. 2.
    Bagshaw SM, George C, Bellomo R (2008) Early acute kidney injury and sepsis: a multicentre evaluation. Crit Care 12:R47PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Rewa O, Bagshaw SM (2014) Acute kidney injury-epidemiology, outcomes and economics. Nat Rev Nephrol 10:193–207PubMedCrossRefGoogle Scholar
  4. 4.
    Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S et al (2005) Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 294:813–818PubMedCrossRefGoogle Scholar
  5. 5.
    Prowle JR, Ishikawa K, May CN, Bellomo R (2010) Renal plasma flow and glomerular filtration rate during acute kidney injury in man. Ren Fail 32:349–355PubMedCrossRefGoogle Scholar
  6. 6.
    Bove T, Zangrillo A, Guarracino F (2014) Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial. JAMA 312:2244–2253PubMedCrossRefGoogle Scholar
  7. 7.
    Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J (2000) Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 356:2139–2143PubMedCrossRefGoogle Scholar
  8. 8.
    Woods LL (1993) Mechanisms of renal hemodynamic regulation in response to protein feeding. Kidney Int 44:659–675PubMedCrossRefGoogle Scholar
  9. 9.
    Sharma A, Mucino MJ, Ronco C (2014) Renal Functional reserve and renal recovery after acute kidney injury. Nephron Clin Pract 127:94–100PubMedCrossRefGoogle Scholar
  10. 10.
    Meyer TW, Ichikawa I, Zatz R, Brenner BM (1983) The renal hemodynamic response to amino acid infusion in the rat. Trans Assoc Am Physicians 96:76–83PubMedGoogle Scholar
  11. 11.
    Roberts PR, Black KW, Zaloga GP (1997) Enteral feeding improves outcome and protects against glycerol-induced acute renal failure in the rat. Am J Respir Crit Care Med 156:1265–1269PubMedCrossRefGoogle Scholar
  12. 12.
    Abel RM, Beck CH Jr, Abbott WM, Ryan JA Jr, Barnett GO, Fischer JE (1973) Improved survival from acute renal failure after treatment with intravenous essential L-amino acids and glucose. Results of a prospective, double-blind study. N Engl J Med 288:695–699PubMedCrossRefGoogle Scholar
  13. 13.
    Singer P (2007) High-dose amino acid infusion preserves diuresis and improves nitrogen balance in non-oliguric acute renal failure. Wien Klin Wochenschr 119:218–222PubMedCrossRefGoogle Scholar
  14. 14.
    Doig GS, Simpson F, Finfer S, Delaney A, Davies AR, Mitchell I et al (2008) Effect of evidence-based feeding guidelines on mortality of critically ill adults: a cluster randomized controlled trial. JAMA 300:2731–2741PubMedCrossRefGoogle Scholar
  15. 15.
    Doig GS, Simpson F, Bellomo R, The ANZICSCTG (2009) Improved nutritional support is associated with reduced renal dysfunction in critical illness: a post hoc exploratory subgroup analysis. Am J Respir Crit Care Med 179:A1567Google Scholar
  16. 16.
    Schulz KF, Grimes DA (2002) Allocation concealment in randomised trials: defending against deciphering. Lancet 359:614–618PubMedCrossRefGoogle Scholar
  17. 17.
    Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829PubMedCrossRefGoogle Scholar
  18. 18.
    Simpson F, Sweetman EA, Doig GS (2010) A systematic review of techniques and interventions for improving adherence to inclusion and exclusion criteria during enrolment into randomised controlled trials. Trials 11:17PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Bernard GR, Doig GS, Hudson LD, Lemeshow S, Marshall JC, Russel J et al (1995) Quantification of organ failure for clinical trials and clinical practice. Am J Respir Crit Care Med 151:A323Google Scholar
  20. 20.
    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III, Feldman HI et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150:604–612PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Stevens LA, Coresh J, Schmid CH, Feldman HI, Froissart M, Kusek J et al (2008) Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3418 individuals with CKD. Am J Kidney Dis 51:395–406PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Zubrod C, Schneiderman MA, Frei E, Brindley C, Gold GL, Shnider B et al (1960) Appraisal of methods for the study of chemotherapy of cancer in man: comparative therapeutic trial of nitrogen mustard and triethylene thiophosphoramide. J Chronic Dis 11:7–33CrossRefGoogle Scholar
  23. 23.
    Ware JE Jr, Sherbourne CD (1992) The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 30:473–483PubMedCrossRefGoogle Scholar
  24. 24.
    Haybittle JL (1971) Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol 44:793–797PubMedCrossRefGoogle Scholar
  25. 25.
    Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV et al (1976) Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer 34:585–612PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Doig GS, Simpson F, Sweetman EA, Heighes PT, on behalf of the Nephro-Protective Trial Management Committee (2013) Statistical analysis plan for a multi-centre randomised controlled trial: nephro-protective effects of L-amino acids in critically ill patients., SydneyGoogle Scholar
  27. 27.
    Delanaye P, Cavalier E, Morel J, Mehdi M, Maillard N, Claisse G et al (2014) Detection of decreased glomerular filtration rate in intensive care units: serum cystatin C versus serum creatinine. BMC Nephrol 15:9PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Carlier M, Dumoulin AF, Janssen AF, Picavet S, Vanthuyne S, Vanthuyne S, Van Eynde R, Van Eynde RF et al (2015) Comparison of different equations to assess glomerular filtration in critically ill patients. Intensive Care Med 41:427–435PubMedCrossRefGoogle Scholar
  29. 29.
    Woods LL, Smith BE, De Young DR (1993) Regulation of renal hemodynamics after protein feeding: effects of proximal and distal diuretics. Am J Physiol 264:R337–R344PubMedGoogle Scholar
  30. 30.
    Juraschek SP, Appel LJ, Anderson CA, Miller ER III (2013) Effect of a high-protein diet on kidney function in healthy adults: results from the OmniHeart trial. Am J Kidney Dis 61:547–554PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R (2004) A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 350:2247–2256PubMedCrossRefGoogle Scholar
  32. 32.
    Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B et al (2006) Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 354:2564–2575PubMedCrossRefGoogle Scholar
  33. 33.
    Dickerson RN, Medling TL, Smith AC, Maish GO III, Croce MA, Minard G et al (2013) Hypocaloric, high-protein nutrition therapy in older vs. younger critically ill patients with obesity. J Parenter Enteral Nutr 37:342–351CrossRefGoogle Scholar
  34. 34.
    Bagshaw SM, Uchino S, Kellum JA, Morimatsu H, Morgera S, Schetz M et al (2013) Association between renal replacement therapy in critically ill patients with severe acute kidney injury and mortality. J Crit Care 28:1011–1018PubMedCrossRefGoogle Scholar
  35. 35.
    Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P (2004) Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204–R212PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S et al (2009) Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med 361:1627–1638PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2015

Authors and Affiliations

  • Gordon S. Doig
    • 1
    • 8
    Email author
  • Fiona Simpson
    • 1
  • Rinaldo Bellomo
    • 2
  • Philippa T. Heighes
    • 1
  • Elizabeth A. Sweetman
    • 1
  • Douglas Chesher
    • 3
    • 7
  • Carol Pollock
    • 3
  • Andrew Davies
    • 2
  • John Botha
    • 4
  • Peter Harrigan
    • 5
  • Michael C. Reade
    • 6
  1. 1.The Northern Clinical School Intensive Care Research UnitUniversity of SydneySydneyAustralia
  2. 2.School of Public Health and Preventive MedicineMonash UniversityMelbourneAustralia
  3. 3.The Northern Clinical SchoolUniversity of SydneySydneyAustralia
  4. 4.Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneAustralia
  5. 5.John Hunter HospitalNewcastleAustralia
  6. 6.Burns, Trauma and Critical Care Research CentreUniversity of QueenslandBrisbaneAustralia
  7. 7.New South Wales Health, PathologyNewcastleAustralia
  8. 8.Intensive Care UnitRoyal North Shore HospitalSt LeonardsAustralia

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