Iron Deficiency After Kidney Transplantation

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

Disclosures

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

In This Article

ID in KTRs—Definitions, Epidemiology and Aetiology

In KTRs, ID has been strongly and independently associated with a higher mortality risk in two studies of KTRs with relatively good graft function [estimated glomerular filtration rate (eGFR) 52 ± 20 mL/min and 53 ± 19 mL/min, respectively; Table 1].[2,3] Some but not all studies suggest that iron status may also influence kidney damage and graft outcomes.[3,34] Recently, studies in non-transplant populations suggested that peri-operative ID is an important prognostic factor, and that it might be beneficial to correct non-anaemic ID prior to surgery.[36–39] Whether this also applies to KTRs has not been studied so far. Although the aetiologies that may underlie the observed adverse outcomes have not been elucidated, several mechanisms could be involved.

Cardiac Effects of ID

Given the associations of ID with all-cause mortality in KTRs (Table 1), and since cardiovascular disease is the most common cause of death in KTRs, it seems plausible that ID has adverse effects on the cardiovascular system in KTRs, as shown in other populations. No studies have so far directly assessed the association between ID and fatal or non-fatal cardiovascular outcomes in KTRs. However, it has been shown that ferritin and EPO are inversely correlated, possibly because ID promotes resistance to endogenous EPO, and that a higher EPO level is associated with a higher risk of both cardiovascular and all-cause mortality in KTRs.[40] Moreover, ID might contribute to the development of heart failure (HF), a major cause of morbidity and mortality in KTRs.[41] Although systolic heart function usually improves after transplantation, diastolic dysfunction (HF with preserved ejection fraction) tends to remain.[42] There is also an elevated incidence of incident HF in KTRs,[43] which is strongly associated with anaemia both in KTRs and in the general population.[43,44] To our knowledge, it is unknown whether ID is associated with incident HF in KTRs, although it has been described that N-terminal prohormone of brain natriuretic peptide (NTproBNP) levels are much higher in KTRs with ID compared with iron-sufficient KTRs (Table 1).[2]

Bound to Hb and myoglobin, respectively, iron has a pivotal role in oxygen transport through the body and oxygen storage in myocytes. Iron is also directly involved in various steps of cellular energy metabolism. It is an essential component of aconitase and succinate dehydrogenase, catalyst enzymes of the Krebs cycle.[4] In ID, decreased intracellular oxygen availability and impaired function of the Krebs cycle force the cell towards anaerobic glycolysis. Since muscle tissue is highly dependent on aerobic glucose metabolism, it is likely that ID compromises cardiac and skeletal muscle cell function. In vitro, ID impairs mitochondrial respiration and cardiomyocyte contractility.[45,46] In animal models, a low-iron diet caused structural cardiac defects, cardiomyocyte hypertrophy and reduced left ventricular ejection fraction (LVEF).[47,48]

Multiple studies have reported strong associations between ID and decreased exercise tolerance in patients with chronic heart failure (CHF) with either reduced or preserved left LVEF, which occur independently of Hb concentrations.[49,50]

Since 2007, six randomized controlled trials (RCTs) have addressed the effects of intravenous (IV) iron supplementation in iron-deficient patients with CHF; most of them also had mildly to moderately impaired kidney function (Table 2). IV iron supplementation resulted in an improved quality of life and exercise capacity and reduced the incidence of acute HF compared with placebo or standard treatment. Interestingly, ID correction also had significant effects in non-anaemic patients in most trials. In a meta-analysis of four RCTs, IV administration of ferric(III)carboxymaltose (FCM) significantly reduced cardiovascular mortality.[51] Evaluation of iron status and correction of ID are now integrated with the management of CHF patients according to guidelines of the European Society of Cardiology.[52] Meanwhile, several large trials in acute and chronic HF are ongoing to clarify the effects of ID correction on clinical outcomes.[53] Given the high prevalence and impact of HF in KTRs, the role of ID and the therapeutic value of iron supplementation in this population should be elucidated.

ID, Fibroblast Growth Factor 23 and Mortality Risk

Emerging data, both in the general population and in KTRs, show that ID is associated with elevated fibroblast growth factor 23 (FGF23) levels and suggest that the association between ID and increased mortality in KTRs is at least partly mediated by FGF23.[54,55]

FGF23 is a phosphaturic hormone secreted by osteocytes. FGF23 reduces phosphate reabsorption from the proximal tubule of the kidney and suppresses 1,25-dihydroxyvitamin D levels.[56] In CKD, FGF23 increases progressively and there may be a 1000-fold increase in ESRD. After kidney transplantation, FGF23 levels decrease but often remain elevated during the first weeks to months, and sometimes even years after transplantation, contributing to a tendency to hypophosphataemia.[57–59]

FGF23 has been independently associated with an increased risk of cardiovascular and all-cause mortality and allograft loss in KTRs.[60,61] It is likely that off-target effects of high FGF23 levels underlie these associations, as several animal studies have shown that intact FGF23 causes left ventricular hypertrophy.[62] Further mechanisms by which FGF23 may lead to adverse outcomes include over-stimulation of the renin–angiotensin–aldosterone system, volume overload via effects on renal sodium handling[63–65] and promotion of inflammation.[66] Although studies report inconsistent effects of FGF23 on vascular calcification in other populations, FGF23 was an independent predictor of vascular stiffness in KTRs.[67]

More studies are needed to elucidate the role of FGF23 as intermediate between ID and adverse outcomes, particularly in the KTR population.

Iron and Infection

Bacteria need iron to thrive, and compete to acquire it.[68] Some pathogenic bacteria, including Enterobacteria, Pseudomonas and Neisseria species, have adapted to iron scarcity and can express siderophores, compounds with a high affinity for iron, to obtain iron from the environment.[68,69] At the same time, ID may directly affect the immune system, as discussed in more detail below.[70] In KTRs, this is of particular relevance because in these patients the balance between suppression of the allo-immune response and the risk of infection resulting from immunosuppressive therapy is narrow. An overview of studies addressing the association between ID and infection or the effect of iron therapy on incidence of infections in KTRs is provided in Table 1.

Clinical studies confirm that ID can protect against bacterial and parasitic infections,[71] and that iron overload is associated with worse prognosis in patients suffering from bacteraemia, sepsis, tuberculosis and Human Immunodeficiency Virus (HIV).[72–74] In KTRs, a ferritin concentration of >500 μg/L in the first weeks after transplantation has been associated with a higher risk of infection (26% versus 41%).[33] In the same study, TSAT was not associated with the risk of infection, which suggests that inflammation rather than ID may have been the driving factor for higher ferritin levels.[35]

In contrast, other studies suggest that ID can increase susceptibility to bacterial infection. In a general population cohort of 61 852 people, a lower TSAT was associated with a higher risk of bacteraemia, even after correction for chronic diseases.[75] Less is known about the effect of ID on viruses. Cytomegalovirus (CMV) replication in vascular endothelial cells is reduced after iron chelation in vitro, which may be relevant to KTRs as primo CMV infection and CMV reactivation are common in these patients.[76]

processing....