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Ascorbic acid as an adjunct therapy for hyporesponsive anemia in Erythropoietin-treated hemodialysis patients: A systematic review and meta-analysis

This systematic review and meta-analysis of ten randomized trials suggests that ascorbic acid supplementation modestly improves hemoglobin levels, transferrin saturation, and erythropoietin responsiveness in hyporesponsive hemodialysis patients by enhancing iron mobilization, although the overall evidence certainty is low and safety data remain unclear.

Original authors: España De la Rosa Valdez, Montserrat Villa Sanchez, Salma Alejandra Beltran Covarrubias, Angelo Magallanes Bajana, Alejandro Chen Liang, Yeison Cruz Castillo, Michelle Sámano Sánchez, Shreya Shambhavi

Published 2026-07-02

📖 5 min read🧠 Deep dive

CC BY 4.0

Original authors: España De la Rosa Valdez, Montserrat Villa Sanchez, Salma Alejandra Beltran Covarrubias, Angelo Magallanes Bajana, Alejandro Chen Liang, Yeison Cruz Castillo, Michelle Sámano Sánchez, Shreya Shambhavi, Vaidarshi Abbagoni, Oscar Yasser Pena Zapata, Jose Antonio García Erce, Ernesto Calderón-Martinez

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

The Big Picture: A Team Effort to Fix a Broken Engine

Imagine the human body as a car. Hemoglobin is the fuel that carries oxygen to keep the engine running. In people with Chronic Kidney Disease (CKD) who are on hemodialysis (a machine that cleans their blood), this "fuel" often runs low, causing anemia.

Usually, doctors give these patients a special booster shot called Erythropoietin (EPO). Think of EPO as a "gas pedal" that tells the bone marrow to make more fuel (hemoglobin).

The Problem: Sometimes, the car is so rusty or the engine is so clogged that stepping on the gas pedal (giving EPO) doesn't work very well. The car still won't go fast enough. This is called "hyporesponsive anemia."

The Question: The researchers asked: If we add a little bit of Vitamin C (Ascorbic Acid) to the mix, does it help the gas pedal work better?

The Experiment: What Did They Do?

The authors didn't test this on new patients. Instead, they acted like detectives gathering clues from 10 different studies (involving 431 patients) that had already been done. They looked at data from countries like Iran, Egypt, Taiwan, the US, and Turkey.

They checked to see if adding Vitamin C to the standard treatment changed the numbers on the patients' blood tests.

The Findings: What Happened?

Here is what the "detectives" found when they combined all the data:

More Fuel (Hemoglobin): The patients who took Vitamin C saw a small but noticeable increase in their hemoglobin levels.
- Analogy: It's like adding a small turbocharger to the engine. It didn't turn the car into a race car, but it definitely helped it move faster than before.
Better Fuel Delivery (TSAT): The amount of iron actually available to the bone marrow increased significantly.
- Analogy: Imagine the iron is sitting in a warehouse (the body's stores), but the delivery trucks are stuck in traffic. Vitamin C seemed to clear the traffic jam, allowing the iron to get to the factory floor where it's needed.
Less "Traffic" (TIBC): The measure of how much iron could be carried (Total Iron Binding Capacity) went down.
- Analogy: This is like seeing empty delivery trucks driving around. Since the iron is actually being used up by the factory, there are fewer empty trucks waiting for a load.
Smaller Warehouses (Ferritin): The levels of stored iron (ferritin) went down.
- Analogy: This confirms the "traffic cleared" theory. The iron wasn't sitting in the warehouse anymore; it was being used to build fuel.
Less Gas Needed (EPO Dose): Patients needed slightly less of the EPO "gas pedal" to get the same result.
- Analogy: Because the engine was running more efficiently, the driver didn't have to press the pedal as hard.
The "Iron in the Blood" Mystery: Interestingly, the actual amount of iron floating in the blood didn't change much.
- Analogy: It's like the factory is using the iron so fast that the supply line in the blood stays steady, even though the warehouse is emptying out.

The Catch: How Sure Are We?

While the results look promising, the researchers are very cautious. They used a grading system (like a report card) to judge how trustworthy the evidence is.

The Grade: Most of the findings got a "Low" or "Very Low" grade.
Why? The studies were very different from each other (some gave high doses, some low; some for 2 months, some for 6). It's like trying to compare recipes for chocolate cake where one baker uses cocoa powder, another uses melted chocolate, and another uses chocolate syrup. Because the "recipes" were so different, it's hard to say for sure exactly how much Vitamin C is the "perfect" amount.
Safety: The paper explicitly states that long-term safety was not checked. We don't know if taking high doses of Vitamin C for a long time causes other problems (like kidney stones or calcium buildup) based on this specific paper.

The Bottom Line

The paper concludes that Vitamin C might be a helpful "sidekick" for patients whose anemia isn't responding well to standard treatment. It seems to help the body use its iron more efficiently, leading to slightly better blood levels and less need for expensive EPO shots.

However, because the evidence is shaky (low certainty) and safety wasn't fully tested in this review, the authors say we cannot recommend it as a standard rule yet. We need more perfect, well-designed experiments to be sure it works safely for everyone.

In short: Vitamin C looks like a promising tool to help unclog the iron delivery system in dialysis patients, but we need more research before we put it in the standard toolkit.

Technical Summary: Ascorbic Acid as an Adjunct Therapy for Hyporesponsive Anemia in Erythropoietin-Treated Hemodialysis Patients

Problem Statement
Anemia is a pervasive complication of chronic kidney disease (CKD), affecting up to 95% of patients undergoing hemodialysis (HD). While Erythropoiesis-Stimulating Agents (ESAs) combined with iron supplementation constitute the standard of care, a significant subset of patients (5–10%) exhibits hyporesponsiveness, defined as the failure to achieve target hemoglobin levels despite high-dose ESA therapy. This condition is associated with adverse outcomes, including increased reliance on blood transfusions and higher mortality. Current guidelines do not routinely incorporate ascorbic acid (vitamin C) into anemia management protocols, despite its known role in enhancing iron bioavailability by reducing ferric (Fe³⁺) to ferrous (Fe²⁺) iron and potentially mitigating inflammation. There is a need for rigorous synthesis of existing evidence to determine if ascorbic acid supplementation can improve ESA responsiveness in this specific population.

Methodology
This study is a systematic review and meta-analysis conducted in accordance with PRISMA guidelines and prospectively registered in PROSPERO (CRD420251054491).

Data Sources: A comprehensive search was performed across PubMed, Cochrane, Scopus, EMBASE, Web of Science, CINAHL, and Google Scholar up to April 2026.
Eligibility Criteria: The review included only randomized controlled trials (RCTs) and crossover trials involving adult hemodialysis patients with erythropoietin-hyporesponsive anemia.
Intervention: Ascorbic acid supplementation (various routes, doses, and frequencies) compared to placebo or standard treatment.
Outcomes: Primary outcomes included Hemoglobin (Hb), erythropoietin (EPO) dose, ferritin, serum iron, transferrin saturation (TSAT), and total iron-binding capacity (TIBC). Secondary outcomes included C-reactive protein (CRP).
Analysis: Data were analyzed using R software with a random-effects meta-analysis (DerSimonian-Laird approach). Heterogeneity was assessed via $I^2$ statistics, and the certainty of evidence was evaluated using the GRADE framework.

Key Contributions and Results
The analysis synthesized data from 10 studies involving 431 patients (220 in the ascorbic acid group, 211 in the control group). The studies were geographically diverse, with major contributions from Iran, Egypt, and Taiwan, and utilized both RCT and crossover designs.

Hemoglobin (Hb): Ascorbic acid significantly increased hemoglobin levels compared to controls (Mean Difference [MD] = 1.03 g/dL; 95% CI: 0.63–1.43; $p < 0.01$ ). However, heterogeneity was high ( $I^2 = 88.0\%$ ). Sensitivity analysis excluding one outlier study reduced heterogeneity to 0.0% while maintaining a significant effect (MD = 0.86 g/dL).
Transferrin Saturation (TSAT): A significant increase in TSAT was observed (MD = 9.87%; 95% CI: 4.69–15.06; $p < 0.01$ ), though heterogeneity remained substantial ( $I^2 = 93.7\%$ ).
Total Iron-Binding Capacity (TIBC): TIBC decreased significantly (MD = −34.36 µg/dL; 95% CI: −59.08 to −9.63; $p < 0.01$ ), suggesting enhanced iron mobilization.
Ferritin: Ferritin levels were significantly lower in the treatment group (MD = −52.90; $p = 0.04$ ), consistent with the mobilization of iron stores.
EPO Dose: A modest but significant reduction in weight-adjusted erythropoietin dose was noted (MD = −21.29 IU/kg/week; $p < 0.01$ ), with no heterogeneity ( $I^2 = 0.0\%$ ).
Serum Iron: No statistically significant effect was found on serum iron levels (MD = −4.62 µg/dL; $p = 0.81$ ), with high heterogeneity ( $I^2 = 92.0\%$ ).
Inflammation (CRP): Among the limited studies reporting CRP, all indicated a reduction following supplementation.

Significance and Claims
The paper concludes that ascorbic acid may offer modest benefits for hemodialysis patients with ESA-hyporesponsive anemia. The observed improvements in hemoglobin and TSAT, coupled with reduced ferritin and TIBC, suggest a mechanism of enhanced iron mobilization and utilization rather than an expansion of total iron stores. The reduction in required EPO dosage further supports the potential for ascorbic acid to improve ESA responsiveness.

However, the authors explicitly state that the certainty of the evidence is low to very low for most outcomes (very low for Hb, iron, and TIBC; low for TSAT and EPO dose) due to serious inconsistency, imprecision, and suspected publication bias. The evidence for ferritin was rated as moderate. Consequently, the authors assert that current evidence is insufficient to support the routine use of ascorbic acid in clinical guidelines. They emphasize that safety concerns, particularly regarding long-term oxalate accumulation, remain unclear. The study calls for well-designed, adequately powered trials with standardized dosing and extended follow-up to definitively establish the therapeutic role and safety profile of ascorbic acid in this context.