Iron-Deficiency Anemia in Non-Dialysis CKD

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Anemia is a common complication of chronic kidney disease (CKD) that develops early in the course of disease and worsens as CKD progresses.1 Anemia is twice as prevalent among patients with CKD compared with the general population (15.4% vs 7.6%), with the prevalence of anemia among patients with CKD rising from 8.4% in stage 1 to 53.4% in stage 5.2 Although diminished erythropoietin production by the kidneys is a common cause of anemia in patients with CKD, iron deficiency also can be a contributing factor.1,3 Extensive research has resulted in a wealth of information about iron status and its association with anemia in dialysis patients, but this association is less well studied in the non-dialysis CKD (ND-CKD) population.4 Studies suggest that a substantial proportion of patients with ND-CKD may have iron deficiency, based on the findings of bone marrow biopsies and the conventional blood iron indices transferrin saturation (TSAT) and serum ferritin. Here are examples from the literature:

  • A study of 100 anemic (hemoglobin less than 11 g/dL) patients with ND-CKD who underwent bone marrow aspiration—which is considered the gold standard for assessing iron deficiency—found that 48% had depleted iron stores in their bone marrow and 17% had TSAT less than 20% and serum ferritin level less than 100 ng/mL,5 which are widely used criteria for diagnosing iron deficiency.6
  • Israeli investigators who performed bone marrow biopsies on 47 patients with ND-CKD who had anemia of unknown cause reported that 46 of them had no evidence of any iron deposits in the bone marrow, consistent with the presence of severe iron deficiency.6
  • A study of 102 patients with ND-CKD entering a hemodialysis (HD) program showed that 28.4% had iron deficiency.4 The authors commented: "To our surprise, there was a very high prevalence of iron deficiency in patients starting dialysis."
  • Japanese researchers who conducted a prospective study of 951 patients with ND-CKD (the CKD-ROUTE study) found that 15% of patients had iron deficiency, which the investigators defined as TSAT of 20% or less and serum ferritin of 100 ng/mL or less.7
  • An analysis of NHANES (National Health and Nutrition Examination Survey) 1988–2004 data found low iron indices in most individuals with CKD.8 Among those with a creatinine clearance of less than 60 mL/min (CKD stages 3–5), the percentage of individuals with either TSAT less than 20% or serum ferritin less than 100 ng/mL was 57.8% to 58.8% in men and 69.9% to 72.8% in women.

Increased mortality

Anemia is a risk factor for mortality among patients with ND-CKD. In the CKD-ROUTE study, researchers found that patients who had anemia with or without iron deficiency had a 3-fold increased risk of all-cause mortality and a nearly 4-fold increased risk of cardiovascular mortality compared with controls who had neither anemia nor iron deficiency.7 In the anemic patients without iron deficiency, the proportion of those who were prescribed erythropoiesis-stimulating agents (ESAs) rose from 31.1% at baseline to 68.9% at 6 months. In patients with both iron deficiency and anemia, the proportion of those prescribed iron supplementation increased from 18.5% at baseline to 48.1% at 6 months. The authors concluded that iron prescriptions for anemic patients with iron deficiency did not sufficiently increase compared with the increase in ESA prescriptions. "These results suggest that it is necessary to assess iron deficiency and to appropriately use iron supplementation," the authors concluded.

Inflammation and iron assessment

TSAT and serum ferritin are the most widely used laboratory parameters for assessing iron status, but both of these markers are subject to excessive biological variability and require caution when used to guide iron supplementation in patients with CKD.9 These markers show relatively poor correlation with bone marrow stores and erythropoietic response to iron treatment.1 Underlying inflammation, which is common in patients with CKD, complicates the diagnosis of iron-deficiency anemia. Inflammation increases levels of hepcidin, a peptide hormone synthesized mainly in the liver. It is a key regulator of iron metabolism that inhibits release of iron from macrophages and hepatocytes and blocks intestinal absorption of dietary iron. TSAT values usually are low (less than 20%) in patients with high hepcidin levels due to inflammation because iron is not released for binding to transferrin. Ferritin values rise to above 100 ng/mL, possibly indicating adequate body stores, the presence of inflammation, or both.1 Patients with functional iron-deficiency anemia respond to iron supplementation, which helps to distinguish it from anemia caused by inflammation.1 Szu-Chun Hung, MD, and Der-Cherng Tarng, MD, PhD, pointed out in an editorial in the American Journal of Kidney Diseases that bone marrow iron reflects stored iron, not the iron readily available for erythropoiesis in patients receiving ESAs. "To date, the only definite way to show functional iron deficiency in clinical practice is to evaluate the erythropoietic response to iron administration."10

Alternative and novel iron biomarkers

Although TSAT and serum ferritin are the most widely used iron biomarkers, other laboratory tests available to US clinicians may provide more accurate assessments of iron status. These include reticulocyte hemoglobin content (CHr), percentage of hypochromic red cells (PHRC), and soluble transferrin receptor (sTfR).

lthough TSAT and serum ferritin are the most widely used iron biomarkers, other laboratory tests available to US clinicians may provide more accurate assessments of iron status. These include reticulocyte hemoglobin content (CHr), percentage of hypochromic red cells (PHRC), and soluble transferrin receptor (sTfR).

CHr is a measure of the hemoglobin content of reticulocytes, newly formed red blood cells (RBCs). As Jay B. Wish, MD, explained in a review article, CHr provides a "snapshot of how much iron was available for RBC production in a clinically relevant timeframe."11

PHRC assays measure the hemoglobin concentration in erythrocytes rather than hemoglobin content. It takes into account the absolute amount of hemoglobin as well as the size of RBCs. As Dr Wish points out, the major impediment to the use of this test in the United States is that erythrocytes tend to expand during storage. Most of the large dialysis chains ship blood samples to national laboratories for analyses, and there is considerable storage time from when blood samples are collected until they are analyzed.11

The sTfR test is based on the fact that iron deficiency will cause erythroblasts in the bone marrow to increase presentation of membrane transferrin receptor. "If a patient is not receiving sufficient iron and erythropoiesis is being stimulated by an ESA, then increased transferrin receptors will become expressed on the erythroblasts, some of which come off and will be detectable in the circulation," Dr Wish explained.11

Hepcidin

As mentioned previously, elevated levels of hepcidin decrease absorption of dietary iron and impair release of iron stores in hepatocytes and macrophages. These elevated levels may be the result of underlying inflammation as well as diminished kidney function. As kidney function deteriorates, the ability to clear hepcidin may decrease, leading to higher hepcidin levels.12 Evidence suggests that hepcidin may be a useful biomarker of iron status. As Guido D'Angelo, MD, of Azienda Ospedaliera S.Antonio Abate di Callarate, Varese, Italy, observed in a review article,13 serum and urinary hepcidin concentrations in pure iron-deficiency anemia are significantly decreased and are even undetectable by some currently used methods. "Even in the absence of anemia, hepcidin appears to be a sensitive indicator of iron deficiency," he noted. "Moreover, compared to hematocrit or hemoglobin, a decrease in hepcidin is an early marker of iron deficiency together with transferrin saturation and decreased ferritin."


Iron Deficiency in CKD:
An Interview with Jeffrey S. Berns, MD

Jeffrey S. Berns, MD, is Professor of Medicine and Pediatrics in the University of Pennsylvania's Perelman School of Medicine in Philadelphia. He recently co-authored a review article in Seminars in Nephrology titled, “Diagnosis of Iron Deficiency in Chronic Kidney Disease.” Last year, he wrote an article for Renal & Urology News titled, “Managing Anemia in Cancer Patients with CKD.”

How should clinicians think about iron-deficiency anemia in non-dialysis versus dialysis patients?
Iron assessment in both patient populations can be problematic. The laboratory tests that we have for assessing iron deficiency are not very good. Iron testing has become a routine part of dialysis patient anemia management, but I'm not so sure that it's become an equivalently common part of non-dialysis CKD patient iron assessment. Whether patients are on dialysis or not, it's important to not assume that erythropoietin deficiency is the only thing going on. It's important not to forget that a patient may have iron deficiency. It's more likely that a CKD patient seen in the office might be started on an erythropoiesis-stimulating agent without regular follow-up of what's happening to iron sufficiency over time compared to dialysis patients.

Given the unreliability of conventional iron indices (TSAT and serum ferritin), how does a clinician clinch the diagnosis of IDA in non-dialysis CKD patients?
The most important thing is whether patients are going to respond to supplemental iron to achieve a hemoglobin goal. Sometimes I think it's just worth giving iron. Unless you know for a fact they will not respond, giving iron may sometimes be the best diagnostic approach rather than additional laboratory testing. There are CKD patients who probably are more likely to respond to iron supplementation than meet laboratory criteria for iron deficiency. In the hemodialysis patient, it's easy to give intravenous iron because intravenous access is already established, whereas in the office patient with chronic kidney disease, and similarly for the patient on peritoneal dialysis, we don't have established intravenous access. There's a tendency for clinicians to more often at least try oral iron in those patient populations.

Should clinicians increase their use of alternative biomarkers, such as reticulocyte hemoglobin content, that have been shown to provide a more accurate reflection of iron status?
These tests have never really caught on in the United States. The major reason is that the machines to measure them are not readily available. I'm not sure that any of these tests are sufficiently reliable across a very heterogeneous population to consistently say, "yes, this patient would benefit, no, this patient would not." I think they give us hints, but not a definitive answer.

Given that inflammation mediates iron homeostasis via its effect on hepcidin, should laboratory tests for CKD anemia include inflammatory markers (e.g.,C-reactive protein, IL-6)?
Not at this time. I don't think this has been looked at in a sufficiently systematic way, and we don't really yet have reliable and standardized tests. And I think we would end up with more tests that don't give us a clear answer.


The potential utility of hepcidin as a biomarker in kidney disease emerged from a study by Joshua Zaritsky, MD, et al.14 Theresearchers measured serum hepcidin in 48 pediatric patients with CKD stage 2–4 (PCKD2–4), 32 adult patients with CKDstage 2–4 (ACKD2–4), and 26 pediatric patients with stage 5 CKD on peritoneal dialysis (PCKD5D). Results showed significantly elevated hepcidin levels in all of the CKDgroups compared with healthy controls. Median hepcidin levels were 127.3, 269.9, and 652.4 ng/ mL in the PCKD2–4, ACKD2–4, and PCKD5D groups, respectively, compared with 25.3 and 72.9 ng/mL in the pediatric and adult controls, respectively. In PCKD2–4, only ferritin correlated with hepcidin. In ACKD2–4, ferritin and sTfR were associated with hepcidin, whereas GFR was inversely correlated.14 In multivariate analysis that incorporated all 3 groups, hepcidin was predicted by ferritin, C-reactive protein, and whether the patient had CKD stage 5D vs CKD stages 2–4.

"These findings suggest that increased hepcidin across the spectrum of CKD may contribute to abnormal iron regulation and erythropoiesis and may be a novel biomarker of iron status and erythropoietin resistance," Dr Zaritsky and colleagues concluded.14

In a review article, Derek S. Larson, MD, and Daniel W. Coyne, MD, say hepcidin holds promise as an important biomarker of iron metabolism, but observed: "At present, the measurement of hepcidin is erratic and does not provide any current diagnostic value over ferritin and other available iron studies."15

NGAL

Another biomarker with potential usefulness in assessing iron status in patients with CKD is plasma neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of acute kidney injury. A recent study showed that plasma NGAL was independently associated with TSAT and was superior to serum ferritin in both sensitivity and specificity in identifying iron deficiency in patients with pre-dialysis CKD.16 "The main finding in the present study is that the plasma NGAL is associated with iron indices and might be a more useful marker than serum ferritin for determining the iron status in pre-dialysis CKD patients," the authors wrote.

Conclusion

Iron deficiency is common among patients with ND-CKD and anemia, but diagnosing it remains a challenge in many cases because of underlying inflammation that influences iron metabolism in a way that makes it difficult to interpret TSAT and serum ferritin values, the most widely used iron indices. Yet correction of iron deficiency, such as with iron supplementation, may be necessary for the successful treatment of anemia in a substantial proportion of the ND-CKD population. Thus, additional clinical considerations may be warranted for these patients. ■


REFERENCES

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  16. Kim IY, Kim JH, Lee DW et al. Plasma neutrophil gelatinase-associated lipocalin is associated with iron status in anemic patients with pre-dialysis chronic kidney disease. Clin Exp Nephrol 2017; published online ahead of print.
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