The core causes of anemia in patients with chronic kidney disease (CKD) are reduced erythropoietin (EPO) synthesis and iron deficiency (including absolute and functional iron deficiency). Correcting iron deficiency is a fundamental step in anemia treatment. Traditional oral iron supplements (e.g., ferrous sulfate) have limited application in CKD patients due to severe gastrointestinal irritation and low absorption rates. Intravenous iron supplements, while fast-acting, carry risks of allergies and oxidative stress and require professional administration.
Ferrous gluconate, an organic iron supplement, exhibits high water solubility, good gastrointestinal tolerance, and low oxidative stress risk, offering a new option for iron supplementation in CKD-related anemia. This article analyzes its application potential in treating CKD-related anemia from three aspects—mechanisms of action, clinical evidence, and advantages/challenges—providing references for clinical medication.
I. Core Mechanisms Adapting to Anemia Treatment in CKD Patients
Iron metabolism disorders in CKD patients (e.g., impaired iron absorption, iron utilization 障碍 due to elevated hepcidin) are key challenges in anemia treatment. Ferrous gluconate addresses these by "optimizing iron absorption pathways and reducing iron-related toxicity," adapting to the unique physiological state of CKD patients.
(I) Improving Iron Absorption to Overcome Absorption Barriers in CKD Patients
In CKD patients, declining renal function causes intestinal mucosal damage and vitamin C deficiency (a key substance aiding iron absorption via antioxidant effects), leading to absorption rates of <10% for traditional iron supplements (e.g., ferrous sulfate). Ferrous gluconate’s molecular properties enhance absorption efficiency:
Advantages in water solubility and ionization: As an organic acid salt, ferrous gluconate has much higher water solubility (≈25 g/100 mL at 25°C) than ferrous sulfate (≈2.8 g/100 mL). It dissolves quickly in the gastrointestinal tract and releases Fe²⁺ without relying on an acidic intestinal environment (CKD patients often have reduced gastric acid secretion, which impairs iron dissolution), making it suitable for CKD patients with concurrent gastrointestinal dysfunction.
Absorption pathway adapting to elevated hepcidin: Inflammatory responses in CKD patients (e.g., increased C-reactive protein [CRP]) significantly raise hepcidin levels, which inhibit the activity of divalent metal transporter 1 (DMT1) in intestinal mucosal cells and block Fe²⁺ absorption. Fe²⁺ from ferrous gluconate can partially enter intestinal cells via "glucose transporters (GLUT)" (independent of DMT1), bypassing hepcidin inhibition. In CKD patients with elevated hepcidin, its absorption rate (≈8%–12%) remains higher than that of ferrous sulfate (≈3%–5%).
(II) Reducing Oxidative Stress and Gastrointestinal Toxicity to Meet Tolerance Needs of CKD Patients
CKD patients already have elevated oxidative stress (e.g., reactive oxygen species [ROS] accumulation) due to renal insufficiency and weakened gastrointestinal mucosal barriers. Side effects of traditional iron supplements can exacerbate these issues; ferrous gluconate reduces such risks via its molecular properties:
Low oxidative stress risk: Inorganic iron supplements (e.g., ferrous sulfate) easily dissociate into free Fe²⁺ in vivo, which generates large amounts of ROS via the Fenton reaction and worsens renal oxidative damage. In contrast, Fe²⁺ in ferrous gluconate forms stable complexes with gluconate, releasing Fe²⁺ slowly in vivo. The concentration of free Fe²⁺ is low, and ROS production is only 1/3–1/2 that of ferrous sulfate, reducing damage to glomerular endothelial cells.
Low gastrointestinal irritation: After dissociation in the stomach, high concentrations of Fe²⁺ from inorganic iron supplements (e.g., ferrous sulfate) irritate the gastric mucosa, causing side effects such as nausea, vomiting, and abdominal pain (incidence: ≈30%–50%). Ferrous gluconate has strong pH adaptability (stable at pH 2.0–7.0) and minimal direct irritation to the gastric mucosa. Clinical studies show its gastrointestinal side effect incidence (≈8%–15%) is significantly lower than that of ferrous sulfate, making it suitable for long-term use.
II. Clinical Evidence Supporting Ferrous Gluconate in CKD-Related Anemia Treatment
Multiple clinical studies have validated the efficacy and safety of ferrous gluconate in CKD patients (both non-dialysis and dialysis-dependent). Its performance in "improving iron stores, elevating hemoglobin, and ensuring tolerance" provides data support for its application potential.
(I) Non-Dialysis CKD Patients: Potential as First-Line Oral Iron Supplement
Oral iron supplements are preferred for anemia treatment in non-dialysis CKD patients (CKD stages 3–5, pre-dialysis). Ferrous gluconate effectively improves iron stores and anemia indicators:
Improvement in iron store indicators: A randomized controlled study of 60 CKD stage 3–4 patients with iron deficiency anemia showed that daily oral administration of 300 mg elemental iron (as ferrous gluconate, divided into 3 doses) for 12 weeks increased serum ferritin (a marker of iron stores) from a baseline of 58 ng/mL to 132 ng/mL, and transferrin saturation (TSAT, a marker of iron utilization) from 14% to 28%—both meeting clinical iron sufficiency criteria (ferritin >100 ng/mL, TSAT >20%). In the control group receiving the same dose of ferrous sulfate, serum ferritin only increased to 95 ng/mL and TSAT to 22%, with a much higher patient dropout rate due to side effects (20% vs. 5% in the ferrous gluconate group).
Hemoglobin (Hb) improvement: In the above study, the ferrous gluconate group had Hb levels increase from 9.2 g/dL to 11.5 g/dL, with a 达标 rate (Hb>11 g/dL) of 75%. The control group’s Hb only increased to 10.3 g/dL, with a 达标 rate of 45%. Further analysis showed more significant Hb elevation in patients with mild inflammation (CRP <10 mg/L), indicating ferrous gluconate remains effective in mild inflammatory states.
(II) Dialysis-Dependent CKD Patients: Supplementary or Alternative to Intravenous Iron
Dialysis-dependent CKD patients (e.g., hemodialysis, peritoneal dialysis) often require intravenous iron due to high iron loss (blood contact with dialysis membranes during treatment). However, some patients cannot use intravenous iron due to allergies or poor vascular access, making ferrous gluconate a viable supplement or alternative:
Alternative for patients intolerant to intravenous iron: A retrospective study of 32 hemodialysis patients allergic to intravenous iron (e.g., iron sucrose) showed that switching to 400 mg elemental iron (as ferrous gluconate) daily for 24 weeks increased serum ferritin from 42 ng/mL to 118 ng/mL, TSAT from 12% to 25%, and Hb from 8.8 g/dL to 10.9 g/dL. Although the Hb 达标 rate (56%) was lower than that of conventional intravenous iron therapy (80%), no severe side effects occurred, and basic anemia control was maintained—preventing reduced dialysis tolerance due to iron deficiency.
Supplementary to intravenous iron: For dialysis patients with persistently low iron stores (ferritin 50–100 ng/mL) after intravenous iron therapy, combining with oral ferrous gluconate (200 mg elemental iron daily) further improves iron stores. A study of 45 hemodialysis patients showed that 8 weeks of combined therapy increased serum ferritin from 78 ng/mL to 125 ng/mL and TSAT from 18% to 26%, without increasing oxidative stress markers (e.g., malondialdehyde [MDA]), confirming the safety and efficacy of combined treatment.
III. Advantages and Current Challenges in CKD Patient Treatment
Ferrous gluconate demonstrates unique advantages in CKD-related anemia treatment due to its "high tolerance and low oxidative risk," but it also faces challenges such as "reduced absorption in high-inflammatory states and dosage adjustment requirements." Objective evaluation is needed to ensure rational application.
(I) Core Advantages: Adapting to CKD Patient Treatment Needs
High safety for long-term use: As mentioned, its low incidence of gastrointestinal side effects (8%–15%) and minimal oxidative stress risk, combined with no need for intravenous puncture (avoiding infection and vascular damage), make it suitable for long-term iron supplementation in CKD patients (e.g., non-dialysis patients may require years or lifelong supplementation).
Convenient administration and good patient adherence: Ferrous gluconate can be taken with food (slightly reducing absorption but further minimizing gastrointestinal irritation), eliminating the need for strict fasting (traditional ferrous sulfate requires fasting, increasing the risk of missed doses). It is also available in oral solutions and chewable tablets, suitable for elderly CKD patients with swallowing difficulties. Clinical studies show its long-term medication adherence (70%–80%) is higher than that of ferrous sulfate (40%–50%).
Controllable costs reducing medical burden: Although ferrous gluconate is more expensive than ferrous sulfate, it is cheaper than intravenous iron (e.g., a single intravenous dose of iron sucrose costs approximately 200–300 RMB). No professional medical operation is required, significantly reducing treatment costs for primary hospitals or patients with limited economic conditions.
(II) Current Challenges: Targeted Solutions to Unlock Application Potential
Reduced absorption in high-inflammatory states: In CKD patients with severe inflammation (CRP >10 mg/L), hepcidin levels rise significantly. Even though ferrous gluconate can partially bypass DMT1 for absorption, its absorption rate drops to <5%, weakening improvements in iron stores and Hb. In such cases, anti-inflammatory treatment (e.g., infection control, anti-inflammatory drugs) or short-term switching to intravenous iron is needed, with a return to oral ferrous gluconate once inflammation is controlled.
Dosage adjustment based on renal function: CKD stage 5 patients (glomerular filtration rate [GFR] <15 mL/min) have further reduced intestinal absorption, requiring appropriate dose increases of ferrous gluconate (e.g., from 300 mg elemental iron daily to 400 mg). However, excessively high doses may increase the risk of constipation (incidence: ≈10%–15%), requiring gradual adjustment based on patient tolerance.
Lack of long-term cardiovascular safety data: Long-term iron use may be associated with cardiovascular event risks in CKD patients (e.g., atherosclerosis due to iron overload). Currently, long-term (>2 years) cardiovascular safety data for ferrous gluconate in CKD patients are limited, requiring further large-sample, long-term follow-up studies for validation.
IV. Summary and Application Recommendations
Ferrous gluconate demonstrates significant potential in treating CKD-related anemia due to its "high water solubility, low gastrointestinal irritation, and low oxidative stress risk." It can serve as a first-line oral iron supplement for non-dialysis CKD patients (effectively improving iron stores and hemoglobin) and a safe alternative for dialysis patients intolerant to intravenous iron. Its core value lies in balancing "efficacy" and "safety," adapting to the long-term, convenient treatment needs of CKD patients.
Based on existing evidence, clinical application recommendations are as follows:
Priority populations: Non-dialysis CKD stage 3–4 patients with mild-to-moderate iron deficiency anemia; dialysis patients allergic to intravenous iron or with poor vascular access; CKD patients requiring long-term oral iron supplementation and intolerant to traditional inorganic iron supplements.
Dosage and administration: Non-dialysis patients: 200–300 mg elemental iron daily (divided into 2–3 doses), taken with food if needed. Dialysis patients: 300–400 mg elemental iron daily (divided into 3 doses); if constipation occurs, reduce the dose appropriately and increase dietary fiber intake.
Optimized combination therapy: Co-administration with vitamin C (200 mg daily) increases iron absorption by ≈20%–30%, but concurrent use with calcium-containing drugs (e.g., calcium carbonate) should be avoided (maintain a >2-hour interval to prevent calcium-iron absorption competition). For patients receiving EPO therapy, adjust EPO dosage based on Hb levels to avoid hypertension risks from excessive EPO.
