Iron Deficiency After Kidney Transplantation

Joanna Sophia J. Vinke; Marith I. Francke; Michele F. Eisenga; Dennis A. Hesselink; Martin H. de Borst


Nephrol Dial Transplant. 2021;36(11):1976-1985. 

In This Article

Iron and the Immune System

Cellular Immunity

Acute cellular rejection, mainly orchestrated by T-lymphocytes, is one of the major threats for kidney allograft survival. Although data on the role of iron in kidney transplantation specifically are scarce, iron seems to play an important role in immune cell function. T-cell activation leads to increased cytokine production and IL-2 receptor stimulation; both processes depend on iron.[70,81–83] The T-cell receptor is co-expressed with both CD28 and the TfR,[70] a transmembrane protein that facilitates the uptake of transferrin-bound iron from the circulation into the T cell. In addition to reducing TfR stimulation, ID also decreased the expression of the co-stimulatory molecule CD28 on thymocytes and splenocytes in mice.[84]

ID affects T-cell proliferation as well, since iron is an essential cofactor in various steps in DNA synthesis.[82,85] Both TfR upregulation and iron abundance have been associated with increased cell cycle progression, while ID decreased lymphocyte proliferation in mice and humans.[86–89] T-cell differentiation and maturation also require iron.[89–91] Decreased T-lymphocyte counts, CD4+ concentrations and CD4+/CD8+ ratios have been observed in some, but not all studies in iron-deficient patients.[89,90,92–94]

ID may impair T-cell function through decreased production of IL-2, interferon-γ, tumour necrosis factor (TNF)-α, IL-10, IL-6 or IL-4, as observed in the majority of studies in mice and humans with ID.[83,88,92,95,96] In the context of acute vascular rejection, ID may also affect the influx of T cells in the endothelium by influencing the expression of endothelial adhesion molecules such as endothelial–leucocyte adhesion molecule-1 and intercellular adhesion molecule-1.[76]

Overall, most studies seem to indicate that iron is important for T-cell proliferation and function. This underlines the relevance of future studies addressing the clinical impact of ID and iron supplementation on cellular immunity in kidney transplantation.

Humoral Immunity

T-helper cells may activate B-lymphocytes, triggering the production of immunoglobulins against Humane Leukocyte Antigen (HLA) molecules, endothelial cell antigens and ABO blood group antigens that may in turn activate the complement system and drive antibody-mediated rejection.[97] Until recently, there was little evidence of any impact of ID on B-lymphocytes.[98,99] Yet, a very recent study revealed an important role for iron in T-cell independent B-cell activation and in B-cell proliferation, and documented impaired antibody responses during ID in mice and humans.[100] Although previous studies showed conflicting data on the association between iron status and immunoglobin concentrations, the recent work suggests that ID influences not only T-cell- but also B-cell-mediated immunity.[100]

Innate Immunity

The innate immune system can escalate organ graft rejection through activation of T-lymphocytes and by acting directly on the kidney transplant. Activated by foreign proteins through Toll-like receptors, macrophages promote rejection.[97] Macrophages have an important role in iron storage and recycling as well.[4] However, iron-overload in macrophages attenuates their anti-pathogenic and pro-inflammatory functions.[34,72] Importantly, macrophage function also depends on iron and iron-containing haemoproteins.[81,101,102] Iron is involved in macrophage activation and differentiation, as well as prostaglandin synthesis and killing capacity.[101] Finally, ID decreases the expression of Major Histocompatibility Complex (MHC) Class I molecules and thereby may enhance recognition and activation of Natural Killer (NK) cells by macrophages.[103] Hence, alterations in iron metabolism may affect all these facets of macrophage biology. This is supported by the observation that monocyte and macrophage phagocytic capacity and oxidative burst activity, or release of reactive oxygen species after activation, is impaired in children with IDA.[92] Iron-depleted macrophages had a reduced expression of IL-1β and TNF-α in response to a pro-inflammatory stimulus.[102] After induction of toxic nephritis, characterized by macrophage infiltration, iron-deficient rats showed less proteinuria and better kidney function.[102]

Ischaemia and reperfusion during kidney transplantation lead to a sterile inflammatory response driving renal fibrosis: ischaemia–reperfusion injury (IRI). Granulocytes and neutrophils in particular are involved in IRI but also attract T-lymphocytes, promoting cellular rejection.[104] In granulocytes, IDA impairs the oxidative burst and pathogen killing capacity.[89,92] Together, these findings point towards an important role for iron in innate immunity, and suggest that ID could impair the inflammatory response.

IRI and iron homoeostasis are closely linked. In a mouse model, renal IRI results in an iron shift from the liver and macrophages towards the kidneys and circulation, through the induction of the iron exporter ferroportin.[105] Hepcidin treatment, decreasing iron availability, reduced IRI, oxidative stress, renal epithelial cell apoptosis, acute tubular necrosis, neutrophil infiltration and inflammation, and improved renal function.[105] These results suggest that low iron concentrations may protect against IRI. This is supported by the observation that iron chelation during organ preservation reduces IRI in several animal models of heart, kidney or liver allograft transplantation.[106–108]

In contrast, a protective effect of high iron concentrations has been proposed by others.[34,109] Increased intra-renal iron concentrations in ferroportin knock-out mice provided protection against IRI.[109] Vaugier et al. also found a protective effect of iron against IRI.[34] Mice with iron overload (hfe−/−) were less susceptible to IRI compared with wild-type mice. This protective effect of iron was attributed to a decreased recruitment of inflammatory macrophages, together with impaired macrophage responsiveness to stimulation by Toll-like receptor agonists and increased activation of the antioxidant response.[34]

In conclusion, iron is pivotal for the proliferation, activation and function of T- and B-lymphocytes and macrophages. In the context of organ preservation before transplantation, ID and iron overload both appear to reduce IRI. How these observations ultimately impact clinical outcomes after kidney transplantation remain unclear, since only observational data on clinical outcomes are available.