Effect of Lactoferrin on Hemoglobin, Erythroferrone, and Hepcidin Levels in Chronic Kidney Disease Patients With Anemia: A Post-hoc Analysis

Anemia affects nearly 60% of patients with stage 4-5 chronic kidney disease (CKD) in India.^1-3 Functional iron deficiency, driven by elevated hepcidin and inflammation-associated suppression of erythropoiesis, is a major contributor to anemia. Hepcidin regulates systemic iron by degrading ferroportin, whereas erythroferrone, produced by erythroblasts, counteracts hepcidin to promote iron availability during active erythropoiesis.⁴ Chronic inflammation and reduced renal clearance increase hepcidin levels, limiting intestinal iron absorption and iron release from stores.⁵ Our team published a pilot study to evaluate the effectiveness of lactoferrin, an iron-binding glycoprotein with anti-inflammatory properties, in improving anemia in patients with CKD.⁶ We found a modest benefit of add-on lactoferrin. This post hoc analysis in the stored samples evaluates whether this small beneficial effect of lactoferrin is associated with any changes in the iron metabolism parameters, hepcidin, and erythroferrone.

Of the 46 patients reported in the published pilot, stored samples and complete data of 40 patients with stage 5 CKD with anemia were considered for this post hoc analysis. The mean age was 42.1±13.7 years, and 65% were male. All participants were on maintenance hemodialysis and stable ESA therapy (mean dose 141.2 ± 18.7 IU/kg/week) throughout the study duration. Diabetic kidney disease (35%) and hypertensive nephropathy (30%) were the leading CKD etiologies. Twelve were on stable iron supplementation for 3 months before and throughout the study and were iron-replete. Changes in parameters from baseline to follow-up have been presented in Table 1. Inflammatory markers were high (ESR 47.3±22.1 mm/h; CRP 9.4±6.5 mg/L) in these patients. Hemoglobin (Hb) improved from 8.20±1.23, 95% CI (7.8, 8.6) to 8.93±2.01 g/dL, 95% CI (8.3, 9.5) (p = 0.0049), reflecting a favorable hematinic response. Erythroferrone levels declined markedly from 6.21±3.91, 95% CI (4.3, 8.1) to 4.08±2.33 ng/mL, 95% CI (2.7, 5.5) (p = 0.0041). By contrast, hepcidin showed no significant change.

Lactoferrin may have a beneficial role in managing anemia in both CKD and non-CKD populations. Its anti-inflammatory effects have been noted in small trials and observational studies, including our own, which demonstrated a significant Hb increase from 8.18 g/dL to 8.96 g/dL at 4 weeks, although changes in inflammatory markers were inconsistent.^6,S1,S2 Consistent with earlier findings, we observed significant improvement in Hb and iron parameters despite no change in hepcidin levels. Significant decline in erythroferrone alongside improvement in Hb appears counterintuitive. However, decreased erythroferrone reflects reduced erythropoietic stress following Hb improvement, rather than impaired iron signaling, especially since ESA doses remained unchanged. Additionally, lactoferrin may enhance iron availability independently of the erythroferrone-hepcidin axis, reducing the need for elevated erythroferrone.

Unlike the reported effects of lactoferrin in patients with iron deficiency with normal renal function and in pregnant women with anemia, the hemopoietic and anti-inflammatory effects of lactoferrin seem to be variable in CKD. Our findings suggest that lactoferrin primarily enhances iron absorption and mobilization rather than modulating the hepcidin and inflammation, as evidenced by stable hepcidin levels and reduced erythroferrone. The latter indicates diminished erythropoietic stress or correction of anemia by lactoferrin. Additionally, CRP did not change significantly. ESR improved significantly, but it may be attributable to improvement in Hb alone. The absence of change in hepcidin and CRP levels in patients may reflect the heightened inflammatory burden associated with advanced anemia, dialysis procedure per se, and catheter-related inflammation.^S3 Our analysis may have underestimated the effect on inflammation due to the small sample size and short follow-up. Previous pediatric CKD studies have also suggested reduced efficacy with increasing disease severity, raising the possibility that longer treatment duration or higher doses may be necessary to influence inflammatory pathways in adults.^S4 No formal sample size was calculated for this pilot study. The lack of a concurrent control group limits the findings to observational and hypothesis-generating rather than confirmatory conclusions. Trials with longer follow-up and clinical endpoints will yield more definitive evidence.

To conclude, this post-hoc analysis examined the effects of oral lactoferrin on erythropoiesis and iron regulation in CKD-associated anemia and demonstrated a significant 4-week increase in Hb, with concurrent improvement in iron indices and a reduction in erythroferrone. Effects on inflammatory biomarkers and hepcidin were inconclusive. These findings suggest a potential role for lactoferrin in modulating erythropoietic pathways and support further evaluation in larger controlled studies.