Randomized Controlled Trial Comparing Lactoferrin+Iron with Iron Alone for Iron Deficiency Anemia in CKD

KEY POINTS: Lactoferrin+iron significantly improved hemoglobin and iron indices versus iron alone in CKD patients with iron deficiency anemia. Lactoferrin reduced hepcidin and inflammatory markers, suggesting improved iron utilization using anti‐inflammatory mechanisms. Three patients with iron deficiency anemia had elevated inflammatory markers, higher among patients with CKD on dialysis than those not on dialysis. BACKGROUND: Lactoferrin, a multifunctional iron‐binding glycoprotein with anti‐inflammatory properties, is reported to be effective in anemia in pregnant women and patients with malignancy but has not been tested elaborately in CKD. METHODS: In this randomized, open‐label trial, 185 patients (intention‐to‐treat) with iron‐deficiency anemia (hemoglobin [Hb] <10 g/dl, transferrin saturation <20%) were enrolled: 90 with patients with CKD not on dialysis (CKD‐ND) and 95 with dialysis‐dependent CKD (patients with CKD on dialysis [CKD‐5D]). Patients were randomized to receive either oral iron (30 mg/d liposomal iron) or oral iron+lactoferrin (100 mg twice daily) for 3 months. The primary outcome was change in Hb. Secondary outcomes included iron indices and inflammatory markers (C‐reactive protein, IL‐6, erythrocyte sedimentation rate, and hepcidin). RESULTS: In the intention‐to‐treat analysis, lactoferrin+iron resulted in significantly greater improvements in Hb and iron parameters than iron alone in both patients with CKD‐ND and those with CKD‐5D. Mean Hb increased by 1.95±1.19 versus 1.33±0.86 g/dl in patients with CKD‐ND and by 1.73±0.96 versus 1.11±0.93 g/dl in patients with CKD‐5D receiving lactoferrin+iron and iron alone, respectively. Improvements in iron indices were also greater with add‐on lactoferrin treatment. Mean difference in hepcidin levels were ‐20.24±15.99 versus ‐16.03±40.65 ng/dl in patients with CKD‐ND and ‐15.29±8.73 versus ‐20.99±20.16 ng/dl in patients with CKD‐5D treated with lactoferrin+iron and iron alone, respectively. CONCLUSIONS: Among patients with CKD‐associated anemia, adjunctive lactoferrin therapy improved Hb and iron parameters compared with oral iron alone in both non‐dialysis‐dependent and dialysis‐dependent patients. Lactoferrin was also associated with modest improvements in inflammatory status, although effects on individual inflammatory markers were inconsistent. These findings suggest that lactoferrin may be a useful adjunct to oral iron therapy for the management of anemia in CKD, especially in resource‐limited settings. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Clinical Trials Registry of India, CTRI/2020/04/024746.