Due to renal failure, hemodialysis patients experience reduced synthesis of erythropoietin (EPO), iron loss (e.g., blood loss during dialysis, occult gastrointestinal bleeding), and iron utilization disorders. The incidence of anemia in this population exceeds 90%, seriously impairing quality of life and survival rate. As an important type of oral iron supplement, ferrous gluconate is characterized by relatively low gastrointestinal irritation and stable bioavailability, playing a crucial role in iron replacement therapy for anemia in hemodialysis patients. Its application requires comprehensive evaluation based on patients’ iron metabolism indicators, tolerance, and combined treatment regimens. Standardized use can effectively correct iron deficiency, enhance the therapeutic response to EPO, and alleviate anemia symptoms. This article systematically analyzes the key application points of ferrous gluconate in anemia management for hemodialysis patients from aspects including mechanism of action, applicable scenarios, administration protocols, and precautions.
I. Core Mechanisms for Anemia Management in Hemodialysis Patients
The core pathological link of anemia in hemodialysis patients lies in the synergistic effect of "iron deficiency" and "EPO insufficiency" — iron is a key raw material for hemoglobin synthesis, while EPO is the core hormone promoting erythropoiesis. By supplementing absorbable iron, ferrous gluconate provides the material basis for hemoglobin synthesis, improves iron stores, and enhances the therapeutic effect of EPO. The specific mechanisms are as follows:
1. Supplementing Absorbable Iron to Directly Support Hemoglobin Synthesis
After entering the human body, ferrous gluconate dissociates into divalent iron ions (Fe²⁺) in the gastrointestinal tract. These ions are absorbed into the bloodstream via the "divalent metal transporter 1 (DMT1)" in small intestinal mucosal cells, then bind to transferrin and are transported to bone marrow hematopoietic stem cells. Within the stem cells, Fe²⁺ participates in hemoglobin synthesis: it combines with protoporphyrin IX to form heme, and 4 heme molecules assemble with 1 globin chain to form hemoglobin. This ultimately promotes red blood cell maturation, increases hemoglobin (Hb) levels (e.g., from 80 g/L to the target range of 110–120 g/L), and alleviates anemia.
2. Improving Iron Stores to Correct Functional Iron Deficiency
Hemodialysis patients often suffer from "absolute iron deficiency" (iron storage indicators such as serum ferritin < 200 ng/mL) or "functional iron deficiency" (normal iron stores but ineffective utilization, e.g., transferrin saturation (TSAT) < 20%). Ferrous gluconate can continuously supplement iron to increase iron stores in tissues such as the liver and bone marrow (elevating serum ferritin) and improve transferrin saturation (increasing TSAT). This ensures that iron can be effectively taken up and utilized by the bone marrow, avoiding "EPO resistance" (i.e., increased EPO dosage without significant Hb elevation) caused by "insufficient iron raw materials" during EPO therapy.
3. Mitigating the Impact of Iron-Related Inflammation
Hemodialysis patients are often accompanied by chronic inflammation (e.g., hemodialysis membrane bioincompatibility, infection), which increases hepcidin levels. Hepcidin inhibits intestinal iron absorption and macrophage iron release, exacerbating iron deficiency. Although ferrous gluconate does not directly reduce hepcidin, its continuous iron supplementation can partially offset hepcidin’s inhibitory effect on iron utilization, maintaining iron supply for hematopoiesis. It is particularly suitable for patients with mild inflammatory status (C-reactive protein (CRP) < 10 mg/L).
II. Applicable Scenarios and Administration Protocols
The application of ferrous gluconate in anemia management for hemodialysis patients must strictly follow the principle of "individualized assessment and stratified use." Applicable scenarios and protocols are determined based on patients’ iron metabolism indicators, anemia severity, and tolerance to avoid iron overload or insufficient treatment due to blind supplementation.
(I) Applicable Scenarios
Mild to Moderate Iron-Deficiency Anemia: Suitable for patients with serum ferritin of 200–500 ng/mL, TSAT of 15%–20%, and Hb of 90–110 g/L. As a first-line oral iron supplement, it can be used alone or in combination with low-dose EPO therapy (e.g., EPO 50–100 IU/kg per week).
Intolerance or Contraindication to Intravenous Iron: For patients with allergic reactions (e.g., rash, dyspnea) to intravenous iron (e.g., iron sucrose, iron dextran) or contraindications such as severe renal insufficiency (eGFR < 15 mL/min/1.73 m²) or severe infection (CRP > 20 mg/L), ferrous gluconate can be used as an alternative.
Maintenance-Phase Iron Supplementation: After severe iron deficiency is corrected with intravenous iron (e.g., serum ferritin > 500 ng/mL, TSAT > 25%), patients enter the anemia maintenance phase (target Hb: 110–120 g/L). Ferrous gluconate can be used to maintain iron stores, avoiding iron overload risks (e.g., hepatic iron deposition) caused by long-term intravenous iron use.
(II) Administration Protocols
1. Dose Determination
The dose of ferrous gluconate is calculated based on the content of "elemental iron." The routine recommended dose for hemodialysis patients is 100–200 mg of elemental iron per day, administered orally in 2–3 divided doses (e.g., each tablet containing 0.3 g ferrous gluconate, corresponding to 35 mg elemental iron; 2–3 tablets per dose, 3 times daily). The specific dose should be adjusted according to iron metabolism indicators:
If serum ferritin increases by < 100 ng/mL and TSAT increases by < 5% after 4 weeks of treatment, and the patient has no significant gastrointestinal discomfort, the dose can be increased to 200–300 mg of elemental iron per day.
If serum ferritin > 800 ng/mL or TSAT > 50%, administration must be stopped immediately to avoid iron overload (which increases the risk of infection and cardiovascular events).
2. Administration Method
To improve bioavailability, attention should be paid to administration time and dietary matching:
Administration Time: Take on an empty stomach (e.g., 1 hour before meals or 2 hours after meals), as calcium and phytates in food inhibit iron absorption. For patients with poor gastrointestinal tolerance (e.g., abdominal distension, diarrhea), administration can be adjusted to after meals — although bioavailability decreases by approximately 30%, gastrointestinal irritation is reduced.
Avoid Concurrent Use with Absorption Interferents: Do not take with calcium-containing preparations (e.g., calcium carbonate), phosphate binders (e.g., sevelamer), or tannic acid-rich foods (e.g., strong tea, coffee) (an interval of ≥ 2 hours is required). These substances form insoluble complexes with Fe²⁺, reducing absorption. Ferrous gluconate can be taken with vitamin C (200–500 mg per day), which reduces Fe³⁺ to Fe²⁺ and doubles bioavailability.
3. Treatment Course and Monitoring
The treatment course is determined by the anemia correction target and changes in iron stores, usually divided into "treatment phase" and "maintenance phase":
Treatment Phase: Lasts 8–12 weeks. Monitor serum ferritin, TSAT, and Hb every 4 weeks until Hb reaches 110–120 g/L, serum ferritin reaches 200–500 ng/mL, and TSAT reaches 20%–30%.
Maintenance Phase: After reaching the target, adjust the dose to 50–100 mg of elemental iron per day. Monitor iron metabolism indicators every 8–12 weeks to maintain them within the target range and prevent recurrence of iron deficiency after discontinuation.
III. Tolerance Management and Adverse Reaction Management
Due to weak gastrointestinal mucosal function (e.g., stimulation by uremic toxins, slowed gastrointestinal peristalsis), hemodialysis patients are prone to gastrointestinal adverse reactions from oral iron supplements, which affects treatment compliance. Although ferrous gluconate is less irritating than ferrous sulfate, reasonable measures are still needed to manage tolerance and address adverse reactions promptly.
(I) Common Adverse Reactions and Management
1. Gastrointestinal Reactions (Most Common)
Manifestations include nausea, abdominal distension, abdominal pain, diarrhea, or constipation, mostly occurring in the early treatment stage (first 2 weeks). Management measures include:
Dose Adjustment: Start with a low dose (e.g., 50–100 mg elemental iron per day) and gradually increase to the target dose to allow the gastrointestinal tract to adapt.
Administration Time Adjustment: Take after meals or with a small amount of food (avoid high-calcium, high-tannic acid foods).
Symptomatic Treatment: For constipated patients, use osmotic laxatives such as lactulose or polyethylene glycol (avoid stimulant laxatives such as senna). For patients with diarrhea, take smectite powder to protect the intestinal mucosa. If symptoms are severe, switch to other oral iron supplements (e.g., iron polysaccharide complex) or evaluate the possibility of using intravenous iron.
2. Tooth Staining
Long-term use of liquid ferrous gluconate (e.g., in children or patients with swallowing difficulties) may cause teeth discoloration. This can be avoided by taking the medication with a straw and rinsing the mouth with water after administration. The staining can be removed by dental cleaning and poses no health risks.
3. Allergic Reactions (Rare)
Manifestations include rash and pruritus; severe cases may present with urticaria. Discontinue the medication immediately, and administer oral antihistamines (e.g., loratadine) to relieve symptoms. For subsequent use of intravenous iron, strict allergy testing is required.
(II) Tolerance Optimization for Special Populations
Elderly Patients (> 65 Years Old): With weaker gastrointestinal function, the recommended initial dose is 50 mg elemental iron per day, increasing by 50 mg every 2 weeks. Strengthen constipation monitoring and use mild laxatives preventively.
Patients with Diabetes: Some patients may experience slight blood glucose elevation after taking iron supplements (iron affects insulin sensitivity). Strengthen blood glucose monitoring and adjust hypoglycemic regimens to avoid significant blood glucose fluctuations.
Patients with Concurrent Gastrointestinal Diseases (e.g., Gastritis, Peptic Ulcer): Use under doctor guidance, preferentially taking after meals. Avoid concurrent use with gastric mucosal protectants (e.g., hydrotalcite) (interval ≥ 2 hours); if necessary, combine with acid suppressants (e.g., omeprazole) to reduce gastric mucosal irritation.
IV. Precautions for Combined Use with Other Treatments
Anemia management in hemodialysis patients often requires combination with drugs such as EPO, vitamin B₁₂, and folic acid. When ferrous gluconate is used in combination with these drugs, attention should be paid to interactions to ensure therapeutic synergy and avoid efficacy interference.
1. Combination with Erythropoietin (EPO)
Synergistic Mechanism: EPO requires a large amount of iron raw materials to promote erythropoiesis. In case of iron deficiency, EPO cannot exert its effect (i.e., "EPO resistance"). Ferrous gluconate supplementation enhances EPO sensitivity, reduces EPO dosage (usually by 20%–30%), and lowers the risks of EPO-related hypertension and thrombosis.
Precautions: Monitor Hb weekly in the early stage of combination to avoid excessive Hb increase (no more than 20 g/L per week), which may cause a sharp rise in blood pressure. If Hb does not increase despite increased EPO dosage, prioritize evaluating iron stores (to rule out EPO resistance caused by iron deficiency) rather than continuing to increase EPO dosage.
2. Combination with Vitamin B₁₂ and Folic Acid
Synergistic Mechanism: Vitamin B₁₂ and folic acid are key coenzymes for red blood cell maturation. Deficiency leads to "megaloblastic anemia." When combined with iron-deficiency anemia (common in hemodialysis patients due to malnutrition), simultaneous supplementation is required; otherwise, iron supplementation alone cannot effectively correct anemia.
Precautions: Vitamin B₁₂ and folic acid do not affect iron absorption and can be taken with ferrous gluconate. It is recommended to monitor serum vitamin B₁₂ and folic acid levels every 3 months. If deficient, supplement promptly (1000 μg oral vitamin B₁₂ per day, 5 mg oral folic acid per day).
3. Combination with Dialysis-Related Drugs
Phosphate Binders (e.g., Sevelamer, Calcium Carbonate): Inhibit iron absorption; take with an interval of ≥ 2 hours from ferrous gluconate.
Antihypertensive Drugs (e.g., ACEI/ARB Class): Some patients may experience slight blood pressure reduction after taking iron supplements. Monitor blood pressure to avoid hypotension; adjust antihypertensive drug dosage if necessary.
Antibiotics (e.g., Tetracyclines, Quinolones): Fe²⁺ forms chelates with antibiotics, reducing antibiotic efficacy; take with an interval of ≥ 3 hours.
As an important oral iron supplement for anemia management in hemodialysis patients, ferrous gluconate provides raw materials for hemoglobin synthesis by supplementing iron, improves iron stores, and enhances EPO therapeutic response. It is particularly suitable for patients with mild to moderate iron deficiency, intolerance to intravenous iron, or those in the maintenance phase of iron supplementation. Its application must follow the principle of "individualized dosage, standardized administration, and regular monitoring." Bioavailability can be improved by taking on an empty stomach and combining with vitamin C, while gastrointestinal adverse reactions should be managed and concurrent use with absorption-interfering drugs/foods avoided. When combined with EPO, vitamin B₁₂, or folic acid, attention should be paid to synergistic effects and interactions to ensure anemia correction and reduce complication risks. In clinical practice, protocols should be dynamically adjusted based on patients’ iron metabolism indicators, tolerance, and treatment goals to balance efficacy and safety, ultimately improving the anemia status and quality of life of hemodialysis patients.
