The Fascinating but Deceptive Ferritin

Kamyar Kalantar-Zadeh,Grace H Lee,Kourosh Kalantar-Zadeh

doi:10.2215/cjn.01390406

Abstract

Although the emergence of erythropoiesis-stimulating agents has revolutionized the anemia management of chronic kidney disease (CKD) in the past two decades, strategies to assess iron (Fe) status and to provide Fe supplementation have remained indistinct. The reported cases of hemochromatosis in dialysis patients from the pre-erythropoiesis-stimulating agent era along with the possible associations of Fe with infection and oxidative stress have fueled the "iron apprehension." To date, no reliable marker of Fe stores in CKD has been agreed on. Serum ferritin continues to be the focus of attention. Almost half of all maintenance hemodialysis patients have a serum ferritin >500 ng/ml. In this ferritin range, Fe supplementation currently is not encouraged, although most reported hemochromatosis cases had a serum ferritin >2000 ng/ml. The moderate-range hyperferritinemia (500 to 2000 ng/ml) seems to be due mostly to non-Fe-related conditions, including inflammation, malnutrition, liver disease, infection, and malignancy. Recent epidemiologic studies have shown that a low, rather than a high, serum Fe is associated with a poor survival in maintenance hemodialysis patients. In multivariate adjusted models that mitigate the confounding effect of malnutrition-inflammation, serum ferritin <1200 ng/ml and Fe saturation ratio in 30 to 50% range are associated with the greatest survival in maintenance hemodialysis patients. Although ferritin is a fascinating molecule, moderate hyperferritinemia is a misleading marker of Fe stores in patients with CKD. It may be time to revisit the utility of serum ferritin in CKD and ask ourselves whether its measurement has helped us or has caused more confusion and controversy.

Highlights

The anemia of chronic kidney disease (CKD) is associated with poor outcome, including higher death risk in both maintenance dialysis patients [1] and individuals who have CKD stages 3 to 5 and are not yet on dialysis [2]
Examining prospectively collected historical data of a large national dialysis patients database with 58,058 hemodialysis patients in the United States over a 2-yr observation period (July 2001 through June 2003), we recently found that after extensive time-dependent and multivariate adjustment including for malnutrition-inflammation-cachexia syndrome (MICS) surrogates, the presence of serum ferritin levels between 200 and 1200 ng/ml was associated with the lowest all-cause and cardiovascular death risk (Figure 3) [37]
“In the opinion of the [Kidney Disease Outcomes Quality Initiative (K/DOQI)] Work Group, there is insufficient evidence to recommend routine administration of intravenous Fe if serum ferritin level is greater than 500 ng/ml

Summary

Limitations

Painful, semiquantitative Invasive, risk for complications, semiquantitative Investigational; limited experience in CKD Moderately high levels are mostly due to non–Fe-related conditions Denominator (TIBC) can be low in malnutrition and/or inflammation Diurnal fluctuation, can be low in inflammation Limited data in CKD, cutoff level debatable Samples cannot be shipped to outside laboratories Mixed results, unknown cutoff levels. The clinical significance of serum ferritin measurement in patients with CKD seems to be somewhat different than in the general population, and the current guidelines to use serum ferritin for Fe overload screening might be flawed when applied to the CKD population [40] Using such arbitrary upper limits as 500 or 800 ng/ml to recommend withholding Fe administration in patients with CKD may be scientifically flawed, because moderately high levels of serum ferritin do not necessarily indicate Fe overload but most likely inflammation, infection, malnutrition, liver disease, and/or other non–Fe-related factors in CKD. BThe ferritin deficiency syndrome can be present if serum ferritin level is Ͻ50 ng/ml (see text)

Conclusion

Findings

National Kidney Foundation