The effect of augmented protein intake on nitrogen balance: A nested cohort study of the TARGET protein trial.

PURPOSE: The impact of augmenting enteral protein delivery on nitrogen balance, urea generation, and kidney function in critically ill patients remains poorly defined. This study aimed to investigate these effects in a nested cohort within the TARGET Protein trial.

METHODS

We conducted a single-center study nested within a cluster randomized crossover trial. Consecutive patients were enrolled during either the usual protein intake period (n = 52) or the augmented protein intake period (n = 55). Nitrogen balance, its components, plasma urea concentrations, and urea nitrogen accumulation were compared between groups. Multivariable analyses identified factors independently associated with nitrogen balance and incident acute kidney injury (AKI). A causal mediation analysis was performed to assess whether the effect of augmented protein delivery on urea concentrations was mediated through incident AKI.

RESULTS

From day 1 to day 7, mean protein intake was 0.84 ± 0.73 g·kg-1·day-1 in the usual-protein group and 1.35 ± 0.94 g·kg-1·day-1 in the augmented-protein group. Patients receiving augmented protein achieved a less negative nitrogen balance than those receiving usual protein (mean difference, +5 g per day; 95% confidence interval [CI], 0.4 to 10; P = 0.033), driven by greater nitrogen intake (mean difference, +7 g per day; 95% CI, 5 to 10; P < 0.001). Independent predictors of nitrogen balance were ideal body weight (-0.18 g.kg-1; 95% CI, -0.35 to -0.01; P = 0.040), AKI at ICU admission (+4.7 g; 95% CI, 0.10 to 9.3; P = 0.046), and allocation to augmented protein therapy (+5.1 g; 95% CI, 0.43 to 9.7; P = 0.033). Compared with usual protein delivery, augmented protein delivery resulted in higher plasma urea concentrations (median, 14 vs. 11 mmol/L) and greater urea nitrogen accumulation (+3 g; 95% CI, 1.0 to 6.0; P = 0.035). Approximately 60% of the additional positive nitrogen balance was accounted for by urea generation. Among patients without AKI at ICU admission, augmented protein delivery was independently associated with incident AKI (odds ratio, 4.79; 95% CI, 1.14 to 26.4; P = 0.046). In mediation analyses, most of the increase in urea concentrations associated with augmented protein delivery was attributable to a direct effect rather than mediation through incident AKI.

CONCLUSIONS

In critically ill patients, augmented protein delivery resulted in a less negative nitrogen balance but substantially increased urea generation and plasma urea concentrations. These findings suggest that a substantial proportion of additional protein intake may be directed toward nitrogen waste production rather than net anabolic utilization.