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Guideline 1.5 – Evaluation of Anaemia – Baseline Investigations

Guideline 1.5 – Evaluation of Anaemia – Baseline Investigations

We recommend that initial clinical and laboratory evaluation of anaemia should be performed prior to initiation of treatment for anaemia in people with CKD. (1A)

Guideline 1.5.1

We recommend that laboratory evaluation should include the following tests (1B):

  • Full blood count (FBC) including—in addition to the Hb concentration:
  • Red blood cell indices:
  • Mean corpuscular haemoglobin [MCH]
  • Mean corpuscular volume [MCV]
  • Mean corpuscular haemoglobin concentration [MCHC])
  • White blood cell count and differential count
  • Platelet count
  • Absolute reticulocyte count to assess bone marrow responsiveness (if indicated)

Tests to Determine Iron Status:

  • Percentage of hypochromic red blood cells (% HRC), but only if processing of blood sample is possible within 6 hours or
  • Reticulocyte Hb count (CHr) or equivalent tests e.g., reticulocyte Hb equivalent (RET-He) or
  • Combination of transferrin saturation (TSAT) and serum ferritin if the above tests are not available or the person has thalassemia or thalassemia trait
  • Serum ferritin to assess iron stores
  • Plasma/serum C-reactive protein (CRP) to assess possible inflammation

Guidelines 1.5.2

Based on the initial assessment, we recommend in selected cases; the following tests may be useful to diagnose the cause of anaemia (1B):

  • Serum B12 and serum folate concentrations
  • Tests for haemolysis (plasma/serum levels of haptoglobin, lactate dehydrogenase, bilirubin, Coombs’ test)
  • Plasma/serum and/or urine protein electrophoresis
  • Hb electrophoresis
  • Free light chains and bone marrow examination

Rationale

Although relative erythropoietin deficiency is common among people with anaemia and CKD, other potential causes should be identified or excluded. A clinical and laboratory evaluation of the cause of anaemia should precede initiation of ESA therapy. The recommended laboratory evaluation aims at assessing:

  • The degree and cause of anaemia,
  • Bone marrow responsiveness, and
  • Iron stores and iron availability for erythropoiesis.

Anaemia due to causes other than erythropoietin deficiency should be suspected when:

  • The severity of the anaemia is disproportionate to the deficit in kidney function,
  • There is evidence of iron deficiency,
  • There is evidence of haemolysis, or
  • There is evidence of bone marrow disorder as manifest by leucopoenia and/or thrombocytopenia.

a) Assessment of anaemia severity

In people with CKD not yet requiring dialysis and in those on peritoneal dialysis (PD), the timing of the blood sample draw is not critical because plasma volume in these people remains relatively constant. In people receiving haemodialysis (HD) one issue remains to be clarified. Haemoglobin concentrations are routinely measured in people receiving dialysis before dialysis. This potentially leads to lower haematocrit values as a result of dilution from fluid overload prior to ultrafiltration and an underestimate to actual haemoglobin value.

Interdialytic weight gain contributes to a decrease in Hb level, whereas intradialytic ultrafiltration leads to an increase in Hb level. Thus, a pre-dialysis sample underestimates the euvolaemic Hb level, whereas a post-dialysis sample overestimates the euvolaemic Hb. Indeed, changes on haematocrit can vary from the start to the end of dialysis by up to 6% depending on the volume of ultrafiltration. In a study of 68 stable people receiving HD receiving erythropoietin subcutaneously, average mean pre-dialysis Hb was 10 g/L lower than average post-dialysis Hb (1). There was a strong linear inverse correlation between percentage of change in Hb and haematocrit (Hct) values and percentage of change in body weight. In another study of 49 stable HD patients, among all pre-HD and post-HD Hb values, levels measured at the end of short dialysis intervals were closest to the mean Hb value of the week, derived from calculation of the area under the curve for the readings of the week (2). In unit-based haemodialysis persons receiving thrice weekly dialysis, Hb monitoring performed prior to a mid-week haemodialysis session would minimise Hb variability due to the longer inter-dialytic interval between the last treatment of one week and the first of the next.

  1. Movilli E, Pertica N, Camerini C et al. Pre dialysis versus post dialysis haematocrit evaluation during erythropoietin therapy. Am J Kidney Dis 2002; 39:850-853.
  2. Bellizzi V, Minutolo R, Terracciano V et al. Influence of the cyclic variation of hydration status on haemoglobin levels in haemodialysis patients. Am J Kidney Dis 2002; 40:549-555.

b) Assessment of Bone Marrow Responsiveness

In general, anaemia of CKD (anaemia of chronic disease) is normochromic and normocytic and is morphologically indistinguishable from the anaemia of chronic illness. Initial assessment of anaemia in people with CKD should aim at identifying other factors that may influence the response to treatment.

  • In addition to Hb, other indices of the full blood count (FBC) report may provide important clinical information: Macrocytosis could be due to folate or vitamin B12 deficiency.
  • In addition to anaemia of CKD, microcytosis could be due to iron deficiency or haemoglobinopathies.
  • Macrocytosis with leucopenia or thrombocytopenia could be due to several factors such as alcohol intake, nutritional deficit (vitamin B12 or folate deficiency), or myelodysplasia.
  • Serum folate is more prone to variation and can be affected by the person’s diet immediately prior to blood being taken, alcohol, trauma and other factors therefore occasionally red cell folate may need to be measured where serum folate is equivocal.
  • Haemolysis is suggested by the presence of macrocytosis, high lactate dehydrogenase and positive Coombs test.
  • The normal absolute reticulocyte count ranges from 40,000 to 50,000 cells/μL. Although it has a significant inter-patient variability, this test may be useful as a semi-quantitative marker of erythropoietic activity.

c) Evaluating Iron Status in Anaemic People with CKD

The aim of evaluating iron status is to assess:

1. Iron level in tissue stores and

2. The adequacy of iron utilisation for erythropoiesis.

Serum ferritin level is the only available blood marker of storage iron. There are several tests to assess adequacy of iron for erythropoiesis: TSAT, MCV, MCH, percentage of hypochromic red blood cells (HRC) and reticulocyte Hb content (CHr) or RET-He. Serum iron has not routinely been studied in people with CKD.

Tests limitations

  • HRC estimation is a useful test for assessment of iron availability but is limited by the effect of sample storage time and need for special analysers. Long sample storage time (> 6 hours) may spuriously increase HRC. Because a fresh sample is needed, this measure may not be practical in routine clinical practice, especially in satellite dialysis patients.
  • If using percentage of hypochromic red blood cells from a fresh sample is not possible, reticulocyte Hb content (CHr) or RET-He could be a suitable alternative.
  • If testing for CHr (or RET-He) is not feasible, it is preferable to test ferritin and TSAT together because the combination provides an important insight into erythropoiesis, iron storage and iron availability to bone marrow.
  • Low serum ferritin is diagnostic of iron deficiency. High serum ferritin, in addition to expressing the adequacy of iron stores, could be due to inflammatory conditions. TSAT is influenced by nutritional status, timing and inflammation. TSAT is also limited by high day-to-day variations.

Historically in people with NDD-CKD, it was proposed that serum ferritin levels less than 25 ng/mL in males and less than 12 ng/mL in females were suggestive of depletion of iron stores as a cause of anaemia; but serum ferritin level is less reliable in the evaluation of iron stores in people with NDD-CKD and in those receiving HD, because ferritin level is affected by other factors in addition to iron storage status. In relatively healthy people receiving HD, before widespread use of IV iron therapy, the finding of a ferritin level less than 50 ng/mL was not uncommon (1) and was associated with absent bone marrow iron in approximately 80% of people (2). However, in people receiving HD with several co-morbidities, absent iron stores may still be found at ferritin levels approaching or even exceeding 200 ng/mL (3).

Iron-deficiency is most likely to contribute to anaemia when TSAT results are less than 20%. However, the clinical utility of TSAT is impaired by the absence of a diagnostic threshold above which deficient iron utilisation can be excluded as a cause of anaemia (4).

There is little information in literature to guide the approach to people with CKD who show laboratory evidence of iron deficiency. Nevertheless, given the high prevalence of GI blood loss due to variety of causes in this population, deciding on a subsequent management plan, including endoscopy, depends on the clinical presentation. This supports the recommendation that people with CKD who present with anaemia and iron deficiency should undergo careful clinical assessment prior to the initiation of anaemia therapy (5-7).

Reduced iron availability for erythropoiesis can manifest as low mean corpuscular volume (MCV) and mean corpuscular Hb (MCH), but given the relatively long lifespan of circulating erythrocyte, this test will not reflect the existing availability of iron at the time of testing. Testing the reticulocytes for their Hb content (CHr or RET-He) may allow more accurate estimation of iron availability, because reticulocytes are present in the circulation for 4-5 days, so give a discrete population to study. Reduced red cell Hb can be reflective of reduced haem availability or globin. Therefore, the red cell analyte values (%HRC, CHr, Ret-He) may be affected by the presence of haemoglobinopathies (4).

  1. Fishbane S, Lynn RI. The efficacy of iron dextran for the treatment of iron deficiency in haemodialysis patients. Clin Nephrol 1995; 44:238-240.
  2. Fernandez-Rodriguez AM, Guindeo-Casasus MC, Molero-Labarta T et al. Diagnosis of iron deficiency in chronic renal failure. Am J Kidney Dis 1999; 34:508-513.
  3. Kalantar-Zadeh K, Hoffken B, Wunsch H, Fink H et al FC. Diagnosis of iron deficiency anaemia in renal failure patients during the post-erythropoietin era. Am J Kidney Dis 1995; 26:292-299.
  4. KDOQI guidelines on anaemia management: http://www2.kidney.org/professionals/KDOQI/guidelines_anemia/guide1.htm (accessed 15/06/2017.
  5. Coban E, Timuragaoglu A, Meric M. Iron deficiency anaemia in the elderly: Prevalence and endoscopic evaluation of the gastrointestinal tract in outpatients. Acta Haematol 2003; 110:25- 28.
  6. Ioannou GN, Rockey DC, Bryson CL et al. Iron deficiency and gastrointestinal malignancy: A population-based cohort study. Am J Med 2002; 113:276-280.
  7. Ioannou GN, Spector J, Scott K, et al. Prospective evaluation of a clinical guideline for the diagnosis and management of iron deficiency anaemia. Am J Med 2002; 113:281-287.