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Iron deficiency and iron deficiency anaemia in chronic kidney disease — investigation and management

CASE REPORT

A 70-year-old male farmer was referred to the kidney clinic at University Hospital Limerick with a serum creatinine of 254µmol/L and estimated kidney function of 22m/min/1,73m2.

His principal symptoms were shortness of breath on exertion and increasing fatigability that progressed over several weeks. A detailed review of clinical and laboratory records revealed evidence of CKD based on previously elevated creatinine values and progressive decline in glomerular filtration rate (GFR) over many years. The cause of his CKD was attributed to type 2 diabetes, aggravated by a longer history of poorly-controlled hypertension. Two years prior to the clinic visit, he had experienced a myocardial infarction, complicated by atrial fibrillation, and was anticoagulated with warfarin. He also suffered from gastro-oesophageal reflux oesophagitis (GORD) with frequent attacks of heartburn, especially after “sausages and black pudding”. He continued to smoke 20 cigarettes a day on top of a 40 pack-years habit. He denied overt blood loss from the GI tract or other body system. Clinical examination revealed pallor, expiratory wheeze. His laboratory work-up at the clinic yielded the following results.

Laboratory results

Haemoglobin (Hb)                              9.2 g/dl        (13-17.5)

Serum ferritin                                   10ng/ml        (20-300)

Serum iron                                          4.5µmol/L    (11.6-31.3)

Total iron binding capacity (TIBC)     40µmol/L     (42-80)

TSAT %                                             11%                (15-45)

B12                                                     320pg/ml      (200-1,100)

Folate                                                 13ng/ml         (7-36)

Creatinine                                           254µmol/L   (64-111)

eGFR (MDRD)                                  22ml/min/1.73 m²

 

Prescribed medications

Linagliptin 5mg OD

Gliclazide MR 60mg OD

Doxazosin XL 8mg OD

Lercanidipine 20mg OD

Olmesartan 20mg OD

Atorvastatin 20mg OD

Aspirin 75mg OD

Warfarin 3mg OD per INR

Atenolol 50mg OD

Folate 5mg OD

Discussion

Iron deficiency anaemia (IDA) is a major contributor to anaemia among patients with chronic kidney disease (CKD) and is associated with reduced exercise tolerance and impaired quality of life. Studies demonstrate that 60 per cent or more of patients with advanced CKD have iron deficiency (ID) and that the prevalence of ID is likely to reach 100 per cent among CKD patients who are treated with haemodialysis, given that these patients have substantial ongoing iron losses in the order of 3-5g per year. 

The diagnosis of ID and IDA requires careful clinical evaluation of the patient and should include an assessment of core laboratory markers for ID. Although all currently available biomarkers lack precision in the diagnosis of ID, increased utilisation of serum ferritin-a marker of iron stores and the transferrin saturation ratio (TSAT), a marker of functional iron reserves, have permitted increased detection of iron deficiency among patients with CKD. 

Causes of ID and IDA

Several factors conspire to cause ID and IDA among patients with CKD. Reduced dietary intake due to poor appetite, low rates of iron absorption, high prevalence of reflux oesophagitis and peptic ulcer disease, increased blood loss from the gastrointestinal (GI) tract, greater use of antiplatelet agents and anticoagulants, along with increased prescribing of erythrocyte-stimulating agents (ESA) have together contributed to high rates of IDA in CKD patients. Furthermore, patients with CKD endure a significant burden of comorbidity, with higher levels of inflammatory markers and require frequent clinic visits and higher rates of phlebotomy that further amplify iron losses and ID. Consequently, the evaluation of IDA anaemia in patients with CKD requires a careful, methodical approach, both to confirm the presence of IDA and exclude common and treatable underlying causes.

Despite the high prevalence of IDA in CKD patients, it continues to remain under-diagnosed and under-treated in routine clinical practice. While oral iron therapy may be adequate for some patients, for many others it is ineffective due to GI intolerance and poor absorption rates. 

The advent of newer intravenous (IV) iron preparations have provided an alternative and increasingly useful strategy for treating IDA in all stages of CKD, especially among those who are intolerant of oral therapy. The benefits of IV iron therapy over oral iron therapy include guaranteed compliance, better bioavailability, rapid efficacy, greater haemoglobin response, reduced transfusion requirements and less need for treatment with erythropoietin. However, these therapies need to be provided in IV infusion settings by skilled nursing staff and with medical supervision. The increased availability of these facilities in the Irish health system has led to an expansion of IV iron therapy for many patients. The featured case report illustrates some of the challenges and management strategies for the diagnosis and treatment of IDA in CKD.

Diagnosis

The first question to consider is whether or not the patient is iron deficient and if so, whether the pattern is one of absolute or functional ID. It should be noted that the threshold value at which IDA is diagnosed in patients with CKD differs from patients in the general population. In general, serum ferritin values <100ng/ml are required to diagnose ID in CKD, compared to threshold values of <30ng/ml in the general healthy population. 

The laboratory pattern demonstrated in the case report patient is consistent with absolute IDA. The combination of low serum ferritin of 60ng/ml (threshold ferritin <100ng/ml), and the low TSAT of 15% (threshold TSAT <20%) is diagnostic of absolute ID among patients with CKD. In absolute ID, the body’s iron stores are depleted. While this clinical case demonstrates the presence of absolute ID (ie, both serum ferritin and TSAT are reduced), the diagnosis of ID may be more difficult in other situations, for the following reasons. 

For some patients, the serum ferritin is normal or even high (ferritin level >200ng/ml), although the TSAT is reduced <20%. Such patients are deemed to have functional ID. In states of functional iron deficiency, there is inadequate iron supply to meet demand (eg, during ESA therapy despite normal or abundant iron stores). 

Functional ID may occur during inflammatory states where iron is trapped within the reticulo-endothelial system and prevented from being absorbed from the intestinal mucosa. Therefore, the accuracy of the diagnosis of ID is limited due to the presence of imperfect iron biomarkers. Both serum ferritin and TSAT are biomarkers that lack high sensitivity and specificity. For example, while a very low serum ferritin (<30ng/ml) is associated with a high probability of ID indicating depleted iron stores, a high serum ferritin of >100 does not exclude ID. Serum ferritin is an acute phase reactant and may be elevated in patients with acute inflammatory conditions and liver disease. 

Similarly, a low TSAT (TSAT <20%) may indicate the presence of ID in patients with CKD. However, a low TSAT may also occur in patients with chronic inflammatory conditions and malignancy. Thus, the interpretation of the iron biomarkers must be made following a careful clinical evaluation of the patient. Unfortunately, there is no single diagnostic test with absolute precision (high specificity and sensitivity and high positive and negative predictive value), and we therefore have to rely on a combination of these biomarkers in routine clinical practice. 

The gold standard in determining the true iron status of an individual is a bone marrow aspirate, which provides a qualitative assessment of stainable iron in bone marrow cells but such a test is rarely performed, for obvious reasons. In the case report patient, the ongoing ID has led to a reduction in haemoglobin (ie, IDA).

Management strategy

Investigation of ID

Once ID or IDA are confirmed, the next step is to determine whether overt or covert blood loss is the underlying cause. It is imperative that this is progressed in all patients. An essential component of the evaluation of IDA includes a faecal occult blood test (FOB), and if positive, referral for upper and lower GI endoscopy. Failure to perform these essential diagnostics may result in failure to detect a GI source of bleeding, such as an occult neoplasm (especially lower GI) of the intestinal tract. Our case report patient has many risk factors for IDA due to GI blood loss that need careful consideration. 

The obvious contributory factors here include active symptoms of GORD, which almost certainly require further endoscopic evaluation. Moreover, his treatment with warfarin and aspirin may be additional contributors to blood loss from the GI tract. One should note that the symptoms of ID and IDA are non-specific (shortness of breath and fatigue) and indeed may be contributed in part by underlying chronic lung disease (COPD), a substantial smoking history, and indeed his advanced stage of CKD (stage 4). 

Iron treatment strategies

Oral iron treatment in CKD

Correction of ID is essential to replete iron stores and allow normal haematopoiesis. In clinical decision making, one must decide whether the patient should be treated with oral or IV iron therapy. The obvious benefits of oral iron treatment include its availability and ease of prescribing for physicians, low cost and relatively safe profile.  

Commonly-used oral iron preparations include ferrous fumarate and ferrous sulfate. Ferrous sulfate provides 105mg of elemental iron in one 305mg tablet. The dose of oral iron depends on patient age, the estimated iron deficit, the rapidity with which it needs to be corrected and side-effects. 

The recommended daily dose for the treatment of ID in most adults is in the range of 150-200mg of elemental iron daily. As an example, a 325mg ferrous sulfate tablet contains 65mg of elemental iron per tablet; three tablets per day will provide 195mg of elemental iron, of which approximately 25mg is absorbed and utilised. Oral iron should be given between meals if tolerated, and in general, treatment needs to continue for several months before improvements in iron indices are seen and a rise in haemoglobin. The Kidney Disease Improving Global Outcomes (KIDIGO) group recommends a trial of oral iron therapy for patients with CKD and IDA who are not receiving dialysis. For patients with advanced CKD, or requiring haemodialysis, oral iron therapy is usually ineffective in correcting the magnitude of the ID and ongoing iron losses. Furthermore, many patients with CKD are intolerant of oral iron therapy or have a poor response, for the following reasons:

Older patients with poor appetite and oral intake.

Multicomorbidity.

Polypharmacy, including antiplatelet agents and anticoagulants.

GI upset causing intolerance and malabsorption.

Higher iron losses, which cannot be adequately corrected with oral iron therapy. 

 

IV iron treatment

IV iron therapy has become the preferred approach for many patients with moderate-to-advanced CKD and for all patients treated with haemodialysis. Unlike oral iron, IV iron has a predictable response and can correct the ID in non-dialysis CKD patients in one or two treatments compared to three-to-six months of oral iron. 

Although our case report patient was not receiving dialysis, we decided on an IV strategy for a number of reasons. First, the degree of ID was substantial, with significantly reduced storage iron (serum ferritin 10ng/ml). Second, he displayed evidence of ongoing GI blood loss from a combination of active reflux symptoms that was likely further compounded by the use of antiplatelet therapy and warfarin. Third, his burden of prescribed medications was substantial and it was likely that an addition of oral iron would further exacerbate GI intolerance and promote non-compliance. And fourth, the extent of absorption of any prescribed oral treatment from the GI tract was unpredictable. For these reasons, the patient was treated with 1gm of ferric carboxymaltose given as an infusion over 30 minutes at our IV iron clinic. The infusion was completed without complication. After six weeks, repeat iron assessment indicated an improvement in iron indices with acceptable rise in Hb, as outlined below. A referral to the gastroenterologist for upper GI endoscopy revealed evidence of active reflux oesophagitis and a full colonoscopy demonstrated two colonic polyps that were histologically benign.

Repeat laboratory studies at six weeks post-IV iron infusion yielded the following results:

Ferritin 500ng/ml      (20-300)

TSAT % 32%                  (15-45)  

Hb 10.4g/dl                    (13-17.5)

IV iron in clinical practice

Although IV iron preparations became available in the 1990s, early IV iron preparations using high molecular weight (HMW) iron preparations such as iron dextran were associated with frequent and severe anaphylactic reactions. More recent second- and third-generation IV iron preparations have significantly lower rates of anaphylactoid reactions and overall better safety profiles. 

There are several IV iron preparations available in Ireland to treat ID and IDA in CKD patients. These include ferric carboxymaltose, iron isomaltoside, and iron sucrose. All are considered to be equally efficacious in correcting IDA. Moreover, the overall rates of anaphylactic reactions are low (for example, ~6/1,000 for iron isomaltoside and 15/1,000 for ferric carboxymaltose) with new third-generation iron preparations compared with previous HMW iron dextran.

Conclusion

ID and IDA are common in CKD and should be screened for in all patients with confirmed anaemia in CKD. Diagnostic evaluation requires a careful clinical evaluation that includes an assessment of iron stores and functional iron capacity using serum ferritin and TSAT.

Prior to treatment, all patients should always be evaluated for underlying causes of ID, especially blood loss from the GI tract. Oral iron preparations may not be adequate for use in all patients with CKD because of intolerance, impaired absorption, systemic inflammation, and large iron deficits. IV iron therapy using third-generation forms is safe, effective, and results in a predictable rise in haemoglobin levels. Although there is some concern that frequent, large doses of IV iron used in haemodialysis may be associated with higher CV event rates, infection and death, there is no conclusive evidence to date to support any of these hypotheses. 

Future research is required to: improve upon existing biomarkers for the diagnosis of IDA; better define the optimal dosing strategies for treatment of IDA; and to determine the treatment targets for serum ferritin, TSAT and haemoglobin in routine clinical practice. 

Greater awareness of the causes of IDA, improved interpretation of commonly-used biomarkers and increased utilisation of iron replacement strategies are fundamental to improving the care of IDA in these vulnerable patients.

References on request

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