Iron Deficiency, With And Without Anaemia,across Strata Of Kidney Function in Kidney Transplant Recipients

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Anaemia is highly prevalent in kidney transplant recipients (KTRs) and is associated with an increased risk of adverse outcomes [1]. Similarly, iron deficiency (ID) is highly prevalent in KTRs. The latter is attributable to a combination of multiple causes, including increased hepcidin levels and frequent use of proton-pump inhibitors, which impair iron absorption, and frequent use of anticoagulants, which can stimulate iron loss [2, 3]. Until recently, ID was deemed only clinically relevant in the setting of anaemia. We, however, recently showed that ID, independent of anaemia, is associated with an increased risk of death in the patient setting of KTRs [4]. This warrants further investigation into the prevalence of ID, both with and without anaemia, and to ascertain at which stage of kidney function declines these entities become apparent. Hence, in the current study, we aimed to investigate how prevalent ID, with and without anaemia, is in KTRs across strata of kidney function and across chronic kidney disease (CKD) stages.

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For this purpose, we used two separately collected cohorts from our University Medical Center in Groningen, which, respectively, include 795 KTRs [TransplantLines Biobank and Cohort Study (TxLines); NCT03272841] and 707 KTRs [TransplantLines Food and Nutrition Biobank and Cohort Study (TxLines-FN); NCTO2811835][5,6]. The data that support the findings of this study are available from the corresponding author on reasonable request. In brief, all included KTRs, transplanted in the University Medical Center Groningen, were considered stable with a functioning graft 2l year beyond transplantation. All KTRs gave written informed consent and approval by the institutional review board was obtained in both studies(METc 2008/186 and METC 2014/077). Both studies adhered to the principles of the declaration of Helsinki. Serum iron was measured using a colourimetric assay, ferritin using an immunoassay, and transferrin using an immunoturbidimetric assay (all Roche Diagnostics, Mannheim, Germany). Transferrin saturation(TSAT)(%)was calculated as 100× serum iron（μmol/L）/25× transferrin （g/L）. ID was defined as TSAT<20% and ferritin <300ug/L [8]. Renal function was determined by estimating glomerular filtration rate (eGFR)by applying the Chronic Kidney Disease Epidemiology Collaboration equation. Anaemia was defined as haemoglobin <12g/dL (females) and<13g/dL (males)9]. For the current analyses, we excluded KTRs using iron supplementation and/or erythropoietin (n=67 in TxLines cohort; n=50 in TxLines-FN cohort) or having missing data on iron status (n=7 in TxLines-FN cohort), resulting in 728 KTRs and 650 KTRs, respectively. As sensitivity analyses, we used an alternative definition of ID, namely TSAT<20% and ferritin <100ug/L[10]. Also, we compared prevalences of ID without anaemia in KTRs with those in patients having CKD and in the general population. To this end, we used the Prevention of Renal and Vascular End-stage Disease (PREVEND) study[11]. CKD was defined based on an eGFR <60mL/min/1.73m² or albuminuria >30mg/24h or albumin-to-creatinine ratio之30mg/g. In CKD, we used the same definitions for ID as in KTRs, whereas in the general population ID was defined as ferritin <15μg/L (females) and ferritin <30 ug/L(males).

The baseline characteristics are described in Supplementary data, Tables S1 and S2. The TxLines cohort included728 KTRs (mean age 56±13years;61% males) with a mean eGFR of 52.7±17.6mL/min/1.73 m² and median transplant vintage of 3.8(1.0-10.0) years. The TxLines-FN cohort included 650 KTRs (mean age 53±13years;59% males)with a mean eGFR of 54±20 mL/min/1.73 m² and median transplant vintage of 5.3 (1.8-12.0) years. Anaemia was present in 26% and32%, ID was present in 37% and 30% and ID independent of anaemia was present in 25% and 17% of the two respective cohorts.

We found that in the TxLines cohort, across strata of kidney function, ID independent of anaemia was highly prevalent in the early stages of CKD, with prevalences of >25% in almost all strata of eGFR 50 to >90mL/min/1.73m²（Supplementary data, Table S3). Across further degrees of kidney dysfunction, anaemia became more prevalent and the presence of ID independent of anaemia decreased. Similarly, in the TxLines-FNcohort, the highest prevalence of ID independent of anaemia was present in the same group of KTRs with eGFR 50 to>90mL/min/1.73 m'(Supplementary data, Table S4).

When subdividing kidney function into CKD stages, in both cohorts ID independent of anaemia was most prevalent in CKD stages I and I(Figure l and Supplementary data, Figure S1).In the TxLines cohort, ID, independent of anaemia, was also the most prevalent in CKD stage Ia(Figure 1). With the advancing of the CKD stage, anaemia was more prevalent, whereas the prevalence of ID without anaemia diminished.

In sensitivity analyses, using the alternative definition for ID, we found a similar pattern for ID without anaemia with higher prevalence in the early stages of CKD (Supplementary data, Tables S3 and S4).In CKD patients present in the general population cohort (n=962; Supplementary data, Table S5), ID without anaemia was also prominently present across strata of eGFR, preferentially in early CKD stages, whereas in the general population (n=5182; Supplementary data, Table S6)ID without anaemia was not highly prevalent(<5% across strata of eGFR 60 to >90 mL/min/1.73 m~).

In this study, we show that ID independent of anaemia is highly prevalent in KTRs, with particularly high prevalence at the early stages of CKD and frequencies approaching 25% of the population. At lower degrees of kidney function, anaemia becomes more overt and ID without anaemia is less frequently encountered. It should be kept in mind that anaemia is an end-stage of depleted iron stores and that besides erythropoiesis iron plays a pivotal role in many cellular processes, including the synthesis of DNA, electron transport and cellular proliferation differentiation [13]. Studies in chronic heart failure patients have underscored the importance of ID independent of anaemia [14, 15]. Recently, we showed an association of ID independent of anaemia with a higher risk of death in KTRs; however, no causality can be attributed to this study due to the observational design [4]. Therefore, randomized controlled trials specifically investigating the relevance of ID independent of anaemia are eagerly needed to assess whether clinicians should be more aware of this entity.

Here, we present data that ID without anaemia in KTRs is especially present in early CKD stages, that is stages I-IIa. Further research delineating the clinical relevance of this entity seems warranted.