Risk Factors Associated with Hyporesponsiveness to Erythropoietin in Chronic Kidney Disease Patients on Hemodialysis Who Present Anemia: A Multicenter Case-Control Study

Abstract

Background: Anemia represents a significant complication in patients with advanced chronic kidney disease (CKD) on hemodialysis, primarily caused by reduced renal erythropoietin production. Despite erythropoiesis-stimulating agents (ESAs) being the cornerstone of treatment, hyporesponsiveness to these agents remains a clinical challenge with implications for patient outcomes. Objective: To identify and quantify risk factors associated with hyporesponsiveness to erythropoietin in patients with CKD on hemodialysis who present with anemia. Methods: This multicenter case–control study analyzed data from 784 hemodialysis patients receiving erythropoietin therapy across six dialysis centers in Ecuador between January and December 2019. Hyporesponsiveness was defined as requiring ≥ 200 IU/kg/week of erythropoietin alfa for ≥3 consecutive months to maintain target hemoglobin levels (10–12 g/dL). Demographic, clinical, and laboratory parameters were compared between hyporesponsive cases (n = 123) and responsive controls (n = 661). Bivariate and multivariate logistic regression analyses were performed to identify independent risk factors. Results: The prevalence of erythropoietin hyporesponsiveness was 15.69%. A multivariate analysis identified female sex (adjusted OR = 1.96; 95% CI: 1.20–3.20; p < 0.001), age < 50 years (adjusted OR = 4.25; 95% CI: 2.42–7.47; p < 0.001), serum albumin < 4.0 g/dL (adjusted OR = 10.53; 95% CI: 6.53–16.98; p < 0.001), ferritin ≥ 800 ng/mL (adjusted OR = 7.28; 95% CI: 4.22–12.57; p < 0.001), transferrin saturation < 20% (adjusted OR = 9.27; 95% CI: 5.47–15.69; p < 0.001), parathyroid hormone ≥ 500 pg/mL (adjusted OR = 1.89; 95% CI: 1.16–3.09; p = 0.011), and use of renin–angiotensin system blockers (adjusted OR = 2.25; 95% CI: 1.36–3.71; p = 0.002) as independent risk factors for erythropoietin hyporesponsiveness. Conclusions: Multiple demographic, clinical, and laboratory factors independently contribute to erythropoietin hyporesponsiveness in hemodialysis patients. Identification of these risk factors may guide clinicians in developing individualized treatment approaches, optimizing erythropoietin dosing, and implementing targeted interventions to improve anemia management in this vulnerable population.

1. Introduction

Anemia represents one of the most prevalent complications in patients with advanced chronic kidney disease (CKD), affecting approximately 80–90% of individuals with end-stage renal disease (ESRD) requiring renal replacement therapy [1,2]. The etiology of renal anemia is multifactorial, with the primary mechanism being the diminished capacity of the diseased kidneys to produce adequate amounts of erythropoietin (EPO), a glycoprotein hormone essential for erythropoiesis [3]. Additional contributing factors include shortened erythrocyte lifespan, uremic-induced bone marrow suppression, iron deficiency, chronic inflammation, and nutritional deficiencies [4,5].

The introduction of erythropoiesis-stimulating agents (ESAs) in the late 1980s revolutionized the management of renal anemia, significantly reducing the need for blood transfusions and improving patients’ quality of life [6]. However, a substantial proportion of patients exhibit a suboptimal response to ESA therapy, a condition termed “ESA hyporesponsiveness” or “EPO resistance” [7]. This phenomenon is clinically defined as the requirement for persistently high doses of EPO (greater than 200 IU/kg/week) to maintain target hemoglobin levels between 10 and 12 g/dL or the inability to achieve these targets despite high-dose therapy [8,9].

The clinical significance of EPO hyporesponsiveness extends beyond the immediate challenge of anemia management. Multiple observational studies have demonstrated associations between EPO hyporesponsiveness and increased morbidity and mortality in dialysis patients [10,11]. Moreover, high-dose ESA therapy has been linked to adverse cardiovascular outcomes, as evidenced by landmark trials, including the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study, the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), and the Normal Hematocrit Trial [12,13,14]. Specifically, EPO doses exceeding 6000 units per week have been associated with a 1.2- to 1.5-fold increased risk of mortality in hemodialysis patients [15].

The mechanisms underlying EPO hyporesponsiveness are complex and multifaceted. Current evidence suggests roles for absolute and functional iron deficiency, inflammation, secondary hyperparathyroidism, malnutrition, inadequate dialysis, and certain medications, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) [16,17,18]. However, the relative contributions of these factors, particularly in different patient populations, remain incompletely characterized. Furthermore, patient-specific determinants, such as age, sex, comorbidities, and dialysis vintage, may influence the response to ESA therapy through mechanisms that are not fully elucidated [19,20].

Despite the clinical importance of identifying and addressing factors contributing to EPO hyporesponsiveness, there remains a paucity of comprehensive studies examining multiple potential determinants simultaneously in diverse patient populations. Additionally, many existing studies have been conducted in North American, European, or East Asian populations, with limited data from Latin American patients who may exhibit distinct risk profiles due to genetic, socioeconomic, and healthcare system differences [21,22].

We hypothesize that multiple factors, including demographic characteristics, nutritional status, iron parameters, and comorbidities, independently contribute to EPO hyporesponsiveness in Latin American hemodialysis patients. The present study aims to address these knowledge gaps by identifying and quantifying the risk factors associated with EPO hyporesponsiveness in an Ecuadorian cohort of patients with CKD on maintenance hemodialysis who present with anemia. Through a multicenter case–control design, we investigate the relationships between EPO hyporesponsiveness and a comprehensive array of demographic, clinical, laboratory, and treatment-related parameters. The findings of this study may inform more tailored approaches to anemia management, facilitate early identification of patients at risk for hyporesponsiveness, and guide targeted interventions to optimize ESA therapy while minimizing potential risks associated with high-dose treatment.

2. Materials and Methods

2.1. Study Design and Inclusion Criteria

We conducted an observational, analytical, multicenter case–control study examining factors associated with erythropoietin (EPO) hyporesponsiveness in chronic kidney disease (CKD) patients on hemodialysis. The study protocol was approved by the Institutional Review Board (IRB) of all participating centers, and the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. As this was a retrospective study using anonymized medical records, the requirement for individual patient informed consent was waived by the IRB. Patient confidentiality and data protection were maintained throughout the study process in compliance with institutional and national regulations for handling patient information. Due to the retrospective nature of the analysis using anonymized data, the requirement for individual informed consent was waived. Figure 1 shows a methodological flowchart for a case–control study. The diagram begins with an initial population at the top, which is then divided into groups through a “selection criteria.” From there, it splits into two main branches: one for “case groups” and another for “control groups.” Both branches lead to their respective samples. In the center of the diagram, there is a section that appears to describe shared inclusion/exclusion criteria. The bottom portion displays the outcomes divided into categories, with four different types of results shown as endpoints of the study.

2.2. Selection Criteria and Definition of Cases and Controls

Eligible participants were adults (≥18 years) with stage 5 CKD on maintenance hemodialysis for at least 3 months prior to enrollment who were receiving EPO therapy.

Cases (n = 123) were defined as patients requiring ≥200 IU/kg/week of EPO alfa for a continuous period of ≥3 months to maintain hemoglobin levels between 10 and 12 g/dL, consistent with established definitions in the literature [23,24]. Controls (n = 661) were defined as patients responsive to lower doses of EPO while maintaining the same target hemoglobin levels of 10–12 g/dL. A control-to-case ratio of approximately 5:1 was employed to maximize statistical power while maintaining feasibility [25].

Exclusion criteria comprised (1) hospitalization within the preceding 3 months, as acute illness can transiently affect EPO responsiveness; (2) absence of EPO therapy; (3) active malignancy or hematological disorders; (4) recent blood transfusion (within 3 months); and (5) incomplete medical records precluding accurate assessment of key variables.

2.3. Data Collection and Variables

Data were extracted from anonymized electronic medical records and dialysis charts using a standardized collection form. The variables collected included the following:

• Demographic characteristics: Age, sex, dialysis vintage (months on hemodialysis);
• Anthropometric measurements: Height, weight, body mass index (BMI) calculated as weight (kg)/height (m)²;
• Comorbidities: Diabetes mellitus, hypertension, cardiovascular disease, hypothyroidism;
• Hemodialysis parameters: Dialysis adequacy (Kt/V calculated using single-pool Daugirdas second-generation formula), urea reduction ratio (URR), type of vascular access (arteriovenous fistula, graft, or catheter), frequency and duration of dialysis sessions;
• Medications: Use of renin–angiotensin system inhibitors (ACEIs or ARBs), iron supplementation, phosphate binders, and vitamin D analogs;
• Laboratory parameters: Hemoglobin, hematocrit, serum ferritin, transferrin saturation (TSAT), serum albumin, intact parathyroid hormone (iPTH), high-sensitivity C-reactive protein (hs-CRP), and serum calcium and phosphorus levels.

Laboratory tests were performed by the respective centers’ clinical laboratories, all of which adhere to standardized methods and quality control procedures in accordance with international guidelines. EPO dosing was normalized by patient weight and expressed as IU/kg/week to allow for meaningful comparisons across patients of different body sizes. Routes of EPO administration were recorded, with all patients receiving intravenous administration during hemodialysis sessions to ensure standardization of delivery methods.

2.4. Statistical Analysis

Sample size calculation determined that 123 cases and 615 controls would provide 80% power to detect an odds ratio of 1.8 for risk factors with a prevalence of 30% among controls, using a two-sided alpha of 0.05. Data analysis was performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA).

A Kolmogorov–Smirnov test was applied to assess the normality of distribution for continuous variables. Normally distributed continuous variables are presented as mean ± standard deviation, while non-normally distributed variables are presented as median with interquartile range (IQR: 25th–75th percentiles). Categorical variables are expressed as frequencies and percentages.

Bivariate analysis was performed to compare the characteristics of cases and controls. For continuous variables, a Student’s t-test was used for normally distributed data and a Mann–Whitney U test for non-normally distributed data. Categorical variables were compared using the Chi-square test or Fisher’s exact test as appropriate.

To identify independent risk factors for EPO hyporesponsiveness, we performed multivariate logistic regression analysis. Variables with p < 0.10 in the bivariate analyses were included in the initial model. Continuous variables were dichotomized based on clinically relevant thresholds from the literature or from the distribution observed in our study population [26]. These thresholds included age (<50 vs. ≥50 years), BMI (<23 vs. ≥23 kg/m²), albumin (<4.0 vs. ≥4.0 g/dL), ferritin (<800 vs. ≥800 ng/mL), transferrin saturation (<20% vs. ≥20%), and iPTH (<500 vs. ≥500 pg/mL).

The final model was built using a backward elimination approach (likelihood ratio test). Multicollinearity was assessed using variance inflation factors, with values > 5 considered indicative of significant collinearity. A Hosmer–Lemeshow test was used to evaluate goodness-of-fit of the final model. Results are presented as adjusted odds ratios (aOR) with 95% confidence intervals (CI). For all analyses, a two-sided p-value < 0.05 was considered statistically significant.

2.5. Sensitivity Analyses

To assess the robustness of our findings, we conducted several sensitivity analyses: (1) redefining EPO hyporesponsiveness using alternative thresholds (≥300 IU/kg/week and EPO resistance index ≥ 10 IU/kg/week/g/dL); (2) stratifying analyses by dialysis vintage (<12 months vs. ≥12 months); and (3) examining the associations separately in diabetic and non-diabetic patients to assess potential effect modification.

3. Results

3.1. Study Population Characteristics

Of the 784 hemodialysis patients who received EPO therapy during the study period, 123 (15.69%) exhibited hyporesponsiveness as defined by the requirement for ≥200 IU/kg/week of EPO for ≥3 consecutive months. The remaining 661 patients (84.31%) were classified as responders. The demographic and clinical characteristics of the study population are presented in

Table 1. General characteristics of the study population.

Characteristic	Total (n = 784)	Responders (n = 661)	Hyporesponders (n = 123)	p-Value
Female sex, n (%)	325 (41.5)	254 (38.4)	71 (57.7)	<0.001
Age (years), median (IQR)	61 (36–77.5)	63 (40–78)	50 (28–74)	<0.001
Time on hemodialysis (months), median (IQR)	28.5 (6–76)	28 (5–76)	29 (7–75)	0.385
Anthropometric measurements
Body mass index (kg/m2), median (IQR)	23.69 (19.43–29.48)	23.7 (19.46–29.69)	22.98 (19.03–27.73)	0.005
BMI classification, n (%)				0.038
Underweight (<18.5 kg/m2)	41 (5.2)	35 (5.3)	6 (4.9)
Normal (18.5–24.9 kg/m2)	468 (59.7)	383 (58.0)	85 (69.1)
Overweight (25.0–29.9 kg/m2)	209 (26.7)	182 (27.5)	27 (22.0)
Obese (≥30.0 kg/m2)	66 (8.4)	61 (9.2)	5 (4.1)
Erythropoietin treatment
EPO dose (IU/kg/week), median (IQR)	99.9 (44.6–236.6)	89.41 (42.3–150.62)	247.42 (215.7–343.94)	<0.001
Comorbidities, n (%)
Diabetes	256 (32.7)	226 (34.2)	30 (24.4)	0.033
Hypothyroidism	36 (4.6)	30 (4.5)	6 (4.9)	0.869
Medications, n (%)
RAS blockers	309 (39.4)	244 (36.9)	65 (52.8)	<0.001

Note: Data are presented as median (interquartile range) for non-normally distributed continuous variables and as number (percentage) for categorical variables. p-values were calculated using Mann–Whitney U test for continuous variables and Chi-square test for categorical variables. IQR = interquartile range; BMI = body mass index; EPO = erythropoietin; RAS = renin–angiotensin system.

. The study cohort comprised 459 males (58.5%) and 325 females (41.5%), with a median age of 61 years (interquartile range [IQR]: 36–77.5). Patients in the hyporesponder group were significantly younger than those in the responder group (median age 50 vs. 63 years, p < 0.001). Female sex was significantly more prevalent among hyporesponders compared to responders (57.7% vs. 38.4%, p < 0.001). The median body mass index (BMI) was significantly lower in hyporesponders compared to responders (22.98 vs. 23.7 kg/m², p = 0.005). When classified by BMI categories, hyporesponders had a higher proportion of patients with normal BMI (69.1% vs. 58.0%) and lower proportions of overweight (22.0% vs. 27.5%) and obese (4.1% vs. 9.2%) individuals compared to responders. The median time on hemodialysis was 28.5 months (IQR: 6–76) for the entire cohort, with no significant difference between hyporesponders and responders (29 vs. 28 months, p = 0.385). As expected by the study definition, the median EPO dose was substantially higher in the hyporesponder group compared to the responder group (247.42 vs. 89.41 IU/kg/week, p < 0.001). With respect to comorbidities, diabetes mellitus was significantly less prevalent among hyporesponders compared to responders (24.4% vs. 34.2%, p = 0.033), while the prevalence of hypothyroidism did not differ significantly between groups (4.9% vs. 4.5%, p = 0.869). The use of renin–angiotensin system blockers was significantly more common in hyporesponders than in responders (52.8% vs. 36.9%, p < 0.001).

3.2. Dialysis Parameters and Laboratory Findings

Table 2. Dialysis treatment characteristics and laboratory parameters of the study population.

Parameter	Total (n = 784)	Responders (n = 661)	Hyporesponders (n = 123)	p-Value
Dialysis parameters
Urea reduction rate (%), median (IQR)	70.08 (62.48–77.78)	70.11 (62.30–78.13)	70.00 (65.00–75.80)	0.716
Kt/V, median (IQR)	1.5 (1.21–1.81)	1.5 (1.2–1.82)	1.5 (1.29–1.71)	0.465
Catheter as vascular access, n (%)	85 (10.8)	70 (10.6)	15 (12.2)	0.648
Laboratory parameters
Albumin (g/dL), median (IQR)	4.28 (3.7–4.6)	4.32 (3.79–4.6)	3.96 (3.41–4.29)	<0.001
Hemoglobin (g/dL), median (IQR)	11.1 (9.6–12.5)	11.3 (10.0–12.6)	10.0 (8.4–11.0)	<0.001
Hematocrit (%), median (IQR)	32.7 (28.3–36.8)	33.3 (29.5–37.17)	29.5 (24.78–32.45)	<0.001
Ferritin (ng/mL), median (IQR)	804.38 (150.84–1825.59)	723.93 (118.45–1761.82)	1350.9 (538.68–2000)	<0.001
Transferrin saturation (%), median (IQR)	33.61 (19.77–47.54)	34.00 (22.00–47.37)	30.21 (11.48–50.40)	<0.001
Parathyroid hormone (pg/mL), median (IQR)	375.24 (135.3–1191.0)	356.48 (132.2–1081.44)	511.3 (146.5–2030.2)	<0.001
Calcium (mg/dL), median (IQR)	8.7 (8.1–9.4)	8.8 (8.2–9.5)	8.5 (7.9–9.2)	0.023
Phosphorus (mg/dL), median (IQR)	4.9 (3.7–6.2)	4.8 (3.6–6.0)	5.3 (4.1–6.5)	0.012
hs-CRP (mg/L), median (IQR)	3.7 (1.5–8.2)	3.2 (1.3–7.5)	5.8 (2.8–11.3)	<0.001

Note: Data are presented as median (interquartile range) for non-normally distributed continuous variables and as number (percentage) for categorical variables. p-values were calculated using Mann–Whitney U test for continuous variables and Chi-square test for categorical variables. IQR = interquartile range; Kt/V = dialysis adequacy index; hs-CRP = high-sensitivity C-reactive protein.

summarizes the dialysis treatment parameters and laboratory findings in the study population. The median urea reduction ratio (URR) was 70.08% (IQR: 62.48–77.78) for the entire cohort, with no significant difference between hyporesponders and responders (70.00% vs. 70.11%, p = 0.716). Similarly, the median Kt/V was 1.5 (IQR: 1.21–1.81) for the entire cohort, with no significant difference between groups (p = 0.465). The proportion of patients using a central venous catheter for vascular access was comparable between hyporesponders and responders (12.2% vs. 10.6%, p = 0.648).

Laboratory parameters showed several significant differences between groups. Hyporesponders had significantly lower median serum albumin levels compared to responders (3.96 vs. 4.32 g/dL, p < 0.001). As expected, hyporesponders exhibited lower median hemoglobin (10.0 vs. 11.3 g/dL, p < 0.001) and hematocrit values (29.5% vs. 33.3%, p < 0.001) than responders.

Iron status parameters differed significantly between groups. Hyporesponders demonstrated substantially higher median serum ferritin levels compared to responders (1350.9 vs. 723.93 ng/mL, p < 0.001), while having lower median transferrin saturation (30.21% vs. 34.00%, p < 0.001). Additionally, hyporesponders exhibited markedly higher median parathyroid hormone (PTH) levels compared to responders (511.3 vs. 356.48 pg/mL, p < 0.001).

In terms of calcium–phosphorus metabolism, hyporesponders showed lower serum calcium levels (8.5 vs. 8.8 mg/dL, p = 0.023) and higher phosphorus levels (5.3 vs. 4.8 mg/dL, p = 0.012) compared to responders. High-sensitivity C-reactive protein (hs-CRP) levels were significantly elevated in the hyporesponsive group (5.8 vs. 3.2 mg/L, p < 0.001), indicating a higher inflammatory burden.

3.3. Bivariate Analysis of Risk Factors for EPO Hyporesponsiveness

In the bivariate analysis, female sex was significantly associated with EPO hyporesponsiveness (OR = 2.19, 95% CI: 1.48–3.23, p < 0.001). Age less than 50 years conferred nearly a 4-fold increased risk of hyporesponsiveness compared to age ≥ 50 years (OR = 3.85, 95% CI: 2.56–5.78, p < 0.001). A BMI less than 23 kg/m² was significantly associated with hyporesponsiveness (OR = 1.60, 95% CI: 1.09–2.35, p = 0.017). Diabetes mellitus appeared to be inversely associated with hyporesponsiveness (OR = 0.62, 95% CI: 0.40–0.97, p = 0.033), suggesting a potential protective effect. The use of renin–angiotensin system blockers was significantly associated with increased risk of hyporesponsiveness (OR = 1.92, 95% CI: 1.30–2.82, p < 0.001). Among dialysis parameters, neither the URR (OR = 1.08, 95% CI: 0.49–2.37, p = 0.848) nor Kt/V (OR = 1.06, 95% CI: 0.50–2.24, p = 0.877) nor vascular access type (OR = 1.17, 95% CI: 0.65–2.11, p = 0.601) showed significant associations with EPO hyporesponsiveness. Laboratory parameters demonstrated strong associations with hyporesponsiveness. Serum albumin < 4.0 g/dL was associated with a more than fivefold increased risk (OR = 5.29, 95% CI: 3.52–7.93, p < 0.001). Ferritin ≥ 800 ng/mL conferred nearly a fivefold increased risk (OR = 4.78, 95% CI: 3.00–7.60, p < 0.001). Transferrin saturation < 20% was associated with a greater than sixfold increased risk (OR = 6.67, 95% CI: 4.22–10.53, p < 0.001). PTH levels ≥ 500 pg/mL conferred more than twice the risk of hyporesponsiveness (OR = 2.18, 95% CI: 1.48–3.22, p < 0.001). Elevated hs-CRP levels (>5 mg/L) were associated with increased risk (OR = 2.76, 95% CI: 1.85–4.12, p < 0.001).

3.4. Multivariate Analysis of Independent Risk Factors for EPO Hyporesponsiveness

Table 3. Multivariate logistic regression analysis of risk factors for erythropoietin hyporesponsiveness.

Variable	Adjusted OR	95% CI	p-Value
Female sex	1.96	1.20–3.20	0.007
Age < 50 years	4.25	2.42–7.47	<0.001
BMI < 23 kg/m2	1.02	0.58–1.78	0.963
Albumin < 4.0 g/dL	10.53	6.53–16.98	<0.001
Ferritin ≥ 800 ng/mL	7.28	4.22–12.57	<0.001
Transferrin saturation < 20%	9.27	5.47–15.69	<0.001
Parathyroid hormone ≥ 500 pg/mL	1.89	1.16–3.09	0.011
Diabetes	0.78	0.44–1.39	0.405
Use of RAS blockers	2.25	1.36–3.71	0.002

Note: The model’s Nagelkerke R² = 0.564, indicating that 56.4% of the variation in erythropoietin hyporesponsiveness is explained by the included variables. OR = odds ratio; CI = confidence interval; BMI = body mass index; RAS = renin–angiotensin system.

presents the results of the multivariate logistic regression analysis, which identified independent risk factors for EPO hyporesponsiveness after adjustment for potential confounders. The model demonstrated good predictive performance (Nagelkerke R² = 0.564, Hosmer–Lemeshow test p = 0.724), explaining approximately 56.4% of the variability in EPO hyporesponsiveness. Female sex remained an independent risk factor in the adjusted model (adjusted OR = 1.96, 95% CI: 1.20–3.20, p = 0.007). Age < 50 years was confirmed as a strong independent predictor (adjusted OR = 4.25, 95% CI: 2.42–7.47, p < 0.001). BMI <23 kg/m² and diabetes mellitus lost their statistical significance in the multivariate model (p = 0.963 and p = 0.405, respectively). Among laboratory parameters, serum albumin < 4.0 g/dL (adjusted OR = 10.53, 95% CI: 6.53–16.98, p < 0.001), ferritin ≥ 800 ng/mL (adjusted OR = 7.28, 95% CI: 4.22–12.57, p < 0.001), transferrin saturation < 20% (adjusted OR = 9.27, 95% CI: 5.47–15.69, p < 0.001), and PTH ≥ 500 pg/mL (adjusted OR = 1.89, 95% CI: 1.16–3.09, p = 0.011) were all confirmed as independent risk factors. The use of renin–angiotensin system blockers remained significantly associated with hyporesponsiveness in the multivariate model (adjusted OR = 2.25, 95% CI: 1.36–3.71, p = 0.002).

4. Discussion

In this multicenter case–control study, we investigated risk factors associated with erythropoietin (EPO) hyporesponsiveness in chronic kidney disease patients on hemodialysis who present with anemia. Our findings revealed a prevalence of hyporesponsiveness of 15.69%, consistent with previous literature. Luo et al. reported a prevalence of 12.5% [6], while Ingrasciotta et al. documented a higher frequency of 30.3% [7], suggesting that the prevalence may vary, depending on the definition criteria and study population characteristics.

4.1. Demographic Risk Factors

Female sex emerged as an independent risk factor for EPO hyporesponsiveness in our study (adjusted OR = 1.96; 95% CI: 1.20–3.20). This finding is biologically plausible and might be attributed to several mechanisms. The erythropoietic-enhancing effect of testosterone in males likely contributes to better responsiveness [8]. Additionally, we observed that female patients in our cohort were generally younger and potentially experiencing menstrual iron loss, which may exacerbate iron deficiency, a known contributor to EPO hyporesponsiveness.

Interestingly, younger age (<50 years) was strongly associated with hyporesponsiveness (adjusted OR = 4.25; 95% CI: 2.42–7.47), a finding that corroborates the observations by Cizman et al. [16]. This counterintuitive association warrants further investigation, as it contradicts the general understanding that older patients tend to have more comorbidities and inflammation, which could potentially impair EPO responsiveness. The underlying mechanisms for this age-related difference remain to be elucidated and may involve complex interactions between age-related changes in hematopoietic stem cell function, inflammatory profiles, and hormonal factors that differ between Latin American populations and other studied cohorts.

4.2. Nutritional and Metabolic Parameters

Our study identified nutritional parameters strongly associated with EPO hyporesponsiveness. Low albumin levels (<4.0 g/dL) demonstrated the strongest association in our multivariate model (adjusted OR = 10.53; 95% CI: 6.53–16.98). This finding aligns with the criteria established by the International Society of Renal Nutrition and Metabolism (ISRNM) for protein-energy wasting in CKD patients [11]. Hypoalbuminemia may reflect chronic inflammation, malnutrition, or protein loss—all conditions that can impair erythropoiesis and EPO responsiveness.

Similarly, BMI < 23 kg/m² was associated with hyporesponsiveness in the bivariate analysis (OR = 1.60; 95% CI: 1.09–2.35), although this association did not persist in the multivariate model (p = 0.963). This finding partially contrasts with Locatelli et al. [9], who demonstrated a positive association between higher BMI and better EPO response. The “obesity paradox” in dialysis patients suggests that higher BMI may confer a survival advantage [10], potentially through mechanisms that also improve EPO responsiveness, such as increased adipose-tissue-derived leptin, which stimulates erythroid development in vitro [12].

4.3. Iron Metabolism Parameters

Disturbances in iron metabolism significantly contributed to EPO hyporesponsiveness in our cohort. Elevated ferritin levels (≥800 ng/mL) were strongly associated with hyporesponsiveness (adjusted OR = 7.28; 95% CI: 4.22–12.57), consistent with findings by Gillespie et al. [13]. High ferritin in this context likely represents a state of functional iron deficiency and inflammation rather than iron overload. Proinflammatory cytokines, including TNF-α, IL-1, IL-6, and IL-10, induce ferritin expression and promote iron sequestration within macrophages, thereby limiting iron availability for erythropoiesis [15].

Concurrently, low transferrin saturation (<20%) was a significant predictor of hyporesponsiveness (adjusted OR = 9.27; 95% CI: 5.47–15.69), supporting previous findings by Cizman et al. [16]. This parameter reflects inadequate iron availability for erythropoiesis, which may result from either absolute iron deficiency or functional iron deficiency mediated by inflammation-induced hepcidin upregulation [2,17]. The simultaneous presence of high ferritin and low transferrin saturation in our hyporesponsive cohort strongly suggests functional iron deficiency as a predominant mechanism.

An important finding in our study was the significantly higher levels of hs-CRP in the hyporesponsive group, which further supports the role of inflammation in mediating EPO hyporesponsiveness. This is consistent with the evidence that inflammatory cytokines can directly suppress erythropoiesis through multiple mechanisms, including induction of hepcidin expression, inhibition of erythroid progenitor cell proliferation, and enhancement of erythrophagocytosis [14].

4.4. Secondary Hyperparathyroidism

Elevated parathyroid hormone levels (≥500 pg/mL) were independently associated with EPO hyporesponsiveness (adjusted OR = 1.89; 95% CI: 1.16–3.09). This finding is consistent with the known inhibitory effects of excess parathyroid hormone on erythropoiesis through multiple mechanisms: direct inhibition of erythroid progenitor cells, induction of bone marrow fibrosis with subsequent reduction in erythropoietic tissue, and inhibition of endogenous EPO synthesis [20]. Our results confirm the clinical relevance of managing secondary hyperparathyroidism as part of a comprehensive approach to anemia treatment in hemodialysis patients.

4.5. Medication Effects

The use of renin–angiotensin system (RAS) blockers was significantly associated with EPO hyporesponsiveness (adjusted OR = 2.25; 95% CI: 1.36–3.71). This finding aligns with established pathophysiological mechanisms, whereby these medications inhibit angiotensin II-induced EPO release and increase plasma levels of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which impairs hematopoietic stem cell recruitment [18]. Our data provide robust epidemiological support for this association in a large cohort of hemodialysis patients, suggesting that the choice of antihypertensive therapy should be carefully considered in patients with poor EPO response.

4.6. Dialysis Adequacy Parameters

In contrast to some previous studies, we found no significant association between dialysis adequacy parameters (urea reduction rate, Kt/V) and EPO responsiveness. This finding is consistent with results reported by Santos et al. [21], who similarly found no difference in mean Kt/V between responder and hyporesponder groups (1.5 ± 0.1 versus 1.5 ± 0.3; p = 0.495). This suggests that once a minimum threshold of dialysis adequacy is achieved, further improvements may not significantly impact EPO responsiveness, and other factors become more determinant.

4.7. Diabetes as a Potential Protective Factor

Our study revealed an unexpected inverse association between diabetes and EPO hyporesponsiveness in the bivariate analysis (OR = 0.62; 95% CI: 0.40–0.97), though this association did not remain statistically significant in the multivariate model (p = 0.405). This finding is consistent with observations by Nafar et al. [2], who reported a higher likelihood of achieving target hemoglobin levels among diabetic patients. While counterintuitive, given that diabetes is generally associated with more severe anemia in CKD patients [22,23], this phenomenon might be explained by several mechanisms.

Diabetic patients on dialysis often have higher BMI values and potentially increased adipose-tissue-derived leptin, which can stimulate erythropoiesis [12,24]. Additionally, diabetic nephropathy may affect specific nephron segments differently than other causes of CKD, potentially preserving some EPO-producing interstitial fibroblasts. Furthermore, differences in treatment patterns for diabetic versus non-diabetic patients might influence EPO responsiveness. This finding warrants further investigation with larger sample sizes and specific mechanistic studies.

4.8. Comparison with Other Populations

Our study provides important insights into the determinants of EPO hyporesponsiveness in a Latin American population, which has been underrepresented in previous research. When comparing our findings with studies from North American, European, and Asian populations, we observed both similarities and differences. The association of hypoalbuminemia, functional iron deficiency, and secondary hyperparathyroidism with EPO hyporesponsiveness appears consistent across diverse populations [16,17,21].

However, the strong association between younger age and hyporesponsiveness observed in our cohort contrasts with findings from several other regions. This discrepancy may reflect differences in the underlying etiology of CKD, nutritional status, genetic factors influencing iron metabolism, or healthcare system factors affecting patient selection for dialysis and anemia management. The slightly lower prevalence of diabetes in our hyporesponsive group compared to studies from developed countries may also reflect population-specific differences in CKD etiology and progression.

These observations highlight the importance of conducting region-specific studies to identify population-specific risk factors and optimize anemia management strategies accordingly. The findings may help develop more tailored guidelines for EPO dosing and adjunctive therapies in Latin American patients with CKD.

4.9. Strengths and Limitations

Our study has several strengths, including its multicenter design, relatively large sample size, and comprehensive assessment of potential risk factors. The inclusion of multiple inflammatory and nutritional markers allowed for a more nuanced analysis of the complex interplay between these factors in mediating EPO hyporesponsiveness. The use of standardized definitions and statistical methods also enhances the validity and generalizability of our findings.

However, some limitations should be acknowledged. First, the retrospective case–control design precludes definitive causal inferences. Second, although we adjusted for multiple confounders, residual confounding cannot be ruled out. Third, laboratory tests were performed at different centers, potentially introducing inter-laboratory variability despite standardization efforts.

Fourth, we did not systematically collect data on doses and routes of intravenous iron supplementation, active vitamin D analogs, or calcimimetics, which may influence ferritin, transferrin saturation, and PTH levels, respectively. This could potentially introduce residual confounding in our analyses. Additionally, our dichotomization of continuous variables, although based on clinically relevant thresholds, may have resulted in some loss of information.

Fifth, our study focused solely on intravenous EPO administration and did not explore potential differences in responsiveness between various routes of administration or different ESA types. Finally, we did not have data on genetic polymorphisms that might influence EPO responsiveness, which represents an important area for future research.

5. Conclusions

In conclusion, our study identified several independent risk factors for EPO hyporesponsiveness in hemodialysis patients with anemia. Female sex, younger age, hypoalbuminemia, iron metabolism disturbances (high ferritin with low transferrin saturation), secondary hyperparathyroidism, and use of RAS blockers were all significantly associated with poor response to EPO treatment. These findings have important clinical implications for individualizing anemia management in hemodialysis patients.

Early identification of patients at risk for EPO hyporesponsiveness may guide preemptive interventions, such as optimizing nutritional status, correcting iron deficiency with appropriate iron supplementation strategies, managing secondary hyperparathyroidism, and judicious use of RAS blockers. Interestingly, the potential protective effect of diabetes on EPO responsiveness in hemodialysis patients warrants further investigation to elucidate underlying mechanisms.

Our findings in a Latin American population both confirm certain universal risk factors for EPO hyporesponsiveness and highlight potential population-specific differences, particularly regarding the association with younger age. These observations underscore the importance of considering regional and population-specific factors when developing guidelines for anemia management in CKD patients.

Future prospective studies incorporating comprehensive inflammatory marker panels, genetic determinants of EPO responsiveness, and interventional approaches targeting specific risk factors would further enhance our understanding of this clinically challenging condition and improve outcomes for patients with CKD-associated anemia on hemodialysis.