How Free Heme Threatens Kidney Recovery After Solid Organ Transplantation
A single transplant can require up to 24 units of blood — and that lifesaving gift might carry an unexpected risk.
Imagine a life-saving organ transplantation that succeeds, only for the patient to face another critical health crisis: acute kidney injury (AKI). This surprisingly common complication can dramatically alter recovery outcomes. Emerging research points to an unexpected culprit in this process—systemic free heme—a substance released during blood transfusions that often accompany major surgeries.
The connection reveals a delicate balance within medical procedures, where essential treatments can introduce new challenges. Understanding this link represents a crucial step toward protecting vulnerable patients during their most critical moments.
Units of blood needed for some transplants
AKI incidence in heart transplant patients
Days RBCs can be stored, increasing heme release
Solid organ transplantation represents one of modern medicine's greatest achievements, offering hope to patients with end-stage diseases. However, procedures like lung, heart, and liver transplants often involve substantial blood loss, necessitating life-saving packed red blood cell (pRBC) transfusions1 .
Free heme acts as a damage-associated molecular pattern (DAMP), triggering inflammatory signaling pathways in the body5 .
Free heme is both vasoactive and pro-inflammatory, capable of causing microcirculation disturbances and acting as "a strong inductor of complement activation and inflammation"1 .
The body has natural defenses against heme toxicity, primarily the enzyme heme oxygenase-1 (HO-1). This cytoprotective enzyme degrades toxic free heme, releasing beneficial by-products in the process—carbon monoxide, biliverdin/bilirubin, and ferritin9 . However, during the massive heme influx that can accompany transplantation, these protective systems may become overwhelmed.
A compelling prospective clinical study conducted at Hannover Medical School offers striking evidence of free heme's role in transplant-related AKI1 . Researchers compared two patient groups: those undergoing heart transplantation (10 patients) and those receiving kidney transplants (7 patients).
The research team measured free heme levels at multiple time points: before surgery, during surgery, at 6 and 24 hours after surgery, and at 1 and 7 days post-operation. They used a method based on measuring peroxidase enzyme activity to quantify free heme, simultaneously tracking clinical outcome parameters like serum creatinine and lactate dehydrogenase (LDH) levels1 .
The results revealed dramatic differences between the two groups:
Experienced a massive systemic increase in free heme, skyrocketing from baseline levels of approximately 9 fmol/nl to between 3,760 and 17,255 fmol/nl within 30 minutes after surgery1 .
These patients required between 6 and 24 units of packed red blood cells during their procedures and developed AKI at a rate of 60%1 .
| Transplant Type | Patients (n) | pRBC Transfusion (units) | Free Heme Increase | AKI Incidence |
|---|---|---|---|---|
| Heart Transplant | 10 | 6-24 | 9 → 3,760-17,255 fmol/nl | 60% |
| Kidney Transplant | 7 | 0 | Minor | Not reported |
The correlation was clear: procedures requiring more blood transfusions led to higher free heme levels and more frequent kidney injury. This suggests that free heme release from stored blood products may be a significant factor in post-transplant AKI.
The journey from heme exposure to kidney injury involves multiple biological pathways that researchers are just beginning to untangle.
Groundbreaking research published in 2025 revealed a previously unknown mechanism: ACE2 protein avidly binds heme2 . This interaction facilitates heme entry into kidney cells, promoting injury.
In experimental models, ACE2-deficient mice were significantly protected against heme protein-mediated AKI compared to their ACE2-wildtype counterparts2 . They showed less histological kidney damage, reduced expression of apoptosis and ferroptosis markers, and lower overall kidney heme content2 .
This discovery is particularly meaningful because it identifies both heme proteins and heme itself as novel determinants of ACE2 expression2 . It also explains why high levels of myoglobin and heme predict poor outcomes in COVID-19 patients, as the virus uses the same ACE2 receptor for cell entry2 .
Podocyte cytoskeleton alterations; Increased apoptosis
Increased HO-1 expression; Oxidative stress; DNA damage; Mitochondrial and ER dysfunction; NF-κB pathway activation (inflammatory response)
Once inside kidney cells, heme triggers oxidative stress, disrupts cellular structures, and promotes inflammation. Studies examining human podocytes (critical kidney filtration cells) exposed to heme revealed:
The antioxidant N-acetyl cysteine (NAC) partially reduced these effects, indicating that while oxidative stress plays a central role, additional mechanisms contribute to heme-induced cell death8 .
The challenge of heme toxicity extends beyond the transplantation surgery itself into organ preservation. Normothermic machine perfusion (NMP)—a technique that maintains organs at body temperature with an oxygenated red blood cell-based solution—can inadvertently contribute to the problem.
During NMP, red blood cells contacting artificial surfaces and perfusion pumps become damaged, releasing free heme into the perfusate5 . Research shows that older units of RBCs are associated with higher levels of free heme in the perfusate5 .
Levels of free heme increase significantly during the NMP process, rising from approximately 8.56 µM before perfusion to 26.29 µM afterward5 . This occurs even as the technology successfully restores cellular metabolism and replenishes ATP in donated organs5 .
Increase in free heme during normothermic machine perfusion
| Research Tool | Function/Application | Research Context |
|---|---|---|
| Heme Assay Kit (Sigma-Aldrich) | Quantifies free heme levels via peroxidase activity | Used to measure heme in perfusate samples during normothermic machine perfusion5 |
| Human Organ Transplant Panel (NanoString) | Analyzes expression of 770 genes related to transplant pathways | Employed to study inflammatory and stress-related gene expression in kidney biopsies5 |
| Hemín (Sigma Aldrich) | Iron-containing compound used to simulate heme exposure in experimental models | Applied to human podocyte cultures to study heme-induced cellular damage8 |
| N-acetylcysteine (NAC) | Antioxidant used to test oxidative stress mechanisms | Administered to podocytes simultaneously with hemin to determine oxidative stress contribution to damage8 |
| TUNEL Staining | Detects apoptotic cells in tissue samples | Used to quantify apoptosis in kidney tissue sections after heme exposure5 |
Understanding heme's role in AKI opens avenues for potential protective interventions:
The protective benefits of boosting the heme-degrading enzyme HO-1 are well-established in preclinical models. HO-1 induction protects against various kidney insults, and genetic variations in the HO-1 promoter influence AKI risk9 .
Patients with shorter GT repeats in the HO-1 promoter, associated with better HO-1 inducibility, have better outcomes after kidney transplantation9 .
Strategies to measure hemoglobin degradation in pRBCs during storage and prior to transfusion could enhance patient safety1 .
Using fresher blood units or developing alternative oxygen carriers for perfusion circuits might reduce heme-mediated injury.
Targeting the heme-ACE2 interaction or developing specific antioxidants could offer protection.
The partial success of N-acetyl cysteine in reducing heme effects on podocytes suggests combination approaches might be beneficial8 .
The discovery of systemic free heme as a risk factor for AKI after solid organ transplantation represents both a challenge and an opportunity. It highlights the delicate balance in medicine, where life-saving treatments like blood transfusions can introduce new complications.
As researchers continue to unravel the molecular mechanisms connecting heme to kidney damage, clinical practice evolves toward greater patient safety. The goal remains clear: protecting vulnerable patients from additional harm while delivering the full benefits of transplantation medicine.
Future approaches may involve personalized risk assessment, modified blood product management, and targeted therapies to neutralize heme toxicity—ensuring that the gift of transplantation isn't diminished by preventable complications.
This article was developed based on recent scientific research to explain complex medical concepts to a general audience. The information presented is for educational purposes and reflects current scientific understanding.