Background/Objectives: Early prognostication in critically ill patients with low burden of organ dysfunction (BOD) remains challenging. Progranulin (PGRN), a hypoxia inducible and anti-inflammatory protein, may offer prognostic value. We investigated whether PGRN levels predict mortality in ICU patients stratified by their BOD. Methods: In this secondary analysis of a prospectively recruited ICU cohort (n = 99), patients were categorized into low (Sequential Organ Failure Assessment Score (SOFA) ≤ 8) and high (SOFA > 8) BOD groups. Plasma PGRN concentrations were measured every 8 h for up to 5 days. Initial values and kinetic parameters (maximum, mean, and normalized area score (NAS)) were evaluated. Associations with in-hospital mortality were analyzed by univariate logistic regression and area under the receiver operating characteristic curve (AUROC) comparisons. Results: In patients with low BOD (n = 53), the PGRN kinetics were significantly associated with in-hospital mortality, with odds ratios of 1.086 (95% CI 1.027–1.148), 1.102 (95% CI 1.025–1.184), and 1.093 (95% CI 1.021–1.170) for maximum, mean, and NAS values, respectively. The respective AUROC values were 0.815 (p = 0.001), 0.753 (p = 0.010), and 0.738 (p = 0.016). By contrast, none of the PGRN metrics predicted mortality in patients with high BOD (n = 46; all AUROC values < 0.61, p > 0.25). The respective SOFA and CRP metrics were not predictive in low BOD patients. Maximum PGRN levels predicted death at least 32 h in advance. Conclusions: Serial PGRN measurements offer prognostic information, particularly in ICU patients with low BOD, a group whose deterioration is often difficult to anticipate and may be underestimated by conventional scoring systems such as SOFA. These findings support further investigation of PGRN as a tool for early risk stratification in critical illness.

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