Effect of Protein Dosage on Persistent Acute Renal Failure in Critically Ill Patients.

Обзор

Background: Acute kidney injury (AKI) is common in critically ill patients and is associated with worse outcomes, including longer ICU stay, need for dialysis, and higher mortality. Patients with AKI often experience significant protein and calorie loss due to their illness and medical treatments. Providing the right amount of protein may help maintain muscle mass and improve recovery; however, consuming too much protein could potentially worsen kidney function. Current international guidelines recommend adequate protein intake, but the best dose remains uncertain, especially for patients with AKI. Study Purpose: This research will examine whether patients with AKI who receive a higher protein intake (greater than 1.2 g/kg/day) have different outcomes compared to those who receive a standard or lower protein intake (≤1.2 g/kg/day). The primary outcome is whether a higher protein intake leads to a longer recovery time from AKI or worsens kidney function. Study Design: This is a retrospective, multicenter study using data from five hospitals in Argentina. It is designed as a "target trial emulation," meaning researchers will analyze existing patient data as if it were a randomized clinical trial. Patients will be included on the fifth day of their ICU stay and classified into two groups based on their protein intake on day 5: * Group 1 (Standard Protein): ≤1.2 g/kg/day * Group 2 (High Protein): \>1.2 g/kg/day No additional interventions will be performed; data are collected from medical records. Study Population: The study will include adult patients (≥18 years) admitted to the ICU who are receiving exclusive enteral or parenteral nutrition and have AKI (or worsening chronic kidney disease) according to KDIGO criteria. Patients with advanced chronic kidney disease (creatinine clearance \<30 ml/min/1.73 m²) or undergoing hemodialysis at T0, previous kidney transplant, severe liver disease, or BMI \>30 will be excluded. Outcomes: * Primary Outcome: Time to recovery of kidney function within 30 days, measured by creatinine returning close to baseline values. * Secondary Outcomes: Changes in blood urea levels, duration of renal replacement therapy (hemodialysis), ICU length of stay, and 30-day mortality. Statistical Approach: To minimize bias, the study will use advanced statistical methods, including propensity score weighting, to ensure fair comparison between groups. Competing risks (such as death before kidney recovery) will be taken into account in the analysis. Significance: This study will provide important information about the safety and effectiveness of higher protein intake in critically ill patients with AKI. The findings may help guide nutritional strategies in the ICU, optimize kidney outcomes, and improve patient care.

Подробное описание

Background:

Acute kidney injury (AKI) is a frequent complication in critically ill patients and is associated with prolonged hospital stay, need for renal replacement therapy (RRT), and higher mortality. Patients with AKI often develop protein-calorie malnutrition due to increased catabolism, inflammation, and nutrient losses. This is further aggravated when RRT is required, as dialysis contributes to nitrogen and amino acid losses. Clinical guidelines recommend providing an adequate protein intake to support recovery; however, the optimal protein dose remains uncertain.

Recent trials, such as the EFFORT Protein study, suggest that higher protein intake may benefit some critically ill patients, especially those with malnutrition or frailty. However, the same study also indicated potential harm in patients with severe illness or AKI, showing that excessive protein intake (\>2.2 g/kg/day) could worsen kidney outcomes and increase mortality.

Given the uncertainty regarding the actual effect of increased protein intake in patients with AKI-and the possibility that it may be harmful in those with persistent AKI-this study uses a Target Trial Emulation approach to evaluate whether protein intake on the fifth day of ICU admission exceeding 1.2 g/kg/day leads to prolonged duration of AKI in critically ill patients.

Objective:

This study aims to evaluate whether a higher protein intake (\>1.2 g/kg/day) compared with standard or lower intake (≤1.2 g/kg/day) affects the duration of AKI and clinical outcomes in critically ill patients.

Study Design:

This is a retrospective, multicenter study using a target trial emulation design. Patient data will be collected from electronic health records of five tertiary hospitals in Argentina. Eligible patients will be identified on the fifth day of their ICU admission, referred to as Time Zero (T0). Classification into treatment groups will depend on protein intake at T0:

* Group 1: Standard protein intake (≤1.2 g/kg/day) * Group 2: High protein intake (\>1.2 g/kg/day) No interventions will be administered as part of the study; data will be analyzed retrospectively.

Population:

Inclusion criteria: age ≥18 years, ICU admission, exclusive enteral or parenteral nutrition, and presence of AKI or worsening chronic kidney disease as defined by KDIGO criteria (rise in serum creatinine \>0.3 mg/dL within 48 hours, or 1.5-fold increase within 7 days).

Exclusion criteria: advanced chronic kidney disease (creatinine clearance \<30 ml/min/1.73 m²) or dialysis at admission, prior kidney transplant, severe liver disease (Child-Pugh \>7), AKI requiring RRT at baseline (T0), or body mass index \>30.

Primary Outcome: Time to recovery of kidney function within 30 days, defined as return of serum creatinine to ≤1.5 times baseline or ≤30% above baseline, with death considered as a competing event.

Secondary Outcomes:

* Change in blood urea levels at day 14. * Daily change in urea trajectory during the first 14 days. * Days free of AKI and days free of RRT within 30 days. * Mortality at day 30. * ICU length of stay within 30 days. * Reasons for initiation of RRT.

Sample Size: Based on prior literature, we estimated that 172 patients per group are required for non-inferiority testing with 80% power, α = 0.05, and a non-inferiority margin of 2 days of AKI. Adjustments for potential confounders indicate that at least 105 patients per group will be necessary.

Statistical Analysis:

* Primary analysis will be conducted on an intention-to-treat basis. * Propensity score weighting with inverse probability of treatment weighting (IPTW) will be used to adjust for baseline differences between groups. * For time-to-event outcomes (e.g., AKI recovery, ICU discharge, mortality), competing risks will be addressed using Fine-Gray regression. * Continuous outcomes (e.g., urea levels) will be compared using t-tests or Mann-Whitney tests, depending on distribution. Longitudinal changes in urea will be analyzed using mixed-effects models with restricted cubic splines. * Proportions (e.g., mortality) will be compared using logistic regression models adjusted with propensity score weighting.

Ethical Considerations:

This study involves a retrospective review of de-identified patient data. It poses minimal risk, as no interventions are introduced beyond standard care. Confidentiality will be strictly maintained in accordance with national and local regulations, including Argentina's Personal Data Protection Law (Law 25,326). Informed consent will be waived in accordance with CIOMS guidelines, as the study is retrospective, presents minimal risk, and has significant social and scientific value.

Significance:

This study will provide new evidence on the safety and effectiveness of protein dosing in critically ill patients with AKI. The results may inform future guidelines on nutritional therapy in the ICU and optimize outcomes for patients at high risk of kidney complications.

Первичные конечные точки

• Time to recovery of kidney function [Срок оценки: Within 30 days from ICU day 5 (Time Zero) or until ICU discharge, whichever occurs first.]

Вторичные конечные точки (3)

• Change in blood urea levels at day 14 [Срок оценки: 14 days from ICU stay (T0)]
• ICU length of stay [Срок оценки: Within 30 days from ICU day 5 (Time Zero) or until ICU discharge, whichever occurs first.]
• Mortality at 30 days [Срок оценки: Within 30 days or until hospital discharge, whichever occurs first.]

Критерии участия

Критерии включения

• Patients aged 18 years or older admitted to the ICU.
• Patients receiving exclusive enteral or parenteral nutrition
• Acute kidney injury or exacerbated chronic kidney disease according to KDIGO criteria (increase in creatinine greater than 0.3 mg/dL in less than 48 hours or a 1.5-fold increase in baseline creatinine in 7 days)

Критерии исключения

• Patients diagnosed with chronic kidney disease with a creatinine clearance of less than 30 ml/min/m2 or on dialysis at admission.
• Patients with a history of kidney transplantation
• Patients with severe liver disease (Child-Pugh score >7 points)
• Patients with acute kidney injury undergoing renal replacement therapy at T0
• BMI> 30

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Аргентина · 6 центров

• Clinica Bazterrica — Buenos Aires
• Hospital Alemán — Buenos Aires
• Hospital Italiano de Buenos Aires — Buenos Aires
• Hospital Privado Universitario de Córdoba — Córdoba
• Hospital Universitario Austral — Buenos Aires
• Hospital Italiano sede San Justo Agustín Rocca — Buenos Aires

Публикации

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• Doig GS, Simpson F, Bellomo R, Heighes PT, Sweetman EA, Chesher D, Pollock C, Davies A, Botha J, Harrigan P, Reade MC. Intravenous amino acid therapy for kidney function in critically ill patients: a randomized controlled trial. Intensive Care Med. 2015 Jul;41(7):1197-208. doi: 10.1007/s00134-015-3827-9. Epub 2015 Apr 30. PMID 25925203
• Rosa-Diez GJ, Varela F, Crucelegui S, Algranati SL, Greloni G. [Comparison between CKD-EPI and MDRD-equations to estimate glomerular filtration rate in chronic kidney disease patients]. Medicina (B Aires). 2011;71(4):323-30. Spanish. PMID 21893444
• Deane AM, Casaer MP. Editorial: The interaction between protein delivery and blood urea and ammonia during critical illness. Curr Opin Clin Nutr Metab Care. 2024 Mar 1;27(2):144-146. doi: 10.1097/MCO.0000000000001016. Epub 2024 Feb 8. No abstract available. PMID 38320160
• Haines RW, Zolfaghari P, Wan Y, Pearse RM, Puthucheary Z, Prowle JR. Elevated urea-to-creatinine ratio provides a biochemical signature of muscle catabolism and persistent critical illness after major trauma. Intensive Care Med. 2019 Dec;45(12):1718-1731. doi: 10.1007/s00134-019-05760-5. Epub 2019 Sep 17. PMID 31531715
• Gunst J, Kashani KB, Hermans G. The urea-creatinine ratio as a novel biomarker of critical illness-associated catabolism. Intensive Care Med. 2019 Dec;45(12):1813-1815. doi: 10.1007/s00134-019-05810-y. Epub 2019 Oct 16. No abstract available. PMID 31620835
• Haines RW, Prowle JR, Day A, Bear DE, Heyland DK, Puthucheary Z. Association between urea trajectory and protein dose in critically ill adults: a secondary exploratory analysis of the effort protein trial (RE-EFFORT). Crit Care. 2024 Jan 16;28(1):24. doi: 10.1186/s13054-024-04799-1. PMID 38229072
• Heyland DK, Patel J, Compher C, Rice TW, Bear DE, Lee ZY, Gonzalez VC, O'Reilly K, Regala R, Wedemire C, Ibarra-Estrada M, Stoppe C, Ortiz-Reyes L, Jiang X, Day AG; EFFORT Protein Trial team. The effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicentre, pragmatic, registry-based randomised trial. Lancet. 2023 Feb 18;401(1 PMID 36708732

Идентификаторы

NCT: NCT07631221 · 7355

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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