Skip to main content
Download PDF

Erythropoietin as a critical prognostic indicator in ICU patients with sepsis: a prospective observational study

Journal of Intensive Care volume 13, Article number: 17 (2025) Cite this article

Abstract

Background

Erythropoietin (EPO), a glycoprotein hormone primarily produced in the kidneys, plays pleiotropic roles in hematopoietic and non-hematopoietic system. However, the clinical relevance of circulating EPO in sepsis progression and outcomes remains contentious and requires further elucidation.

Methods

Participants were categorized into three groups on the basis of EPO tertiles. The primary outcome was 28-day mortality. Multivariate Cox proportional regression analysis and restricted cubic spline regression were employed to evaluate the association between EPO levels and 28-day mortality in sepsis patients. Subgroup analyses were also conducted. Causal mediation analysis was conducted to explore the potential mediating role of EPO in the relationship between lactate and 28-day mortality.

Results

A total of 267 patients (65.17% male) were included in the study. The 28-day and hospital mortality rates were 23.22 and 31.20%, respectively. Multivariate Cox regression revealed significantly higher 28-day and hospital mortality in the highest EPO tertile compared to the lowest (HR 2.93, 95% CI 1.20–7.22; HR 2.47, 95% CI 1.05–5.81, respectively). Restricted cubic spline analysis demonstrated a progressively increasing mortality risk with elevated EPO levels. Subgroup analyses confirmed the consistency and stability of the effect size and direction across different subgroups. Moreover, causal intermediary analysis revealed that the association between lactate and 28-day mortality was partially mediated by EPO, with a mediation ratio of 12.59%.

Conclusions

Elevated EPO levels in patients with sepsis are correlated with unfavorable prognoses and may function as a prognostic biomarker for adverse outcomes.

Background

Sepsis is a life-threatening condition that arises from infection-induced immune dysfunction, leading to subsequent organ failure [1]. Globally, it is estimated that there are 4.89 million cases of sepsis, with sepsis-related deaths totaling 11 million, accounting for 19.7% of the global mortality [2]. This situation imposes a substantial economic burden on healthcare systems and presents an urgent challenge for public health, particularly in low- and middle-income countries [3]. Early identification of critically ill patients with sepsis is crucial for improving sepsis prognosis [4,5,6]. Although inflammatory markers such as c-reactive protein (CRP) and procalcitonin (PCT) are utilized to predict the severity and prognosis of sepsis, their accuracy and reliability are often the subject of debate [7]. Therefore, there is an urgent need to identify better biomarkers for early recognition of critically ill patients with sepsis.

Erythropoietin (EPO) is a glycoprotein hormone produced primarily in the kidneys that regulates red blood cell production. Its synthesis is stimulated by low oxygen levels. This hypoxia-driven increase in EPO production is intended to enhance oxygen delivery to tissues by promoting erythrocyte maturation and release in the bone marrow [8,9,10,11]. Recent studies have highlighted the non-erythropoietic functions of EPO, which include anti-inflammatory, antioxidant, and cytoprotective properties [12,13,14,15]. These actions contribute to attenuation of the inflammatory response, preservation of immune homeostasis, and mitigation of the severity and duration of inflammation [16,17,18,19]. Several studies have demonstrated that the serum EPO concentration can serve as an early warning indicator of poor prognosis in patients with conditions, such as diabetic chronic kidney disease [20], renal transplantation [21], and heart failure [22].

In the context of sepsis, non-survivors have been observed to exhibit elevated levels of EPO compared with survivors, with endogenous EPO concentrations correlated with indicators of tissue hypoperfusion, such as lactate and the carbon dioxide gap [23]. However, a study has reached the opposite conclusion [24], and the correlation between EPO and the prognosis of patients with sepsis is controversial. Therefore, the aim of this study was to assess the prognostic value of early measurement of the EPO concentration in septic patients admitted to the intensive care unit (ICU).

Methods

Study design and population

This prospective observational study enrolled patients with sepsis who were admitted to the ICU of the Second Affiliated Hospital of Wenzhou Medical University between October 1, 2022, and December 30, 2023. The inclusion criteria consisted of: (1) adherence to the sepsis 3.0 diagnostic criteria [1] and (2) completion of various laboratory tests, including EPO, hemoglobin, CRP, PCT, and others, within 48 h of ICU admission. The exclusion criteria included the following: (1) physiological states related to pregnancy and lactation; (2) the presence of malignant neoplasms undergoing chemotherapy or radiotherapy, organ transplantation, hormonal therapies, or immunosuppressive agents; (3) advanced chronic illnesses (e.g., chronic kidney disease at stages 4 and 5, chronic heart failure classified as NYHA III and IV, end-stage cancer, and COPD at GOLD stages 3 and 4) [25,26,27,28]; (4) interhospital transfer cases; and (5) receiving exogenous EPO therapy, such as recombinant human erythropoietin injections. The study was conducted in accordance with the principles outlined in the Declaration of Helsinki and received approval from the Medical Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University (ethics approval number: LCKY2020-36).

Data collection

Demographic data, including age, sex, and medical history, were collected from the enrolled patients. EPO levels were assessed within 48 h of ICU admission. Additional parameters documented included complete blood count, liver and kidney function tests, CRP, PCT, white blood cell (WBC), arterial oxygen pressure, arterial carbon dioxide pressure, and lactate levels. For data that exceeded the detection limits, the maximum detectable value was utilized. The oxygenation index, age-adjusted Charlson comorbidity index (aCCI), and sequential organ failure assessment (SOFA) score were computed from the collected data. The primary outcome indicator for this study was 28-day mortality, while hospital mortality served as the secondary outcome indicator. Clinical nurses collected blood samples for EPO and other laboratory analyses, which were subsequently sent to the laboratory of the Second Affiliated Hospital of Wenzhou Medical University for processing.

Statistical analysis

Statistical analyses were performed via R software (version 4.3.1) and SPSS software (version 26). The normality of continuous variables was assessed via the Kolmogorov‒Smirnov (K‒S) test. Normally distributed data are presented as the mean ± standard deviation (X ± S), with comparisons between two groups conducted via the independent Student’s t test, whereas comparisons among multiple groups were performed via ANOVA (F test). For data that did not follow a normal distribution, the results are reported as the median (interquartile range) [median (P25, P75)]. Comparisons between two groups were analyzed with the Mann‒Whitney U test, and differences among multiple groups were evaluated via the Kruskal‒Wallis rank‒sum test. Categorical variables are expressed as numbers and percentages (%), with comparisons performed via the chi-square test or Fisher’s exact test as appropriate. Spearman correlation analysis was employed to assess the relationships between continuous variables. Kaplan‒Meier survival curves were generated to illustrate the cumulative survival rate of patients with sepsis, with differences analyzed via the log-rank test. Cox proportional hazards models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the relationship between EPO and the endpoints, adjusting for clinical expertise and prior literature. Variance inflation factors (VIFs) were assessed to detect multicollinearity among variables, where a VIF < 10 suggested that multicollinearity was unlikely to affect estimation.

The specific variables adjusted for are as follows. Model 1: No variables were adjusted. Model 2: Adjusted for age, gender, hypertension, and diabetes. Model 3: In addition to the variables in Model 2, we further adjusted for SOFA score, hemoglobin levels, platelet count (PLT), PCT, glucose, and albumin. Owing to the skewed distribution of EPO, data were transformed using natural logarithms prior to analysis and treated as continuous variables (per 1-SD increment) in multivariate models and mediation analyses. Furthermore, the nonlinear associations between baseline EPO and 28-day, ICU, and in-hospital mortality were explored via a restricted cubic spline regression model with four knots.

The performance of EPO, lactate, SOFA, lactate + SOFA, and EPO + lactate + SOFA was evaluated by assessing their discriminative ability through receiver operating characteristic (ROC) curves and calculating the area under the ROC curve (AUC). In addition, the net reclassification index (NRI) and the integrated discrimination improvement (IDI) index were utilized to further examine the incremental predictive value of EPO + lactate + SOFA in comparison with EPO alone. Stratified analyses were conducted on the basis of age, sex, the SOFA score, lactate levels, oxygenation index, hypertension, diabetes, CKD and types of infections to determine the consistency of the prognostic value of the EPO for outcomes. All the statistical tests were two-tailed, with a significance level established at P < 0.05.

Results

Baseline characteristics

In this prospective cohort study, 267 out of the 350 subjects with sepsis met the inclusion criteria (Fig. 1). The in-hospital and 28-day mortality rates were 32.20% and 23.22%, respectively. Table 1 presents a comparison between patients in the EPO-T1 group and those in the other groups. Notably, patients with elevated EPO levels presented lower hemoglobin levels, red blood cell count, and platelet counts, and a greater incidence of septic shock. Furthermore, these patients had increased SOFA scores, lactate levels, ALT, total bilirubin, and potassium concentrations. The group with elevated EPO levels also experienced higher in-hospital and 28-day mortality rates. In addition, the differences in baseline characteristics between survivors and non-survivors during their hospital stay are shown in Table 2.

Fig. 1
figure 1

Flowchart of the study cohort

Full size image
Table 1 Characteristics and outcomes of participants stratified by EPO status
Full size table
Table 2 Baseline characteristics of the Survivor and Non-survivor groups
Full size table

EPO and 28-day mortality, and hospital mortality

Kaplan‒Meier survival analysis curves were generated to assess the incidence of primary outcomes across groups categorized by EPO tertiles (Fig. 2). Patients with elevated EPO levels had a significantly higher risk of 28-day mortality (log-rank P < 0.0001) and hospital mortality (log-rank P < 0.0048). Cox proportional hazards analysis was conducted to investigate the relationships between EPO levels and both 28-day mortality and hospital mortality. The findings indicated that EPO was independently associated with an increased risk of 28-day mortality (HR 1.3086 [95% CI (1. 0304–1.6618)]; P = 0.0274). However, the correlation with hospital mortality did not reach statistical significance (HR 1.1272; [95% CI (0. 9202–1.3808)]; P = 0.2473). In the fully adjusted Model 3, the hazard ratio (HR) for 28-day mortality in the highest EPO tertile was 2.9382 (95% CI 1.1963–7.2165), whereas for hospital mortality, it was 2.4692 (95% CI 1.0500–5.8069), both compared with the lowest tertile (Table 3). To ensure the robustness of our findings, a sensitivity analysis was conducted by excluding all CKD patients. The results of this analysis remained consistent with the original findings, thereby confirming the stability of our conclusions. Detailed results are provided in Appendix eTable 1. In addition, the restricted cubic splines regression model indicated that the risk of 28-day mortality increased nonlinearly with increasing EPO levels (P for nonlinearity = 0.014). Conversely, the risk of hospital mortality exhibited a linear increase with higher EPO levels (P for nonlinearity = 0.311) (Fig. 3A, B).

Fig. 2
figure 2

Kaplan–Meier survival analysis curves for all-cause mortality. Kaplan–Meier curves showing cumulative probability of 28 days (A), and hospital mortality (B)

Full size image
Table 3 Association between EPO and 28-day mortality
Full size table
Fig. 3
figure 3

A Restricted cubic spline for 28-day mortality. B Restricted cubic spline for hospital mortality

Full size image

As shown in Fig. 4, the AUC values for EPO, the SOFA score, and lactate were comparable, measuring 0.743, 0.772, and 0.754, respectively. Notably, the combination of EPO with the SOFA score and lactate levels resulted in increases in both the AUC and specificity. However, the differences among the models did not reach statistical significance, as indicated by the non-significant net reclassification improvement (NRI) and integrated discrimination improvement (IDI) for both 28-day mortality and hospital mortality (all P > 0.05) (Table 4).

Fig. 4
figure 4

ROC Curves for Evaluating EPO, Lac and SOFA Score of 28 days (A), and hospital mortality (B)

Full size image
Table 4 NRI and IDI index for EPO combined with lactate and SOFA
Full size table

Subgroup analysis

To confirm the relationship between EPO and 28-day mortality, stratified analyses were conducted on the basis of age, sex, the SOFA score, lactate levels, hypertension, diabetes, CKD and types of infections. As illustrated in Fig. 5, EPO was significantly associated with an increased risk of 28-day mortality in specific subgroups of septic patients: those aged ≤55 years [HR (95% CI) 5.6164 (2.1292–14.8152)], with a lactate level of 5 mmol/L [HR (95% CI) 1.531 (1.2071–1.9418)]. In addition, a significant association was noted in patients without hypertension [HR (95% CI) 1.5788 (1.0536–2.366)] and in those without diabetes [HR (95% CI) 1.4896 (1.0719–2.0700)]. No significant interactions were detected between EPO and the incidence of various endpoints within these subgroups (Fig. 5). Furthermore, subgroup analyses were performed based on CKD status, infection type, and admission route. The results indicated no significant interactions between the subgroups, indicating that our findings are consistent and robust across different subgroups. Detailed results are provided in Appendix eTable 2.

Fig. 5
figure 5

Forest plots of hazard ratios for the hospital mortality in different subgroups

Full size image

Mediation analyses

As previously demonstrated, lactate serves as a prognostic risk factor for septic patients [29]. In this study, we established that EPO is associated with 28-day mortality and is correlated with lactate levels, prompting us to conduct mediation analyses. Causal mediation analysis was performed to investigate the potential mediating role of EPO in the relationship between lactate and 28-day mortality. Figure 6 illustrates the mediation model and pathway, with lactate designated as the independent variable, EPO as the mediator, and 28-day mortality as the dependent variable. Our findings revealed that EPO significantly mediates the association between lactate and 28-day mortality. In the unadjusted models, EPO accounted for 18.94% of the association between lactate and 28-day mortality. After adjusting for covariates, the proportion mediated through EPO was found to be 12.59% for the effect of lactate on 28-day mortality. The mediating effect of EPO on the association between lactate and 28-day mortality was significant in both the unadjusted and adjusted models (Table 5).

Fig. 6
figure 6

Mediated analysis model path diagram

Full size image
Table 5 Mediation analysis of EPO in the association between lactate and 28-day mortality
Full size table

Discussion

In this study, we investigated the prognostic value of EPO in sepsis patients admitted to the ICU. We found that that elevated EPO levels were significantly associated with increased 28-day and hospital mortality. Multivariate Cox regression analysis confirmed that EPO is an independent predictor of 28-day mortality, with patients in the highest EPO tertile having nearly three times the risk of death compared to those in the lowest tertile. Restricted cubic spline analysis further validated the nonlinear relationship between EPO levels and mortality risk, underscoring its potential as a prognostic marker in sepsis.

Our results are consistent with previous studies suggesting that elevated EPO levels are linked to poor outcomes in sepsis patients [23, 30, 31]. For instance, Tamion et al. [31] reported that EPO could serve as a biological marker for disease severity in critically ill patients, including those with sepsis. Similarly, Abel et al. [30] found a negative prognostic association between elevated EPO levels and outcomes in septic shock patients. However, Jiang et al. [24] reported contrasting findings, with survivors displaying higher EPO levels than non-survivors. This discrepancy may be attributed to differences in study populations, as Jiang et al. focused exclusively on non-anemic patients, whereas this study included both anemic and non-anemic patients. This highlights the importance of considering patient heterogeneity when interpreting EPO’s prognostic role. In addition, Jiang et al.’s cohort demonstrated higher lactate levels, a lower oxygenation index, and a 28-day mortality rate of 40% compared to 23% in this study, suggesting their patients had more severe clinical conditions.

Despite these findings, the mechanisms underlying the association between EPO and sepsis prognosis remain poorly understood. Preclinical studies have demonstrated that EPO possesses anti-inflammatory properties, inhibiting the release of pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) [15, 32, 33]. Furthermore, EPO treatment has been shown to improve survival in septic mice and mitigate lung injury and lethality in rat models of sepsis-associated ARDS [34, 35]. A randomized controlled trial published in the New England Journal of Medicine also reported a significant reduction in mortality among critically ill patients treated with EPO [36].

However, our findings suggest that elevated EPO levels in septic patients may be associated with poorer outcomes. We hypothesize that this discrepancy may be due to several underlying factors. First, during the early phase of sepsis, both pro-inflammatory and anti-inflammatory responses are heightened, with non-survivors exhibiting more pronounced responses than survivors [37, 38]. Elevated EPO levels in this context may reflect an intensified but dysregulated immune response. In addition, EPO elevation may represent a compensatory mechanism for hypoxia and anemia, which are common in severe infections [39]. Sepsis induces a state of systemic inflammation and widespread tissue hypoxia due to impaired perfusion, resulting in increased EPO production as the body attempts to rectify these deficits. However, it has been shown that inflammatory anemia responds poorly to EPO in sepsis, and while EPO concentrations may be elevated, they are insufficient to correct anemia and hypoxia [40]. This suggests that EPO elevation in sepsis may serve as a marker of disease severity rather than a protective response.

Notably, this study is the first to compare the predictive value of EPO with lactate, SOFA score, and inflammatory markers. We found that EPO’s predictive value for 28-day mortality is noninferior to that of the SOFA score and lactate, and superior to that of conventional inflammatory markers, such as PCT and CRP. This suggests that EPO could be a valuable addition to existing prognostic tools for sepsis.

In addition, we observed that EPO partially mediates the effect of lactate on mortality. This finding implies that EPO may contribute to the adverse outcomes associated with elevated lactate levels, providing new insights into the interplay between EPO and sepsis pathophysiology. Further research is needed to elucidate the mechanisms underlying this relationship.

In subgroup analyses, we found no significant differences in oxygenation indices across EPO level groups, nor was there a significant interaction with hypoxia levels. Similarly, sensitivity analyses and subgroup analyses based on chronic kidney disease (CKD) status yielded consistent results, indicating that the prognostic impact of EPO in sepsis is independent of hypoxia and renal function. We propose that this phenomenon may be attributed to the fact that EPO production in sepsis is influenced not only by oxygen levels and renal function but also by inflammation and anemia, both of which are potent stimulators of EPO synthesis [41,42,43].

Despite these significant findings, this study has several limitations. First, the single-center design may restrict the generalizability of the results, and the observational nature of the study precludes definitive conclusions regarding causality. Second, although our model accounts for numerous covariates, residual confounding cannot be entirely eliminated, which is a common issue in observational studies. Third, the relatively small size of the study population underscores the need for larger multicenter studies to validate these findings. Furthermore, a single measurement of EPO may not fully capture the dynamic changes in EPO levels during the acute phase of sepsis. Future studies should incorporate serial EPO measurements to better understand its temporal relationship with disease progression.

Future research should aim to elucidate the mechanistic pathways linking EPO to sepsis outcomes. Investigating the role of EPO in the inflammatory and immune responses during sepsis could provide deeper insights into its impact on patient prognosis. In addition, exploring therapeutic interventions targeting EPO pathways may offer new strategies for improving sepsis management and patient outcomes.

Conclusion

Elevated EPO levels in patients with sepsis are associated with short-term prognosis and may serve as an early indicator of poor outcomes. The incorporation of EPO measurements into clinical practice could improve the risk stratification and management of sepsis patients. Further research is necessary to clarify the underlying mechanisms and explore the potential therapeutic implications of EPO in the context of sepsis.

Availability of data and materials

The data sets generated and analysed during the current study are not publicly available due privacy or ethical restrictions but are available from the corresponding author on reasonable request.

Abbreviations

EPO:

Erythropoietin

PCT:

Procalcitonin

CRP:

C-reactive protein

WBC:

White blood cell count

SIRS:

Systemic inflammatory response syndrome

SOFA:

Sequential organ failure assessment

aCCI:

Age-adjusted charlson comorbidity index

GCS:

Glasgow coma scale

ICU:

Intensive care unit

ROC:

Area under curve

CI:

Confidence interval

TNF-α:

Tumor necrosis factor-α

IL-1:

Interleukin-1

IL-6:

Interleukin-6

IL-8:

Interleukin-8

MCV:

Mean cell volume

RDW:

Red cell distribution width

BUN:

Blood urea nitrogen

ALT:

Alanine aminotransferase

LOS ICU days:

Intensive care unit length of stay

LOS hospital day:

Hospital length of stay

CKD:

Chronic kidney disease

References

  1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the global burden of disease study. Lancet. 2020;395(10219):200–11.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fleischmann C, Scherag A, Adhikari NKJ, Hartog CS, Tsaganos T, Schlattmann P, et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med. 2016;193(3):259–72.

    Article  CAS  PubMed  Google Scholar 

  4. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med. 2008;36(3):941–52.

    Article  CAS  PubMed  Google Scholar 

  5. Antonelli M, Azoulay E, Bonten M, Chastre J, Citerio G, Conti G, et al. Year in review in Intensive Care Medicine 2010: II. Pneumonia and infections, cardiovascular and haemodynamics, organization, education, haematology, nutrition, ethics and miscellanea. Intensive Care Med. 2011;37(2):196–213.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Schuetz P, Christ-Crain M, Müller B. Procalcitonin and other biomarkers to improve assessment and antibiotic stewardship in infections—hope for hype? Swiss Med Wkly. 2009;139(23–24):318–26.

    CAS  PubMed  Google Scholar 

  7. Pierrakos C, Velissaris D, Bisdorff M, Marshall JC, Vincent J-L. Biomarkers of sepsis: time for a reappraisal. Crit Care. 2020;24(1).

  8. Watts D, Gaete D, Rodriguez D, Hoogewijs D, Rauner M, Sormendi S, et al. Hypoxia pathway proteins are master regulators of erythropoiesis. Int J Mol Sci. 2020;21(21):8131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fisher JW, Birdwell BJ. The production of an erythropoietic factor by the in situ perfused kidney. Acta Haematol. 1961;26:224–32.

    Article  CAS  PubMed  Google Scholar 

  10. Dame C, Fahnenstich H, Freitag P, Hofmann D, Abdul-Nour T, Bartmann P, et al. Erythropoietin mRNA expression in human fetal and neonatal tissue. Blood. 1998;92(9):3218–25.

    Article  CAS  PubMed  Google Scholar 

  11. Tóthová Z, Tomc J, Debeljak N, Solár P. STAT5 as a key protein of erythropoietin signalization. Int J Mol Sci. 2021;22(13):7109.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Habib P, Stamm AS, Zeyen T, Noristani R, Slowik A, Beyer C, et al. EPO regulates neuroprotective transmembrane BAX inhibitor-1 motif-containing (TMBIM) family members GRINA and FAIM2 after cerebral ischemia-reperfusion injury. Exp Neurol. 2019;320:112978.

    Article  CAS  PubMed  Google Scholar 

  13. Tan R, Tian H, Yang B, Zhang B, Dai C, Han Z, et al. Autophagy and Akt in the protective effect of erythropoietin helix B surface peptide against hepatic ischaemia/reperfusion injury in mice. Sci Rep. 2018;8(1):14703.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Brines M, Cerami A. Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J Intern Med. 2008;264(5):405–32.

    Article  CAS  PubMed  Google Scholar 

  15. Suresh S, Rajvanshi PK, Noguchi CT. The many facets of erythropoietin physiologic and metabolic response. Front Physiol. 2019;10:1534.

    Article  PubMed  Google Scholar 

  16. Cantarelli C, Angeletti A, Cravedi P. Erythropoietin, a multifaceted protein with innate and adaptive immune modulatory activity. Am J Transplant. 2019;19(9):2407–14.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Teoh J, Boulos S, Chieng J, Knuckey NW, Meloni BP. Erythropoietin increases neuronal NDPKA expression, and NDPKA up-regulation as well as exogenous application protects cortical neurons from in vitro ischemia-related insults. Cell Mol Neurobiol. 2014;34(3):379–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Arcasoy MO. The non-haematopoietic biological effects of erythropoietin. Br J Haematol. 2008;141(1):14–31.

    Article  CAS  PubMed  Google Scholar 

  19. Jelkmann W. Regulation of erythropoietin production. J Physiol. 2011;589(Pt 6):1251–8.

    Article  CAS  PubMed  Google Scholar 

  20. Wagner M, Alam A, Zimmermann J, Rauh K, Koljaja-Batzner A, Raff U, et al. Endogenous erythropoietin and the association with inflammation and mortality in diabetic chronic kidney disease. Clin J Am Soc Nephrol. 2011;6(7):1573–9.

    Article  CAS  PubMed  Google Scholar 

  21. Molnar MZ, Tabak AG, Alam A, Czira ME, Rudas A, Ujszaszi A, et al. Serum erythropoietin level and mortality in kidney transplant recipients. Clin J Am Soc Nephrol. 2011;6(12):2879–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Belonje AM, Voors AA, van der Meer P, van Gilst WH, Jaarsma T, van Veldhuisen DJ. Endogenous erythropoietin and outcome in heart failure. Circulation. 2010;121(2):245–51.

    Article  CAS  PubMed  Google Scholar 

  23. Tamion F, Le Cam-Duchez V, Menard JF, Girault C, Coquerel A, Bonmarchand G. Serum erythropoietin levels in septic shock. Anaesth Intensive Care. 2005;33(5):578–84.

    Article  CAS  PubMed  Google Scholar 

  24. Jiang Y, Jiang FQ, Kong F, An MM, Jin BB, Cao D, et al. Inflammatory anemia-associated parameters are related to 28-day mortality in patients with sepsis admitted to the ICU: a preliminary observational study. Ann Intensive Care. 2019;9(1):67.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Stevens PE, Levin A. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158(11):825–30.

    Article  PubMed  Google Scholar 

  26. Agusti A, Celli BR, Criner GJ, Halpin D, Anzueto A, Barnes P, et al. Global initiative for chronic obstructive lung disease 2023 report: GOLD executive summary. Am J Respir Crit Care Med. 2023;207(7):819–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. White PD, Myers M. The classification of cardiac diagnosis. JAMA. 1921;77(18):1414–5.

    Article  Google Scholar 

  28. Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. Hoboken: Wiley; 2011.

    Google Scholar 

  29. Li W, Wang M, Zhu B, Zhu Y, Xi X. Prediction of median survival time in sepsis patients by the SOFA score combined with different predictors. Burns Trauma. 2020;8:tkz006.

  30. Abel J, Spannbrucker N, Fandrey J, Jelkmann W. Serum erythropoietin levels in patients with sepsis and septic shock. Eur J Haematol. 1996;57(5):359–63.

    Article  CAS  PubMed  Google Scholar 

  31. Tamion F, Le Cam-Duchez V, Menard JF, Girault C, Coquerel A, Bonmarchand G. Erythropoietin and renin as biological markers in critically ill patients. Crit Care. 2004;8(5):R328–35.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Jelkmann W. Erythropoietin: structure, control of production, and function. Physiol Rev. 1992;72(2):449–89.

    Article  CAS  PubMed  Google Scholar 

  33. Heitrich M, Garcia DM, Stoyanoff TR, Rodriguez JP, Todaro JS, Aguirre MV. Erythropoietin attenuates renal and pulmonary injury in polymicrobial induced-sepsis through EPO-R, VEGF and VEGF-R2 modulation. Biomed Pharmacother. 2016;82:606–13.

    Article  CAS  PubMed  Google Scholar 

  34. Ling H, Lin Y, Bao W, Xu N, Chen L, Zhao L, et al. Erythropoietin-mediated IL-17F attenuates sepsis-induced gut microbiota dysbiosis and barrier dysfunction. Biomed Pharmacotherapy. 2023;165:115072.

    Article  CAS  Google Scholar 

  35. Gao Y, Cao F, Tian X, Zhang Q, Xu C, Ji B, et al. Inhibition the ubiquitination of ENaC and Na, K-ATPase with erythropoietin promotes alveolar fluid clearance in sepsis-induced acute respiratory distress syndrome. Biomed Pharmacotherapy. 2024;174:116447.

    Article  CAS  Google Scholar 

  36. Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med. 2007;357(10):965–76.

    Article  CAS  PubMed  Google Scholar 

  37. Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med. 1996;125(8):680–7.

    Article  CAS  PubMed  Google Scholar 

  38. Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, Remick DG. The pathogenesis of sepsis. Annu Rev Pathol. 2011;6:19–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Loftus TJ, Mira JC, Stortz JA, Ozrazgat-Baslanti T, Ghita GL, Wang Z, et al. Persistent inflammation and anemia among critically ill septic patients. J Trauma Acute Care Surg. 2019;86(2):260–7.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Apple CG, Kelly LS, Kannan KB, Ungaro RF, Moore FA, Brakenridge SC, et al. Ineffective erythropoietin response to anemia in sepsis. Surg Infect. 2022;23(2):142–9.

    Article  CAS  Google Scholar 

  41. Peng B, Kong G, Yang C, Ming Y. Erythropoietin and its derivatives: from tissue protection to immune regulation. Cell Death Dis. 2020;11(2):79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Walden AP, Young JD, Sharples E. Bench to bedside: a role for erythropoietin in sepsis. Crit Care. 2010;14(4):227.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Koury MJ, Haase VH. Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol. 2015;11(7):394–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to express our sincere gratitude to the staff and medical personnel of the Intensive Care Unit at the Second Affiliated Hospital of Wenzhou Medical University for their invaluable support in patient recruitment and data collection. We also extend our appreciation to the laboratory team for their assistance in processing and analyzing the blood samples. In addition, we are grateful to the patients and their families for their participation and cooperation in this study. This research would not have been possible without their contribution. Finally, we thank the National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province, National Key RD Program of China, Wenzhou Municipal Science and Technology Bureau, and Clinical Research Foundation of the 2nd Affiliated Hospital of Wenzhou Medical University for their financial support.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82002093), Natural Science Foundation of Zhejiang Province (Y24H150028), National Key RD Program of China (2022YFC2504404), Wenzhou Municipal Science and Technology Bureau (Y20220086), Clinical Research Foundation of the 2nd Affiliated Hospital of Wenzhou Medical University (SAHoWMU-CR2018-11-134).

Author information

Author notes

  1. Qianping Zhang, Yan Zhang and Xinyi Tian have contributed equally to this work and share the first authorship.

Authors and Affiliations

  1. Department of Anesthesia, Pain and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Qianping Zhang, Xinyi Tian, Kaifan Lin, Jie Weng, Xinyi Fu, Yongjie Chen, Bihuan Cheng, Xiaolong Zhang, Yuqiang Gong, Shengwei Jin & Ye Gao

  2. NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, 200237, China

    Yan Zhang

  3. The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Xuemeng Li

Authors
  1. Qianping Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Yan Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Xinyi Tian
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Kaifan Lin
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Jie Weng
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Xinyi Fu
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Yongjie Chen
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Xuemeng Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Bihuan Cheng
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Xiaolong Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Yuqiang Gong
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Shengwei Jin
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Ye Gao
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

Y.G., S-W.J. and Y-Q. G sponsored, and supervised the work and reviewed the manuscript. Q-P.Z., Y.Z. and X-Y.T. conceived the study, prepared the figures, analyzed the data, and wrote the manuscript. K-F.L. helped to collect and analyze the data. J.W. helped to analyze the data, and prepared figures and revised the manuscript. X-Y.F., Y-J.C. and X-M.L. helped to collect the data. B-H.C and X-L.Z. discussed experimental designs and revised the manuscript. All authors discussed the data, commented on the manuscript, and read and approved the final manuscript.

Corresponding authors

Correspondence to Yuqiang Gong, Shengwei Jin or Ye Gao.

Ethics declarations

Ethics approval and consent to participate

This study was conducted in accordance with the ethical standards set forth by the Declaration of Helsinki. Ethical approval was obtained from the Medical Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University (approval number: LCKY2020-36). Informed consent was obtained from all participants or their legal surrogates before enrollment. For patients unable to provide consent due to their critical condition, consent was obtained from their legal representatives in line with institutional and national guidelines. Participation in the study was voluntary, and participants retained the right to withdraw at any time without any impact on their clinical care. Confidentiality of the participants’ data was strictly maintained throughout the study.

Consent for publication

All participants or their legal surrogates provided written informed consent for the collection, analysis, and publication of anonymized data. For patients unable to provide consent due to their medical condition, consent for publication was obtained from their legal representatives in accordance with institutional guidelines and ethical standards. No identifying personal or clinical information of the participants is included in this manuscript.

Competing interests

The authors declare that there is no conflict of interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Q., Zhang, Y., Tian, X. et al. Erythropoietin as a critical prognostic indicator in ICU patients with sepsis: a prospective observational study. j intensive care 13, 17 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40560-025-00787-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40560-025-00787-x

Keywords

Journal of Intensive Care

ISSN: 2052-0492