Post-prandial tracer studies of protein and amino acid utilisation: what can they tell us about human amino acid and protein requirements?
The British journal of nutrition
Nitrogen balance (NB), the principal methodology used to derive recommendations for human protein and amino acid requirements, has been widely criticised, and calls for increased protein and amino acid requirement recommendations have been made, often on the basis of post-prandial amino acid tracer kinetic studies of muscle protein synthesis, or of amino acid oxidation. This narrative review considers our knowledge of the homeostatic regulation of the FFM throughout the diurnal cycle of feeding and fasting and what can and has been learnt from post-prandial amino acid tracer studies, about amino acid and protein requirements. Within the FFM, muscle mass in well fed weight-stable adults with healthy lifestyles appears fixed at a phenotypic level within a wide range of habitual protein intakes. However homoeostatic regulation occurs in response to variation in habitual protein intake, with adaptive changes in amino acid oxidation which influence the magnitude of diurnal losses and gains of body protein. Post-prandial indicator amino acid oxidation (IAAO) studies have been introduced as an alternative to NB and to the logistically complex 24 h [C-1] amino acid balance studies, for assessment of protein and amino acid requirements. However, a detailed examination of IAAO studies shows both a lack of concern for homeostatic regulation of amino acid oxidation and major flaws in their design and analytical interpretation, which seriously constrain their ability to provide reliable values. New ideas and a much more critical approach to existing work is needed if real progress is to be made in the area.
10.1017/S0007114524000734
Nutritional support for acute kidney injury.
Li Yi,Tang Xi,Zhang Juqian,Wu Taixiang
The Cochrane database of systematic reviews
BACKGROUND:Treatment for acute kidney Injury (AKI) primarily relies on treating the underlying cause and maintaining the patient until kidney function has recovered. Enteral and parenteral nutrition are commonly used to treat nutritional disorders in AKI patients, however their efficacy in treating AKI are still debated. This review was first published in 2010. OBJECTIVES:To evaluate the effectiveness and safety of nutritional support for patients with AKI. SEARCH METHODS:We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Chinese Biomedical Disc, VIP and China National Knowledge Infrastructure (CNKI).Date of last search: 4 July 2012 SELECTION CRITERIA:All randomised controlled trials (RCTs) reported for AKI and nutrition were included. DATA COLLECTION AND ANALYSIS:Authors independently assessed study quality and extracted data. Results were expressed as risk ratio (RR) with 95% confidence intervals (CI) or mean difference (MD). MAIN RESULTS:Eight studies (257 participants) were included. An overall pooled analysis was not performed due to the different interventions used and different outcomes measured. Selection bias was not reported (unclear) in six studies and was adequately reported (low) for random sequence generation in two studies. Participant/personnel blinding was adequately reported in one study and unclear in seven. Incomplete outcome reporting bias was low in six studies and high in two. Selective reporting was low in six studies, unclear in one study, and high in one study. No other biases were detected. There was a significant increase in recovery rate for AKI (RR 1.70, 95% CI 1.70 to 2.79) and survival in dialysed patients (RR 3.56, 95% CI 0.97 to 13.08) for intravenous essential L-amino acids (EAA) compared to hypertonic glucose alone. Compared to lower calorie-total parenteral nutrition (TPN), higher calorie-TPN did not improve estimated nitrogen balance, protein catabolic rate, or urea generation rate; but increased serum triglycerides, glucose, insulin need and nutritional fluid administration. There was no difference between groups in estimated nitrogen balance, but there were differences between urea nitrogen appearance (MD 0.98, 95% CI 0.25 to 1.71) and net protein utilisation (MD 21.50%, 95% CI 0.39 to 42.61). Urea nitrogen appearance was lower in the low nitrogen intake group than in the high nitrogen intake group. There was no significant difference in death between EAA and general amino acids (GAA) (RR 1.52, 95% CI 0.63 to 3.68). High dose amino acids did not improve cumulative water excretion, furosemide requirement, nitrogen balance or death compared to normal dose amino acids. Glucose+EAA+histidin had better nitrogen balance than glucose+GAA; glucose+nitrogen+fat significantly increased serum creatinine compared with glucose+GAA; glucose+EAA+histidin significantly improved nitrogen balance, U/P urea and serum creatinine, but increased plasma urea compared to glucose+nitrogen+fat. AUTHORS' CONCLUSIONS:There was insufficient evidence found to support the effectiveness of nutritional support for AKI. Further high quality studies are required to provide reliable evidence of the effect and safety of nutritional support.
10.1002/14651858.CD005426.pub3
Renal hemodynamic response to intravenous and oral amino acids in animals.
Lang F,Ottl I,Häussinger D,Deetjen P,Ahloulay M,Bankir L
Seminars in nephrology
Oral or parenteral application of amino acids leads to marked hyperfiltration and increased of renal plasma flow. Amino acids stimulate the release of glucagon, which increases hepatic production and release of cyclic adenosine monophosphate (cAMP). In the kidney, the combined effect of cAMP and glucagon increases glomerular filtration rate (GFR), possibly by reducing NaCl concentration at the macula densa and depression of the tubuloglomerular feedback. Vasopressin-dependent urea recycling and delivery to the thick ascending limb could similarly reduce NaCl concentration at the macula densa. Beyond that, amino acids may trigger a hepatorenal reflex or directly interfere with renal function. Mechanisms invoked include dopamine from renal nerves, prostaglandins, nitric oxide (NO), and angiotensin II. At this point, it is not clear to which extent the described mechanisms participate in, permit, or fully account for the hyperfiltrative effect of amino acids.
A Randomized Trial of Intravenous Amino Acids for Kidney Protection.
The New England journal of medicine
BACKGROUND:Acute kidney injury (AKI) is a serious and common complication of cardiac surgery, for which reduced kidney perfusion is a key contributing factor. Intravenous amino acids increase kidney perfusion and recruit renal functional reserve. However, the efficacy of amino acids in reducing the occurrence of AKI after cardiac surgery is uncertain. METHODS:In a multinational, double-blind trial, we randomly assigned adult patients who were scheduled to undergo cardiac surgery with cardiopulmonary bypass to receive an intravenous infusion of either a balanced mixture of amino acids, at a dose of 2 g per kilogram of ideal body weight per day, or placebo (Ringer's solution) for up to 3 days. The primary outcome was the occurrence of AKI, defined according to the Kidney Disease: Improving Global Outcomes creatinine criteria. Secondary outcomes included the severity of AKI, the use and duration of kidney-replacement therapy, and all-cause 30-day mortality. RESULTS:We recruited 3511 patients at 22 centers in three countries and assigned 1759 patients to the amino acid group and 1752 to the placebo group. AKI occurred in 474 patients (26.9%) in the amino acid group and in 555 (31.7%) in the placebo group (relative risk, 0.85; 95% confidence interval [CI], 0.77 to 0.94; P = 0.002). Stage 3 AKI occurred in 29 patients (1.6%) and 52 patients (3.0%), respectively (relative risk, 0.56; 95% CI, 0.35 to 0.87). Kidney-replacement therapy was used in 24 patients (1.4%) in the amino acid group and in 33 patients (1.9%) in the placebo group. There were no substantial differences between the two groups in other secondary outcomes or in adverse events. CONCLUSIONS:Among adult patients undergoing cardiac surgery, infusion of amino acids reduced the occurrence of AKI. (Funded by the Italian Ministry of Health; PROTECTION ClinicalTrials.gov number, NCT03709264.).
10.1056/NEJMoa2403769
Intravenous amino acid therapy for kidney protection in cardiac surgery patients: A pilot randomized controlled trial.
Pu Hong,Doig Gordon S,Heighes Philippa T,Allingstrup Matilde J,Wang Andy,Brereton John,Pollock Carol,Chesher Douglas,Bellomo Rinaldo
The Journal of thoracic and cardiovascular surgery
OBJECTIVE:To determine whether a continuous intravenous infusion of standard amino acids could preserve kidney function after on-pump cardiac surgery. METHODS:Adult patients scheduled to receive cardiac surgery lasting longer than 1 hour on-pump were randomized to standard care (n = 36) or an infusion of amino acids initiated immediately after induction of anesthesia (n = 33). The study's primary outcome measurements assessed renal function. These assessments included duration of renal dysfunction, duration and severity of acute kidney injury (AKI), estimated glomerular filtration rate (eGFR) over time, urine output, and use of renal-replacement therapy. Complications and other measures of morbidity were also assessed. RESULTS:Sixty-nine patients (mean age 71.5 [standard deviation 9.2] years; 19 of 69 women) were enrolled and randomized. Patients received coronary artery bypass graft surgery (37/69), valve surgery (24/69), coronary artery bypass graft and valve surgery (6/69), or other procedures (2/69). Mean on-pump time was 268 [standard deviation 136] minutes. Duration of renal dysfunction did not differ between the groups (relative risk, 0.86; 95% confidence interval [CI], 0.19-3.79, P = .84). However, patients who received the amino acid infusion had a reduced duration of AKI (relative risk, 0.02; 95% CI, 0.005-0.11, P < .0001) and greater eGFR (+10.8%; 95% CI, 1.0%-20.8%, P = .033). Daily mean urine output was also significantly greater in patients who received the amino acid infusion (1.4 ± 0.5 vs 1.7 ± 0.9 L/d; P = .046). CONCLUSIONS:Commencing an infusion of standard amino acids immediately after the induction of anesthesia did not alter duration of renal dysfunction; however, other key measures of renal function (duration of AKI, eGFR and urine output) were significantly improved. These results warrant replication in multicenter clinical trials.
10.1016/j.jtcvs.2018.11.097
Association of Glutamate Infusion With Risk of Acute Kidney Injury After Coronary Artery Bypass Surgery: A Pooled Analysis of 2 Randomized Clinical Trials.
JAMA network open
Importance:Acute kidney injury (AKI) after cardiac surgery is associated with increased morbidity and mortality, and measures to prevent AKI have had limited success. Glutamate has been reported to enhance natural postischemic recovery of the heart, but not among animals and humans with diabetes. Objective:To summarize pooled results from the GLUTAMICS (Glutamate for Metabolic Intervention in Coronary Surgery) trials regarding the effect of glutamate on postoperative AKI among patients without diabetes undergoing coronary artery bypass graft (CABG) surgery. Design, Setting, and Participants:Data on a total of 791 patients without diabetes from 2 prospective, randomized, double-blind multicenter trials performed at 5 cardiac surgery centers in Sweden between October 4, 2005, and November 12, 2009, and between November 15, 2015, and September 30, 2020, were pooled. Patients had acute coronary syndrome, left ventricular ejection fraction of 0.30 or less, or a European System for Cardiac Risk Evaluation II score of 3.0 or more and underwent CABG with or without additional valve procedure. Statistical analysis was performed from May to November 2023. Interventions:Intravenous infusion of 0.125-M l-glutamic acid or saline at 1.65 mL/kg/h for 2 hours during reperfusion, after which the infusion rate was halved and an additional 50 mL was given. Main Outcomes and Measures:The primary end point was AKI, defined as postoperative increase of plasma creatinine of 50% or more, corresponding to the Risk stage or higher in the Risk, Injury, Failure, Loss, and End-Stage kidney disease (RIFLE) criteria. Results:A total of 791 patients without diabetes (391 who received glutamate [mean (SD) age, 69.3 (9.1) years; 62 women (15.9%)] and 400 controls [mean (SD) age, 69.6 (9.5) years; 73 women (18.3%)]) were randomized. Baseline data did not differ between groups. Glutamate was associated with a significantly lower risk of AKI (relative risk, 0.49 [95% CI, 0.29-0.83]). Dialysis was required for 2 patients in the glutamate group and 5 patients in the control group. In multivariable analysis, glutamate remained significantly associated with a protective effect against AKI (odds ratio, 0.47 [95% CI, 0.26-0.86]). In the glutamate and control groups, the rate of postoperative mortality at 30 days or less was 0.5% (2 of 391) vs 1.0% (4 of 400), and the rate of stroke at 24 hours or less was 0.8% (3 of 391) vs 1.8% (7 of 400). Conclusions and Relevance:In this pooled analysis of 2 randomized clinical trials, infusion of glutamate was associated with a markedly lower risk of AKI after CABG among patients without diabetes. The findings are exploratory and need to be confirmed in prospective trials. Trial Registration:ClinicalTrials.gov Identifiers: NCT00489827 and NCT02592824.
10.1001/jamanetworkopen.2023.51743
Renal effects of amino acids and dopamine in renal transplant recipients treated with or without cyclosporin A.
Hansen J M,Olsen N V,Leyssac P P
Clinical science (London, England : 1979)
1. The nephrotoxic effects of cyclosporin A may diminish the ability of the transplanted kidney to increase the glomerular filtration rate and effective renal plasma flow during infusion of dopamine or amino acids. 2. The present study included 16 renal transplant recipients transplanted for more than 6 months. Eight of the patients were on immunosuppressive treatment including cyclosporin A [cyclosporin A group; cyclosporin A dose, 2.7 +/- 0.4 mg/kg; S-creatinine, 105 +/- 12 mumol/l (means +/- SEM)], whereas eight patients had never received cyclosporin A (non-cyclosporin A group; S-creatinine, 89 +/- 6 mumol/l). The renal response to infusion of dopamine and of amino acids was investigated on two separate days. All clearance measurements were carried out at nadir cyclosporin A blood levels. 3. Effective renal plasma flow increased significantly in the non-cyclosporin A group and cyclosporin A group by 31.0 +/- 4.1% and 35.9 +/- 6.6%, respectively, during infusion of dopamine, and by 18.7 +/- 6.7% and 13.9 +/- 5.3%, respectively, during infusion of amino acids. Glomerular filtration rate increased significantly in the non-cyclosporin A group and cyclosporin A group by 15.7 +/- 3.3% and 18.3 +/- 4.7%, respectively, during infusion of dopamine, and by 18.9 +/- 4.5% and 15.0 +/- 3.7%, respectively, during infusion of amino acids. 4. Furthermore, the amino acid- and dopamine-induced increases in proximal tubular outflow (renal clearance of lithium) and calculated changes in renal proximal and distal tubular handling of sodium (and water) were comparable between the two groups of patients. Dopamine caused significant natriuresis in both groups. 5. In conclusion, low-dose cyclosporin A seems not to attenuate the renal haemodynamic and tubular response to infusions of amino acids and of dopamine in renal transplant recipients with a good graft function.
86Y-DOTA0)-D-Phe1-Tyr3-octreotide (SMT487)--a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion.
Jamar François,Barone Raffaella,Mathieu Isabelle,Walrand Stéphan,Labar Daniel,Carlier Pascal,de Camps Joëlle,Schran Horst,Chen TianLing,Smith M Charles,Bouterfa Hakim,Valkema Roelf,Krenning Eric P,Kvols Larry K,Pauwels Stanislas
European journal of nuclear medicine and molecular imaging
The pharmacokinetics and dosimetry of (86)Y-DOTA(0)- d-Phe(1)-Tyr(3)-octreotide ((86)Y-SMT487) were evaluated in a phase I positron emission tomography (PET) study of 24 patients with somatostatin receptor-positive neuroendocrine tumours. The effect of amino acid (AA) co-infusion on renal and tumour uptake was assessed in a cross-over randomised setting. Five regimens were tested: no infusion, 4-h infusion of 120 g mixed AA (26.4 g l-lysine + l-arginine), 4 h l-lysine (50 g), 10 h 240 g mixed AA (52.8 g l-lysine + l-arginine) and 4 h Lys-Arg (25 g each). Comparisons were performed on an intra-patient basis. Infusions of AA started 0.5 h prior to injection of (86)Y-SMT487 and PET scans were obtained at 4, 24 and 48 h p.i. Absorbed doses to tissues were computed using the MIRD3 method. (86)Y-SMT487 displayed rapid plasma clearance and exclusive renal excretion; uptake was noted in kidneys, tumours, spleen and, to a lesser extent, liver. The 4-h mixed AA co-infusion significantly ( P<0.05) reduced (86)Y-SMT487 renal uptake by a mean of 21%. This protective effect was significant on the dosimetry data (3.3+/-1.3 vs 4.4+/-1.0 mGy/MBq; P<0.05) and was further enhanced upon prolonging the infusion to 10 h (2.1+/-0.4 vs 1.7+/-0.2 mGy/MBq; P<0.05). Infusion of Lys-Arg but not of l-lysine was more effective in reducing renal uptake than mixed AA. Infusion of AA did not result in reduced tumour uptake. The amount of (90)Y-SMT487 (maximum allowed dose: MAD) that would result in a 23-Gy cut-off dose to kidneys was calculated for each study: MAD was higher with mixed AA co-infusion by a mean of 46% (10-114%, P<0.05 vs no infusion). In comparison with 4 h mixed AA, the MAD was higher by a mean of 23% (9-37%; P<0.05) with prolonged infusion and by a mean of 16% (2-28%; P<0.05) with Lys-Arg. We conclude that infusion of large amounts of AA reduces renal exposure during peptide-based radiotherapy and allows higher absorbed doses to tumours. The prolongation of the infusion from 4 to 10 h further enhances the protective effect on the kidneys.
10.1007/s00259-003-1117-1