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.

Iron and Allograft Outcomes

Patient data on iron status in relation to kidney allograft outcomes are scarce. A retrospective cohort study in 169 KTRs showed that a higher ferritin concentration was associated with better graft function and graft survival.^[34] In contrast, a cohort study in 438 KTRs found no association between the percentage of hypochromic red blood cells (HRBCs) and graft failure, although there was a trend towards greater graft survival among KTR who received iron therapy at baseline [hazard ratio (HR) = 0.51, 95% confidence interval (CI) 0.24–1.09; P = 0.08].^[3] In a mouse heart transplant model, ID decreased allograft survival due to more severe rejection.^[77] In contrast, a prolonged pancreatic islet or heart allograft survival was observed in rodents following either anti-transferrin receptor (TfR) antibody treatment or iron chelation therapy.^[78–80] While clinical data on the effect of ID on kidney allograft outcomes are limited, more is known on the impact of iron (deficiency) on the immune system in general.

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Abstract and Introduction
ID in KTRs—Definitions, Epidemiology and Aetiology
ID in KTRs—Definitions, Epidemiology and Aetiology
Iron and Allograft Outcomes
Iron and the Immune System
Iron Supplementation in KTRs
Conclusions and Future Directions
References

Table 1. Overview of studies addressing the relationship of ID and supplementation with clinical outcomes in KTRs
References	PMID	N	Design	Primary findings
Cardiovascular disease/all-cause mortality
Eisenga et al. [2]	27516242	700	Cohort study	Independent association of ID with all-cause mortality (fully adjusted HR = 1.77, 95% CI 1.13–2.78; P = 0.01) Higher NTproBNP concentrations in patients with non-anaemic ID [350 (IQR = 127–1069) pg/mL] than in patients without ID [159 (IQR = 72–393) pg/mL]
Winkelmayer et al. [3]	15575912	438	Cohort study	Independent association of %HRBC, an indicator of iron status and metabolic iron utilization, >10% with all-cause mortality (fully adjusted HR = 1.20, 95% CI 1.12–3.79; P = 0.02).
Infectious diseases
Mudge et al. [32]	22290270	102	RCT	Single-dose IV iron polymaltose versus daily oral ferrous sulphate. No difference in infection risk (20% in IV arm versus 24% in oral arm; P = 0.62)
Fernandez-Ruiz et al. [33]	24011120	228	Cohort study	Post-transplant ferritin >500 μg/L associated with any infection (P = 0.006) or bacterial infection (P = 0.02) during the first year No association between TSAT and infection risk during the first year
Vaugier et al. [34]	28784700	169	Cohort study	No difference in BK virus infection between high- (>600 μg/L) and low (<600 μg/L) ferritin groups (10% versus 15%, respectively, in the high quartile; Chi-squared test; P = 0.40)
Fernández-Ruiz et al. [35]	29120522	91	Cohort study	Independent association of high hepcidin-25 (≥72.5 ng/mL) with overall (HR = 3.86, 95% CI 1.49–9.96; P = 0.005) and opportunistic infection (HR = 4.32, 95% CI 1.18–15.75; P = 0.027).

Table 2. Overview of RCT addressing the effect of IV iron on clinical outcomes in patients with chronic HF and ID
Study	PMID	Year	Criteria for anaemia/iron status	Interventions (N)	Mean kidney function at baseline	Follow-up (weeks)	Outcome (intervention versus control)
Toblli et al.	17950147	2007	Hb <12.5 g/dL; TSAT <20%; Ferritin <100 μg/L	IV ISC (n = 20) IV saline (n = 20)	CrCl 39.8 ± 10.1 (ISC) CrCl 37.7 ± 10.2 mL/min (placebo)	24	NTproBNP↓ (P < 0.01) LVEF↑ (P < 0.01) HRQoL↑ (P < 0.01) 6 MWT↑ (P < 0.01)
FERRIC-HF	18191732	2008	Ferritin <100 μg/L or 100–300 μg/L with TSAT <20%	IV ISC (n = 24) Standard care (n = 11)	sCr 109 ± 42 μmol/L (ISC) sCr 104 ± 39 μmol/L (standard care)	18	pVO₂↑ (NS, P = 0.08) NYHA↓ (P = 0.007) GAF↑ (P = 0.002) HRQoL (NS, P = 0.07)
FAIR-HF (+ post hoc studies)	19920054 22297124 25683972	2009, 2015	Ferritin <100 μg/L or 100–300 μg/L with TSAT <20%	IV FCM (n = 304) IV saline (n = 155)	eGFR 63.8 ± 21.2 mL/min (FCM) eGFR 64.8 ± 25.3 mL/min (placebo)	26	GAF↑ (P < 0.001) NYHA↓ (P < 0.001) 6 MWT↑ HRQoL↑ (P < 0.001) eGFR↑ (P = 0.04)
IRON-HF	23680589	2013	Hb 9–12 g/dL; ferritin <500 μg/L; TSAT <20%	IV ISC (n = 10) IV saline (n = 6) Oral FS (n = 7)	sCr 97 ± 27 μmol/L (total cohort)	12	pVO₂ (NS) NYHA (NS) eGFR (NS)
CONFIRM-HF	25176939	2015	Hb <15 g/dL; Ferritin <100 μg/L or 100–300 μg/L with TSAT<20%	IV FCM (n = 150) IV saline (n = 151)	eGFR 66.4 ± 21.7 mL/min (FCM) eGFR 63.5 ± 20.9 mL/min (placebo)	52	6 MWT↑ (P = 0.002) NYHA↓ (P < 0.001) GAF↑ (P = 0.001) HRQoL↑ (P < 0.05) Acute HF↓ (P = 0.009)
EFFECT-HF	28701470	2017	Hb <15 g/dL; Ferritin <100 μg/L or 100–300 μg/L with TSAT <20%	IV FCM (n = 86) Standard care (n = 86)	eGFR 52 ± 13 mL/min (FCM) eGFR 51 ± 12 mL/min (placebo)	24	pVO₂↑ (P = 0.02)^[a] GAF↑ (P < 0.05) NYHA↓ (P < 0.05) NTproBNP↓ (NS)

^aOnly significant after imputation.
FS: ferrous sulphate; VO₂: peak VO₂; HRQoL: health-related quality of life; NYHA: New York Heart Association Class; NTproBNP: N-terminal prohormone of brain natriuretic peptide; 6 MWT: six-minute walk test; GAF: Global Assessment of Functioning; NS: non-significant; CrCl: creatinine clearance; sCr: serum creatinine.

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Iron Deficiency After Kidney Transplantation

Iron and Allograft Outcomes

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