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

ID in KTRs—Definitions, Epidemiology and Aetiology

Definition and Prevalence of ID

Although an iron staining of bone marrow is the gold standard method to assess iron status, a serum ferritin level of <30 μg/L is a widely accepted alternative definition of ID.[4] However, because ferritin is an acute-phase protein, its concentration is increased in most chronic diseases as a result of inflammation, possibly masking co-existing ID. Therefore, transferrin saturation (TSAT) is more reliable in the context of chronic disease.[4] Most studies in patients with low-grade inflammation, including KTRs, use ID definitions based on the combination of ferritin concentration and TSAT.[2,5–8] The prevalence of ID after kidney transplantation varies depending on the definition used and the time after kidney transplantation. In a cohort of 700 stable KTRs who were at least 1 year after transplantation [median time: 5.4 years, interquartile range (IQR) = 1.9–12.0 years], the prevalence of ID defined as a ferritin concentration <300 μg/L and TSAT <20% was 30%.[2] Other cohort studies, all with a median time after transplantation of at least 4 years, found prevalences between 6% and 47%.[9–13]

A longitudinal study suggested that patients with pre-transplant ID remained iron-deficient after transplantation, and ferritin levels tended to decrease in the first months after transplantation. Other studies support the observation that ferritin levels and TSAT tend to decrease after transplantation, as haemoglobin (Hb) rises.[8,14,15] The reduction in ferritin levels after transplantation is more prominent when ferritin levels are initially high.[13,16] This observation suggests that the decrease in ferritin levels is not purely resulting from progressive ID but from an abatement of inflammation as well.

Potential Mechanisms of ID in KTRs. The aetiology of ID after kidney transplantation is multifactorial, as depicted in Figure 1.

Figure 1.

Causes of ID in KTRs. In KTRs, low-grade inflammation and mTOR inhibitors promote hepcidin upregulation. Hepcidin suppresses iron uptake from the gut by inhibiting iron exporter ferroportin on enterocytes. Hepcidin also reduces available iron by inhibiting iron export from monocytes. Meanwhile, iron usage/consumption is increased in KTRs: renewed EPO production promotes erythropoiesis. Usage of anticoagulant medication, frequent blood sampling and in some cases gastro-intestinal and urogenital malignancies result in blood loss. Female KTRs of reproductive age often have a return of their menstrual cycle, another cause of blood loss. Finally, PPIs decrease dietary iron uptake.

Inflammation. Inflammation induces hepcidin expression in the liver through cytokines including interleukin (IL)-6 and bone morphogenetic protein (BMP).[17] In particular, BMP6, a modulator of the renal response to injury, is a major hepcidin-inducing factor through stimulation of hepatocellular Suppressor against Mothers Against Decapentaplegic (SMAD) production.[4] Hepcidin subsequently degrades the iron-exporter ferroportin in enterocytes, leading to a decreased absorption of dietary non-haem iron from the duodenum.[18] Hepcidin also decreases the bioavailability of iron by augmenting its storage in macrophages through systemic degradation of ferroportin. The absorption and handling of iron are comprehensively described elsewhere.[4] Although hepcidin is positively correlated with acute-phase protein ferritin, its correlation with TSAT is inverse in line with the presumed role of inflammation driving ID in these patients.[19–21]

Medication. Medication, including anticoagulants, proton pump inhibitors (PPIs) and immunosuppressive drugs, form another major factor influencing iron status in KTRs. Anticoagulant use frequently causes chronic (microscopic) gastro-intestinal blood loss, resulting in ID. The use of PPIs has also been associated with an increased risk of ID in several populations, including KTRs.[22,23] Mechanistically, it has been suggested that PPIs reduce iron absorption by increasing the gastric pH, thereby inhibiting the reduction of ferric iron [Fe(III)] to ferrous iron [Fe(II)], in turn precluding absorption by enterocytes. The effects of immunosuppressive medication on iron status are not fully understood. Mammalian target of rapamycin inhibitors (mTORis) seem to promote ID. In mice, the mTORi sirolimus and the calcineurin inhibitor (CNI) tacrolimus stimulated hepcidin expression.[24] In humans, mTORi use has been associated with both anaemia and functional ID.[25] Prospective studies showed that a switch from a ciclosporin- to a sirolimus-based immunosuppressive regimen led to a decline in TSAT, while in patients with a ciclosporin dose reduction in TSAT remained stable.[26] In a study where KTRs were switched from a CNI and/or mycophenolic acid (MPA)-based regimen to an everolimus-based immunosuppressive regimen, TSAT also decreased significantly.[27]

Malignancies. KTRs are at increased risk of gastro-intestinal cancers, such as colon carcinoma or intestinal post-transplant lymphoproliferative disorder, which may manifest as ID.[28] Thus, each patient with ID should be verified for the presence of alarm symptoms such as weight loss or rectal blood loss. Also, deep ID accompanied by low mean corpuscular volume or co-existing anaemia should trigger gastro-intestinal work-up. The isolated presence of ID without alarm symptoms, microcytosis or anaemia, which occurs in a considerable group of patients, seems insufficient to justify gastro-intestinal screening.[29] Urinary tract malignancies such as renal cell carcinoma have a much higher prevalence in KTRs as well, and may induce ID through erythrocyturia.[28]

Other Factors. Blood loss during transplant surgery and frequent blood sampling after transplantation may contribute to ID, especially in the early post-transplant phase.[30] Return of the menstruation cycle after successful transplantation could be another contributor to progressive ID.[31] Finally, the increase of serum erythropoietin (EPO) concentrations after kidney transplantation may cause a relative shortage of iron. Use of EPO-stimulating agents before kidney transplantation is associated with a less pronounced ferritin decrease after transplantation.[14]