Bone Marrow Iron in CKD: Correlation With Functional Iron Deficiency

Abstract

Related Article, p. 639Anemia frequently is encountered in patients with chronic kidney disease (CKD). The high prevalence of anemia in patients with CKD, even during its early stages, only recently has gained attention. Published data indicate that ∼50%-60% of patients with stage 4 CKD are anemic, and the prevalence of anemia increases to 75%-92% in patients reaching stage 5 CKD.1Obrador G.T. Roberts T. St. Peter W.L. et al.Trends in anemia at initiation of dialysis in the United States.Kidney Int. 2001; 60: 1875-1884Crossref PubMed Scopus (99) Google Scholar, 2Wen C.P. Cheng T.Y.D. Tsai M.K. et al.All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462293 adults in Taiwan.Lancet. 2008; 371: 2173-2182Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar Untreated, anemia in patients with CKD negatively affects cardiac function, increases cardiovascular risk, and subsequently may lead to further deterioration in kidney function. The relationship between CKD, cardiovascular disease, and anemia constitutes a vicious circle termed the cardiorenal anemia syndrome.3Tarng D.C. Cardiorenal anemia syndrome in chronic kidney disease.J Chin Med Assoc. 2007; 70: 424-429Abstract Full Text PDF PubMed Scopus (14) Google Scholar Although use of erythropoiesis-stimulating agents (ESAs) may improve the quality of life of patients with CKD by correcting anemia, iron deficiency emerges as a major limiting factor in the agents' effectiveness.4Tarng D.C. Huang T.P. Chen T.W. et al.Erythropoietin hyporesponsiveness: from iron deficiency to iron overload.Kidney Int Suppl. 1999; 69: S107-S118Crossref PubMed Google Scholar Provision of sufficient available iron using intravenous (IV) administration is a prerequisite to ensure the optimal response to ESA therapy. However, iron supplementation is a double-edged sword. On one hand, it allows patients to achieve increased hemoglobin concentrations using relatively lower doses of ESAs. On the other hand, it puts them at greater risk of infection, oxidative stress, and cardiovascular disease.5Cavill I. Intravenous iron as adjuvant therapy: a two-edged sword?.Nephrol Dial Transplant. 2003; 18: viii24-viii28Crossref PubMed Google Scholar Our recent study showed that IV iron provokes oxidative damage to peripheral-blood lymphocyte DNA in patients undergoing hemodialysis, especially those with high ferritin levels.6Kuo K.L. Hung S.C. Wei Y.H. Tarng D.C. Intravenous iron exacerbates oxidative DNA damage in peripheral blood lymphocytes in chronic hemodialysis patients.J Am Soc Nephrol. 2008; 19: 1817-1826Crossref PubMed Scopus (79) Google Scholar In addition, Drueke et al7Drueke T. Witko-Sarsat V. Massy Z. et al.Iron therapy, advanced oxidation protein products, and carotid artery intima-media thickness in end-stage renal disease.Circulation. 2002; 106: 2212-2217Crossref PubMed Scopus (339) Google Scholar observed a direct association between administered iron dose and degree of intima-media thickness, an early sign of atherosclerosis. Accurate assessment of iron status in patients with CKD therefore is essential for optimizing iron delivery while avoiding excess iron-induced genotoxicity and long-term complications. In this issue of the American Journal of Kidney Diseases, Stancu et al8Stancu S. Stanciu A. Zugravu A. et al.Bone marrow iron, iron indices, and the response to intravenous iron in patients with non–dialysis-dependent CKD.Am J Kidney Dis. 2010; 55: 639-647Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar add to the body of knowledge about the relationship between bone marrow iron, iron indices, and response to iron infusion in patients with CKD.In contrast to the abundant literature for the contribution of iron deficiency and ESA resistance in hemodialysis patients, little is known about iron status in patients with earlier stages of CKD.9Fishbane S. Iron management in nondialysis-dependent CKD.Am J Kidney Dis. 2007; 49: 736-743Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Patients with CKD theoretically are at low risk of iron deficiency because most factors of blood loss associated with dialysis therapy are not present or are present to a lesser degree in earlier stages. Enhanced erythropoiesis is triggered to a lesser extent because very few patients are treated with ESAs.10Besarab A. Levin A. Defining a renal anemia management period.Am J Kidney Dis. 2000; 36: S13-S23Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar However, recent analyses of National Health and Nutrition Examination Survey (NHANES) III and subsequent NHANES 2-year data sets by Fishbane et al11Fishbane S. Pollack S. Feldman H.I. Joffe M.M. Iron indices in chronic kidney disease in the National Health and Nutritional Examination Survey 1988-2004.Clin J Am Soc Nephrol. 2009; 4: 57-61Crossref PubMed Scopus (124) Google Scholar found that >60% of patients with a creatinine clearance < 60 mL/min had low levels for iron test results, either serum ferritin level < 100 μg/L or transferrin saturation (TSAT) < 20%.12National Kidney FoundationKDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease.Am J Kidney Dis. 2006; 47: S1-S146PubMed Google Scholar The degree of inflammation and oxidative stress is worse in patients with CKD than in healthy persons.13Witko-Sarsat V. Friedlander M. Capeillere-Blandin C. et al.Advanced oxidation protein products as a novel marker of oxidative stress in uremia.Kidney Int. 1996; 49: 1304-1313Crossref PubMed Scopus (1602) Google Scholar, 14Stenvinkel P. Heimburger O. Paultre F. et al.Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure.Kidney Int. 1999; 55: 1899-1911Crossref PubMed Scopus (1491) Google Scholar, 15Tarng D.C. Huang T.P. Wei Y.H. et al.8-Hydroxy-2′-deoxyguanosine of leukocyte DNA as a marker of oxidative stress in chronic hemodialysis patients.Am J Kidney Dis. 2000; 36: 934-944Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Hepcidin, a small peptide produced by the liver, may have a pivotal role in the link between anemia and inflammation in CKD. Hepcidin is induced by inflammation and iron loading. Through the regulation of ferroportin, hepcidin limits iron availability for erythropoiesis by inhibiting intestinal iron absorption and iron release from the liver and reticuloendothelial system.16Young B. Zaritsky A. Hepcidin for clinicians.Clin J Am Soc Nephrol. 2009; 4: 1384-1387Crossref PubMed Scopus (96) Google Scholar Thus, iron deficiency in patients with CKD may indicate not only low iron stores, but also impaired iron delivery associated with inflammation.Iron staining of a bone marrow biopsy specimen is widely regarded as the gold standard for the diagnosis of iron-deficient anemia. Recently, Gotloib et al17Gotloib L. Silverberg D. Shostak A. Iron deficiency is a very common cause of anemia in chronic kidney insufficiency and can often be corrected with IV iron.J Nephrol. 2006; 19: 161-167PubMed Google Scholar showed that 46 of 47 patients with CKD with a mean serum creatinine level of 2.7 mg/dL (239 μmol/L) and hemoglobin level <12 g/dL (<120 g/L) had no iron deposits in bone marrow biopsy specimens despite mean serum ferritin levels >200 ng/mL (>200 μg/L). The high prevalence (>95%) of iron deficiency in the study by Gotloib et al17Gotloib L. Silverberg D. Shostak A. Iron deficiency is a very common cause of anemia in chronic kidney insufficiency and can often be corrected with IV iron.J Nephrol. 2006; 19: 161-167PubMed Google Scholar was in line with the findings of Fishbane et al.11Fishbane S. Pollack S. Feldman H.I. Joffe M.M. Iron indices in chronic kidney disease in the National Health and Nutritional Examination Survey 1988-2004.Clin J Am Soc Nephrol. 2009; 4: 57-61Crossref PubMed Scopus (124) Google Scholar However, these results are not validated by 2 other studies. In 52 patients with CKD with a mean serum creatinine level of 8.0 mg/dL (707 μmol/L) and mean hemoglobin level of 9.36 g/dL (93.6 g/L), Rahman et al18Rahman M.M. Dutta P.K. Hoque M. et al.Evaluation of iron status by bone marrow iron stain and correlation with serum profile in chronic kidney disease (CKD).J Bangladesh Coll Physicians Surg. 2007; 25: 117-120Google Scholar found that only 23% were iron deficient based on the absence of iron staining in bone marrow aspirates. Similarly, Fernandez-Rodriguez et al19Fernandez-Rodriguez A.M. Guindeo-Casasus M.C. Molero-Labarta T. et al.Diagnosis of iron deficiency in chronic renal failure.Am J Kidney Dis. 1999; 34: 508-513Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar showed that 16 of 63 (25%) patients with CKD with a mean serum creatinine level of 9.3 mg/dL (822 μmol/L) and mean hemoglobin level of 10.6 g/dL (106 g/L) had no iron deposits in bone marrow biopsy specimens. Even in dialysis patients, the prevalence of iron deficiency ranged from only 23.5%-40% based on bone marrow iron staining.20Domrongkitchaiporn S. Jirakranont B. Atamasrikul K. et al.Indices of iron status in continuous ambulatory peritoneal dialysis patients.Am J Kidney Dis. 1999; 34: 29-35Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 21Kalantar-Zedeh K. Hoffken B. Wunsch H. Fink H. Kleiner M. Luft F.C. Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era.Am J Kidney Dis. 1995; 26: 292-299Abstract Full Text PDF PubMed Scopus (166) Google Scholar In the study by Kalantar-Zadeh et al,21Kalantar-Zedeh K. Hoffken B. Wunsch H. Fink H. Kleiner M. Luft F.C. Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era.Am J Kidney Dis. 1995; 26: 292-299Abstract Full Text PDF PubMed Scopus (166) Google Scholar the proportion of iron deficiency was 40% using an extremely rigorous bone marrow criterion, but increased to 65% using a less exclusive definition. Taken collectively, there is a large discrepancy in the prevalence of iron deficiency in patients with CKD in various studies.17Gotloib L. Silverberg D. Shostak A. Iron deficiency is a very common cause of anemia in chronic kidney insufficiency and can often be corrected with IV iron.J Nephrol. 2006; 19: 161-167PubMed Google Scholar, 18Rahman M.M. Dutta P.K. Hoque M. et al.Evaluation of iron status by bone marrow iron stain and correlation with serum profile in chronic kidney disease (CKD).J Bangladesh Coll Physicians Surg. 2007; 25: 117-120Google Scholar, 19Fernandez-Rodriguez A.M. Guindeo-Casasus M.C. Molero-Labarta T. et al.Diagnosis of iron deficiency in chronic renal failure.Am J Kidney Dis. 1999; 34: 508-513Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar This may be caused by differences in study populations and diagnostic criteria, small study sizes, and the accuracy of iron staining in bone marrow biopsy specimens or aspirates. Furthermore, most studies did not report patients' inflammatory status or previous iron intake and supplementation.Stancu et al8Stancu S. Stanciu A. Zugravu A. et al.Bone marrow iron, iron indices, and the response to intravenous iron in patients with non–dialysis-dependent CKD.Am J Kidney Dis. 2010; 55: 639-647Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar used iron staining in bone marrow aspirates to evaluate the predictive accuracy of peripheral-iron indices and erythropoietic response to IV iron in 100 anemic patients with CKD who were iron and ESA naive. Most recruited patients had stage 5 CKD (56%). In their report, bone marrow iron stores were depleted in 48% of patients at baseline. One month after IV administration of 1,000 mg of iron sucrose, the proportion of patients with a ≥ 1-g/dL (≥10-g/L) increase in hemoglobin level was higher in iron-depleted than iron-replete patients (65% vs 35%). However, in peripheral-iron indices and the erythropoietic response to IV iron therapy using bone marrow iron (depleted vs replete) as the reference, there were similar areas under the receiver operating characteristic curves of ∼75%. This suggested that serum ferritin, TSAT, and hemoglobin responses to IV iron have equivalent and modest utility in identifying patients with CKD with depleted iron stores.A key strength of that investigation is the use of bone marrow aspirates for the evaluation of iron deficiency. However, several issues need to be clarified. First, the invasive nature of the procedure and risk of complications limit its use in clinical practice. The commonly used method of grading marrow iron is semiquantitative and highly subjective. There still are certain limits even using macrophage and erythroblast iron to assess iron status.22Tham K.T. Cousar J.B. Macon W.R. Silver stain for ringed sideroblasts A sensitive method that differs from Perls' reaction in mechanism and clinical application.Am J Clin Pathol. 1990; 94: 73-76PubMed Google Scholar In particular, results may be imprecise when a bone marrow aspirate is diluted by blood.23Bain B. Clark D. Lampert I. The normal bone marrow.in: Bone Marrow Pathology. 2nd ed. Blackwell Science, Oxford, UK1992: 3-30Google Scholar This may explain why only 3% of their patients were classified as having “anemia of chronic inflammation.” The very low percentage was incompatible with the high prevalence of inflammation in this study because 60% of patients had C-reactive protein levels > 10 mg/L.Second, verification of iron in bone marrow specimens using microscopy cannot distinguish iron repletion from functional iron deficiency. Functional iron deficiency is present when the current iron tests do not indicate depletion of the body's iron stores, but patients respond to additional iron administration with an increase in hemoglobin level at a constant ESA dose.24Nissenson A.R. Strobos J. Iron deficiency in patients with renal failure.Kidney Int Suppl. 1999; 69: S18-S21Crossref PubMed Google Scholar Stancu et al8Stancu S. Stanciu A. Zugravu A. et al.Bone marrow iron, iron indices, and the response to intravenous iron in patients with non–dialysis-dependent CKD.Am J Kidney Dis. 2010; 55: 639-647Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar found that 35% of patients with bone marrow–stainable iron still responded to IV iron supplementation, indicating functional iron deficiency. Therefore, only a modest correlation was present between the erythropoietic response to IV iron and bone marrow iron stores in this study.Third, in patients without discernable bone marrow iron staining, only 65% responded to IV iron therapy. This may occur partly because the absence of stainable iron in bone marrow aspirate may not be an accurate indicator of marrow iron stores because significantly different amounts may be shown in the corresponding needle-biopsy specimen.25Fong T.P. Okafor L.A. Thomas Jr, W. Westerman M.P. Stainable iron in aspirated and needle-biopsy specimens of marrow: a source of error.Am J Hematol. 1977; 2: 47-51Crossref PubMed Scopus (21) Google Scholar It also may be caused in part by ineffective mobilization of IV-administered iron to areas that need iron the most and too short a study period (1 month) to capture the full effect of IV iron on hemoglobin production.26Van Wyck D.B. Roppolo M. Martinez C.O. et al.A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD.Kidney Int. 2005; 68: 2846-2856Crossref PubMed Scopus (166) Google ScholarAlthough bone marrow iron has long been considered the gold standard in evaluating iron deficiency, very few studies have addressed the accuracy of the test, and the value of other tests has been compared mostly against this standard.27Barron B.A. Hoyer J.D. Tefferi A. A bone marrow report of absent stainable iron is not diagnostic of iron deficiency.Ann Hematol. 2001; 80: 166-169Crossref PubMed Scopus (64) Google Scholar Bone marrow iron reflects stored iron, but not the iron readily available for erythropoiesis in patients treated with ESAs. To date, the only definite way to show functional iron deficiency in clinical practice is to evaluate the erythropoietic response to iron administration.24Nissenson A.R. Strobos J. Iron deficiency in patients with renal failure.Kidney Int Suppl. 1999; 69: S18-S21Crossref PubMed Google Scholar In Table 1, as convincingly shown by Stancu et al8Stancu S. Stanciu A. Zugravu A. et al.Bone marrow iron, iron indices, and the response to intravenous iron in patients with non–dialysis-dependent CKD.Am J Kidney Dis. 2010; 55: 639-647Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar and other investigators,20Domrongkitchaiporn S. Jirakranont B. Atamasrikul K. et al.Indices of iron status in continuous ambulatory peritoneal dialysis patients.Am J Kidney Dis. 1999; 34: 29-35Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar bone marrow iron becomes even less sensitive and specific for detecting functional iron deficiency. Because serum ferritin level and TSAT are influenced by inflammation and have excessive variability,33Tarng D.C. The conundrum of serum ferritin measurement in patients with chronic kidney disease.Nat Clin Practice Nephrol. 2009; 5: 66-67Crossref PubMed Scopus (6) Google Scholar, 34Ford B.A. Coyne D.W. Eby C.S. Scott M.G. Variability of ferritin measurements in chronic kidney disease; implications for iron management.Kidney Int. 2009; 75: 104-110Crossref PubMed Scopus (50) Google Scholar 4 studies20Domrongkitchaiporn S. Jirakranont B. Atamasrikul K. et al.Indices of iron status in continuous ambulatory peritoneal dialysis patients.Am J Kidney Dis. 1999; 34: 29-35Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 28Fishbane S. Kowalski E.A. Imbriano L.J. Maesaka J.K. The evaluation of iron status in hemodialysis patients.J Am Soc Nephrol. 1996; 7: 2654-2657PubMed Google Scholar, 29Tessitore N. Solero G.P. Lippi G. et al.The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin.Nephrol Dial Transplant. 2001; 16: 1416-1423Crossref PubMed Scopus (179) Google Scholar, 30Mittman N. Sreedhara R. Mushnick R. et al.Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO.Am J Kidney Dis. 1997; 30: 912-922Abstract Full Text PDF PubMed Scopus (144) Google Scholar point out the diverse sensitivities and specificities of the 2 iron measures (Table 1). The work by Stancu et al8Stancu S. Stanciu A. Zugravu A. et al.Bone marrow iron, iron indices, and the response to intravenous iron in patients with non–dialysis-dependent CKD.Am J Kidney Dis. 2010; 55: 639-647Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar highlights our need for developing alternative iron markers for use in patients with CKD. We recently found that reticulocyte hemoglobin content and transferrin receptor/log ferritin index have greater sensitivity in diagnosing iron deficiency anemia,31Chuang C.L. Liu R.S. Wei Y.H. Huang T.P. Tarng D.C. Early prediction of response to intravenous iron supplementation by reticulocyte haemoglobin content and high-fluorescence reticulocyte count in haemodialysis patients.Nephrol Dial Transplant. 2003; 18: 370-377Crossref PubMed Scopus (71) Google Scholar, 32Chen Y.C. Hung S.C. Tarng D.C. Association between transferrin receptor-ferritin index and conventional measures of iron responsiveness in hemodialysis patients.Am J Kidney Dis. 2006; 47: 1036-1044Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar which compares favorably with serum ferritin level and TSAT in predicting the erythropoietic response to IV iron in hemodialysis patients (Table 1). However, these new methods generally are not available. The reliability and value of these markers of interest have not been tested in CKD populations.Table 1Sensitivity and Specificity of Iron Measures for Detecting Functional Iron Deficiency in Patients With CKDReferencePatientsIron MeasuresSensitivity (%)Specificity (%)Stancu et al8Stancu S. Stanciu A. Zugravu A. et al.Bone marrow iron, iron indices, and the response to intravenous iron in patients with non–dialysis-dependent CKD.Am J Kidney Dis. 2010; 55: 639-647Abstract Full Text Full Text PDF PubMed Scopus (61) Google ScholarCKDBM iron (−)6565Domrongkitchaiporn et al20Domrongkitchaiporn S. Jirakranont B. Atamasrikul K. et al.Indices of iron status in continuous ambulatory peritoneal dialysis patients.Am J Kidney Dis. 1999; 34: 29-35Abstract Full Text Full Text PDF PubMed Scopus (30) Google ScholarPDBM iron (−)2580Ferritin <100 ng/mL13100TSAT <20%20100Fishbane et al28Fishbane S. Kowalski E.A. Imbriano L.J. Maesaka J.K. The evaluation of iron status in hemodialysis patients.J Am Soc Nephrol. 1996; 7: 2654-2657PubMed Google ScholarHDFerritin <100 ng/mL4875TSAT <21%8163Tessitore et al29Tessitore N. Solero G.P. Lippi G. et al.The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin.Nephrol Dial Transplant. 2001; 16: 1416-1423Crossref PubMed Scopus (179) Google ScholarHDFerritin <100 ng/mL3578TSAT <19%5978Mittman et al30Mittman N. Sreedhara R. Mushnick R. et al.Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO.Am J Kidney Dis. 1997; 30: 912-922Abstract Full Text PDF PubMed Scopus (144) Google ScholarHDFerritin <100 ng/mL3853TSAT <20%5060CHr <28 pg7871Tarng et al31Chuang C.L. Liu R.S. Wei Y.H. Huang T.P. Tarng D.C. Early prediction of response to intravenous iron supplementation by reticulocyte haemoglobin content and high-fluorescence reticulocyte count in haemodialysis patients.Nephrol Dial Transplant. 2003; 18: 370-377Crossref PubMed Scopus (71) Google ScholarHDCHr <28 pg7887Tarng et al32Chen Y.C. Hung S.C. Tarng D.C. Association between transferrin receptor-ferritin index and conventional measures of iron responsiveness in hemodialysis patients.Am J Kidney Dis. 2006; 47: 1036-1044Abstract Full Text Full Text PDF PubMed Scopus (33) Google ScholarHDTfR-F >0.69079Note: Erythropoietic response to iron therapy is used as the gold standard for the diagnosis of functional iron deficiency.Abbreviations and definitions: BM iron (−), absence of stainable iron in bone marrow; CHr, reticulocyte hemoglobin content; CKD, chronic kidney disease; HD, hemodialysis; PD, peritoneal dialysis; TfR-F, transferrin receptor/log ferritin index; TSAT, transferrin saturation. Open table in a new tab Bone marrow iron staining lacks accuracy in detecting functional iron deficiency in patients with CKD. The laboratory diagnosis of iron deficiency in patients with CKD has not been perfected because a true gold standard is lacking.35Wish J.B. Assessing iron status: beyond serum ferritin and transferrin saturation.Clin J Am Soc Nephrol. 2006; 1: S4-S8Crossref PubMed Scopus (405) Google Scholar, 36Brugnara C. A hematologic “gold standard” for iron-deficient states?.Clin Chem. 2002; 48: 981-982PubMed Google Scholar Most importantly, how do we confront the reality and advance patient care with the current knowledge that these conventional iron tests may not be ideal for assessing iron status in patients with CKD? When making decisions on iron management, trends in peripheral-iron indices over time should be considered, together with ESA responsiveness, change in hemoglobin levels, and current clinical status. Proper management of iron and ESA therapy in patients with CKD could result in substantial savings by decreasing inappropriate use of iron and ESAs, as well as better quality of care by avoiding exposure to unnecessary therapies or uninformative laboratory tests. Related Article, p. 639 Related Article, p. 639 Related Article, p. 639 Anemia frequently is encountered in patients with chronic kidney disease (CKD). The high prevalence of anemia in patients with CKD, even during its early stages, only recently has gained attention. Published data indicate that ∼50%-60% of patients with stage 4 CKD are anemic, and the prevalence of anemia increases to 75%-92% in patients reaching stage 5 CKD.1Obrador G.T. Roberts T. St. Peter W.L. et al.Trends in anemia at initiation of dialysis in the United States.Kidney Int. 2001; 60: 1875-1884Crossref PubMed Scopus (99) Google Scholar, 2Wen C.P. Cheng T.Y.D. Tsai M.K. et al.All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462293 adults in Taiwan.Lancet. 2008; 371: 2173-2182Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar Untreated, anemia in patients with CKD negatively affects cardiac function, increases cardiovascular risk, and subsequently may lead to further deterioration in kidney function. The relationship between CKD, cardiovascular disease, and anemia constitutes a vicious circle termed the cardiorenal anemia syndrome.3Tarng D.C. Cardiorenal anemia syndrome in chronic kidney disease.J Chin Med Assoc. 2007; 70: 424-429Abstract Full Text PDF PubMed Scopus (14) Google Scholar Although use of erythropoiesis-stimulating agents (ESAs) may improve the quality of life of patients with CKD by correcting anemia, iron deficiency emerges as a major limiting factor in the agents' effectiveness.4Tarng D.C. Huang T.P. Chen T.W. et al.Erythropoietin hyporesponsiveness: from iron deficiency to iron overload.Kidney Int Suppl. 1999; 69: S107-S118Crossref PubMed Google Scholar Provision of sufficient available iron using intravenous (IV) administration is a prerequisite to ensure the optimal response to ESA therapy. However, iron supplementation is a double-edged sword. On one hand, it allows patients to achieve increased hemoglobin concentrations using relatively lower doses of ESAs. On the other hand, it puts them at greater risk of infection, oxidative stress, and cardiovascular disease.5Cavill I. Intravenous iron as adjuvant therapy: a two-edged sword?.Nephrol Dial Transplant. 2003; 18: viii24-viii28Crossref PubMed Google Scholar Our recent study showed that IV iron provokes oxidative damage to peripheral-blood lymphocyte DNA in patients undergoing hemodialysis, especially those with high ferritin levels.6Kuo K.L. Hung S.C. Wei Y.H. Tarng D.C. Intravenous iron exacerbates oxidative DNA damage in peripheral blood lymphocytes in chronic hemodialysis patients.J Am Soc Nephrol. 2008; 19: 1817-1826Crossref PubMed Scopus (79) Google Scholar In addition, Drueke et al7Drueke T. Witko-Sarsat V. Massy Z. et al.Iron therapy, advanced oxidation protein products, and carotid artery intima-media thickness in end-stage renal disease.Circulation. 2002; 106: 2212-2217Crossref PubMed Scopus (339) Google Scholar observed a direct association between administered iron dose and degree of intima-media thickness, an early sign of atherosclerosis. Accurate assessment of iron status in patients with CKD therefore is essential for optimizing iron delivery while avoiding excess iron-induced genotoxicity and long-term complications. In this issue of the American Journal of Kidney Diseases, Stancu et al8Stancu S. Stanciu A. Zugravu A. et al.Bone marrow iron, iron indices, and the response to intravenous iron in patients with non–dialysis-dependent CKD.Am J Kidney Dis. 2010; 55: 639-647Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar add to the body of knowledge about the relationship between bone marrow iron, iron indices, and response to iron infusion in patients with CKD. In contrast to the abundant literature for the contribution of iron deficiency and ESA resistance in hemodialysis patients, little is known about iron status in patients with earlier stages of CKD.9Fishbane S. Iron management in nondialysis-dependent CKD.Am J Kidney Dis. 2007; 49: 736-743Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Patients with CKD theoretically are at low risk of iron deficiency because most factors of blood loss associated with dialysis therapy are not present or are present to a lesser degree in earlier stages. Enhanced erythropoiesis is triggered to a lesser extent because very few patients are treated with ESAs.10Besarab A. Levin A. Defining a renal anemia management period.Am J Kidney Dis. 2000; 36: S13-S23Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar However, recent analyses of National Health and Nutrition Examination Survey (NHANES) III and subsequent NHANES 2-year data sets by Fishbane et al11Fishbane S. Pollack S. Feldman H.I. Joffe M.M. Iron indices in chronic kidney disease in the National Health and Nutritional Examination Survey 1988-2004.Clin J Am Soc Nephrol. 2009; 4: 57-61Crossref PubMed Scopus (124) Google Scholar found that >60% of patients with a creatinine clearance < 60 mL/min had low levels for iron test results, either serum ferritin level < 100 μg/L or transferrin saturation (TSAT) < 20%.12National Kidney FoundationKDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease.Am J Kidney Dis. 2006; 47: S1-S146PubMed Google Scholar The degree of inflammation and oxidative stress is worse in patients with CKD than in healthy persons.13Witko-Sarsat V. Friedlander M. Capeillere-Blandin C. et al.Advanced oxidation protein products as a novel marker of oxidative stress in uremia.Kidney Int. 1996; 49: 1304-1313Crossref PubMed Scopus (1602) Google Scholar, 14Stenvinkel P. Heimburger O. Paultre F. et al.Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure.Kidney Int. 1999; 55: 1899-1911Crossref PubMed Scopus (1491) Google Scholar, 15Tarng D.C. Huang T.P. Wei Y.H. et al.8-Hydroxy-2′-deoxyguanosine of leukocyte DNA as a marker of oxidative stress in chronic hemodialysis patients.Am J Kidney Dis. 2000; 36: 934-944Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Hepcidin, a small peptide produced by the liver, may have a pivotal role in the link between anemia and inflammation in CKD. Hepcidin is induced by inflammation and iron loading. Through the regulation of ferroportin, hepcidin limits iron availability for erythropoiesis by inhibiting intestinal iron absorption and iron release from the liver and reticuloendothelial system.16Young B. Zaritsky A. Hepcidin for clinicians.Clin J Am Soc Nephrol. 2009; 4: 1384-1387Crossref PubMed Scopus (96) Google Scholar Thus, iron deficiency in patients with CKD may indicate not only low iron stores, but also impaired iron delivery associated with inflammation. Iron staining of a bone marrow biopsy specimen is widely regarded as the gold standard for the diagnosis of iron-deficient anemia. Recently, Gotloib et al17Gotloib L. Silverberg D. Shostak A. Iron deficiency is a very common cause of anemia in chronic kidney insufficiency and can often be corrected with IV iron.J Nephrol. 2006; 19: 161-167PubMed Google Scholar showed that 46 of 47 patients with CKD with a mean serum creatinine level of 2.7 mg/dL (239 μmol/L) and hemoglobin level <12 g/dL (<120 g/L) had no iron deposits in bone marrow biopsy specimens despite mean serum ferritin levels >200 ng/mL (>200 μg/L). The high prevalence (>95%) of iron deficiency in the study by Gotloib et al17Gotloib L. Silverberg D. Shostak A. Iron deficiency is a very common cause of anemia in chronic kidney insufficiency and can often be corrected with IV iron.J Nephrol. 2006; 19: 161-167PubMed Google Scholar was in line with the findings of Fishbane et al.11Fishbane S. Pollack S. Feldman H.I. Joffe M.M. Iron indices in chronic kidney disease in the National Health and Nutritional Examination Survey 1988-2004.Clin J Am Soc Nephrol. 2009; 4: 57-61Crossref PubMed Scopus (124) Google Scholar However, these results are not validated by 2 other studies. In 52 patients with CKD with a mean serum creatinine level of 8.0 mg/dL (707 μmol/L) and mean hemoglobin level of 9.36 g/dL (93.6 g/L), Rahman et al18Rahman M.M. Dutta P.K. Hoque M. et al.Evaluation of iron status by bone marrow iron stain and correlation with serum profile in chronic kidney disease (CKD).J Bangladesh Coll Physicians Surg. 2007; 25: 117-120Google Scholar found that only 23% were iron deficient based on the absence of iron staining in bone marrow aspirates. Similarly, Fernandez-Rodriguez et al19Fernandez-Rodriguez A.M. Guindeo-Casasus M.C. Molero-Labarta T. et al.Diagnosis of iron deficiency in chronic renal failure.Am J Kidney Dis. 1999; 34: 508-513Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar showed that 16 of 63 (25%) patients with CKD with a mean serum creatinine level of 9.3 mg/dL (822 μmol/L) and mean hemoglobin level of 10.6 g/dL (106 g/L) had no iron deposits in bone marrow biopsy specimens. Even in dialysis patients, the prevalence of iron deficiency ranged from only 23.5%-40% based on bone marrow iron staining.20Domrongkitchaiporn S. Jirakranont B. Atamasrikul K. et al.Indices of iron status in continuous ambulatory peritoneal dialysis patients.Am J Kidney Dis. 1999; 34: 29-35Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 21Kalantar-Zedeh K. Hoffken B. Wunsch H. Fink H. Kleiner M. Luft F.C. Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era.Am J Kidney Dis. 1995; 26: 292-299Abstract Full Text PDF PubMed Scopus (166) Google Scholar In the study by Kalantar-Zadeh et al,21Kalantar-Zedeh K. Hoffken B. Wunsch H. Fink H. Kleiner M. Luft F.C. Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era.Am J Kidney Dis. 1995; 26: 292-299Abstract Full Text PDF PubMed Scopus (166) Google Scholar the proportion of iron deficiency was 40% using an extremely rigorous bone marrow criterion, but increased to 65% using a less exclusive definition. Taken collectively, there is a large discrepancy in the prevalence of iron deficiency in patients with CKD in various studies.17Gotloib L. Silverberg D. Shostak A. Iron deficiency is a very common cause of anemia in chronic kidney insufficiency and can often be corrected with IV iron.J Nephrol. 2006; 19: 161-167PubMed Google Scholar, 18Rahman M.M. Dutta P.K. Hoque M. et al.Evaluation of iron status by bone marrow iron stain and correlation with serum profile in chronic kidney disease (CKD).J Bangladesh Coll Physicians Surg. 2007; 25: 117-120Google Scholar, 19Fernandez-Rodriguez A.M. Guindeo-Casasus M.C. Molero-Labarta T. et al.Diagnosis of iron deficiency in chronic renal failure.Am J Kidney Dis. 1999; 34: 508-513Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar This may be caused by differences in study populations and diagnostic criteria, small study sizes, and the accuracy of iron staining in bone marrow biopsy specimens or aspirates. Furthermore, most studies did not report patients' inflammatory status or previous iron intake and supplementation. Stancu et al8Stancu S. Stanciu A. Zugravu A. et al.Bone marrow iron, iron indices, and the response to intravenous iron in patients with non–dialysis-dependent CKD.Am J Kidney Dis. 2010; 55: 639-647Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar used iron staining in bone marrow aspirates to evaluate the predictive accuracy of peripheral-iron indices and erythropoietic response to IV iron in 100 anemic patients with CKD who were iron and ESA naive. Most recruited patients had stage 5 CKD (56%). In their report, bone marrow iron stores were depleted in 48% of patients at baseline. One month after IV administration of 1,000 mg of iron sucrose, the proportion of patients with a ≥ 1-g/dL (≥10-g/L) increase in hemoglobin level was higher in iron-depleted than iron-replete patients (65% vs 35%). However, in peripheral-iron indices and the erythropoietic response to IV iron therapy using bone marrow iron (depleted vs replete) as the reference, there were similar areas under the receiver operating characteristic curves of ∼75%. This suggested that serum ferritin, TSAT, and hemoglobin responses to IV iron have equivalent and modest utility in identifying patients with CKD with depleted iron stores. A key strength of that investigation is the use of bone marrow aspirates for the evaluation of iron deficiency. However, several issues need to be clarified. First, the invasive nature of the procedure and risk of complications limit its use in clinical practice. The commonly used method of grading marrow iron is semiquantitative and highly subjective. There still are certain limits even using macrophage and erythroblast iron to assess iron status.22Tham K.T. Cousar J.B. Macon W.R. Silver stain for ringed sideroblasts A sensitive method that differs from Perls' reaction in mechanism and clinical application.Am J Clin Pathol. 1990; 94: 73-76PubMed Google Scholar In particular, results may be imprecise when a bone marrow aspirate is diluted by blood.23Bain B. Clark D. Lampert I. The normal bone marrow.in: Bone Marrow Pathology. 2nd ed. Blackwell Science, Oxford, UK1992: 3-30Google Scholar This may explain why only 3% of their patients were classified as having “anemia of chronic inflammation.” The very low percentage was incompatible with the high prevalence of inflammation in this study because 60% of patients had C-reactive protein levels > 10 mg/L. Second, verification of iron in bone marrow specimens using microscopy cannot distinguish iron repletion from functional iron deficiency. Functional iron deficiency is present when the current iron tests do not indicate depletion of the body's iron stores, but patients respond to additional iron administration with an increase in hemoglobin level at a constant ESA dose.24Nissenson A.R. Strobos J. Iron deficiency in patients with renal failure.Kidney Int Suppl. 1999; 69: S18-S21Crossref PubMed Google Scholar Stancu et al8Stancu S. Stanciu A. Zugravu A. et al.Bone marrow iron, iron indices, and the response to intravenous iron in patients with non–dialysis-dependent CKD.Am J Kidney Dis. 2010; 55: 639-647Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar found that 35% of patients with bone marrow–stainable iron still responded to IV iron supplementation, indicating functional iron deficiency. Therefore, only a modest correlation was present between the erythropoietic response to IV iron and bone marrow iron stores in this study. Third, in patients without discernable bone marrow iron staining, only 65% responded to IV iron therapy. This may occur partly because the absence of stainable iron in bone marrow aspirate may not be an accurate indicator of marrow iron stores because significantly different amounts may be shown in the corresponding needle-biopsy specimen.25Fong T.P. Okafor L.A. Thomas Jr, W. Westerman M.P. Stainable iron in aspirated and needle-biopsy specimens of marrow: a source of error.Am J Hematol. 1977; 2: 47-51Crossref PubMed Scopus (21) Google Scholar It also may be caused in part by ineffective mobilization of IV-administered iron to areas that need iron the most and too short a study period (1 month) to capture the full effect of IV iron on hemoglobin production.26Van Wyck D.B. Roppolo M. Martinez C.O. et al.A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD.Kidney Int. 2005; 68: 2846-2856Crossref PubMed Scopus (166) Google Scholar Although bone marrow iron has long been considered the gold standard in evaluating iron deficiency, very few studies have addressed the accuracy of the test, and the value of other tests has been compared mostly against this standard.27Barron B.A. Hoyer J.D. Tefferi A. A bone marrow report of absent stainable iron is not diagnostic of iron deficiency.Ann Hematol. 2001; 80: 166-169Crossref PubMed Scopus (64) Google Scholar Bone marrow iron reflects stored iron, but not the iron readily available for erythropoiesis in patients treated with ESAs. To date, the only definite way to show functional iron deficiency in clinical practice is to evaluate the erythropoietic response to iron administration.24Nissenson A.R. Strobos J. Iron deficiency in patients with renal failure.Kidney Int Suppl. 1999; 69: S18-S21Crossref PubMed Google Scholar In Table 1, as convincingly shown by Stancu et al8Stancu S. Stanciu A. Zugravu A. et al.Bone marrow iron, iron indices, and the response to intravenous iron in patients with non–dialysis-dependent CKD.Am J Kidney Dis. 2010; 55: 639-647Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar and other investigators,20Domrongkitchaiporn S. Jirakranont B. Atamasrikul K. et al.Indices of iron status in continuous ambulatory peritoneal dialysis patients.Am J Kidney Dis. 1999; 34: 29-35Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar bone marrow iron becomes even less sensitive and specific for detecting functional iron deficiency. Because serum ferritin level and TSAT are influenced by inflammation and have excessive variability,33Tarng D.C. The conundrum of serum ferritin measurement in patients with chronic kidney disease.Nat Clin Practice Nephrol. 2009; 5: 66-67Crossref PubMed Scopus (6) Google Scholar, 34Ford B.A. Coyne D.W. Eby C.S. Scott M.G. Variability of ferritin measurements in chronic kidney disease; implications for iron management.Kidney Int. 2009; 75: 104-110Crossref PubMed Scopus (50) Google Scholar 4 studies20Domrongkitchaiporn S. Jirakranont B. Atamasrikul K. et al.Indices of iron status in continuous ambulatory peritoneal dialysis patients.Am J Kidney Dis. 1999; 34: 29-35Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 28Fishbane S. Kowalski E.A. Imbriano L.J. Maesaka J.K. The evaluation of iron status in hemodialysis patients.J Am Soc Nephrol. 1996; 7: 2654-2657PubMed Google Scholar, 29Tessitore N. Solero G.P. Lippi G. et al.The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin.Nephrol Dial Transplant. 2001; 16: 1416-1423Crossref PubMed Scopus (179) Google Scholar, 30Mittman N. Sreedhara R. Mushnick R. et al.Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO.Am J Kidney Dis. 1997; 30: 912-922Abstract Full Text PDF PubMed Scopus (144) Google Scholar point out the diverse sensitivities and specificities of the 2 iron measures (Table 1). The work by Stancu et al8Stancu S. Stanciu A. Zugravu A. et al.Bone marrow iron, iron indices, and the response to intravenous iron in patients with non–dialysis-dependent CKD.Am J Kidney Dis. 2010; 55: 639-647Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar highlights our need for developing alternative iron markers for use in patients with CKD. We recently found that reticulocyte hemoglobin content and transferrin receptor/log ferritin index have greater sensitivity in diagnosing iron deficiency anemia,31Chuang C.L. Liu R.S. Wei Y.H. Huang T.P. Tarng D.C. Early prediction of response to intravenous iron supplementation by reticulocyte haemoglobin content and high-fluorescence reticulocyte count in haemodialysis patients.Nephrol Dial Transplant. 2003; 18: 370-377Crossref PubMed Scopus (71) Google Scholar, 32Chen Y.C. Hung S.C. Tarng D.C. Association between transferrin receptor-ferritin index and conventional measures of iron responsiveness in hemodialysis patients.Am J Kidney Dis. 2006; 47: 1036-1044Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar which compares favorably with serum ferritin level and TSAT in predicting the erythropoietic response to IV iron in hemodialysis patients (Table 1). However, these new methods generally are not available. The reliability and value of these markers of interest have not been tested in CKD populations. Note: Erythropoietic response to iron therapy is used as the gold standard for the diagnosis of functional iron deficiency. Abbreviations and definitions: BM iron (−), absence of stainable iron in bone marrow; CHr, reticulocyte hemoglobin content; CKD, chronic kidney disease; HD, hemodialysis; PD, peritoneal dialysis; TfR-F, transferrin receptor/log ferritin index; TSAT, transferrin saturation. Bone marrow iron staining lacks accuracy in detecting functional iron deficiency in patients with CKD. The laboratory diagnosis of iron deficiency in patients with CKD has not been perfected because a true gold standard is lacking.35Wish J.B. Assessing iron status: beyond serum ferritin and transferrin saturation.Clin J Am Soc Nephrol. 2006; 1: S4-S8Crossref PubMed Scopus (405) Google Scholar, 36Brugnara C. A hematologic “gold standard” for iron-deficient states?.Clin Chem. 2002; 48: 981-982PubMed Google Scholar Most importantly, how do we confront the reality and advance patient care with the current knowledge that these conventional iron tests may not be ideal for assessing iron status in patients with CKD? When making decisions on iron management, trends in peripheral-iron indices over time should be considered, together with ESA responsiveness, change in hemoglobin levels, and current clinical status. Proper management of iron and ESA therapy in patients with CKD could result in substantial savings by decreasing inappropriate use of iron and ESAs, as well as better quality of care by avoiding exposure to unnecessary therapies or uninformative laboratory tests. Financial Disclosure: The authors declare that they have no relevant financial interests. Bone Marrow Iron, Iron Indices, and the Response to Intravenous Iron in Patients With Non–Dialysis-Dependent CKDAmerican Journal of Kidney DiseasesVol. 55Issue 4PreviewInformation about iron stores and their relationship with transferrin saturation (TSAT), serum ferritin, and the erythropoietic response to iron therapy is scarce in anemic non–dialysis-dependent patients with chronic kidney disease (CKD). We examined the diagnostic utility of peripheral-iron indices and the erythropoietic response to intravenous iron as indices of iron store depletion using bone marrow iron as a reference test in anemic non–dialysis-dependent patients with CKD. Full-Text PDF