Anaemia of CKD is characterised by decreased production of erythropoietin (EPO) and disordered iron homeostasis. The article discusses the etiopathology, clinical evaluation, and treatment of anaemia in chronic kidney disease (CKD).

Anaemia of CKD

Anaemia of chronic kidney disease (CKD) is a form of normocytic, normochromic, hyperproliferative anaemia. It is frequently associated with poor outcomes in chronic kidney disease and confers an increased mortality risk. The disorder starts to develop when the glomerular filtration rate drops below 60 mg/ml.

Etiopathology

Decreased erythropoietin has recently been linked with the downregulation of hypoxia-inducible factor (HIF), a transcription factor that regulates gene expression of erythropoietin. Other factors include;

1. The shortened lifespan of red blood cells.
2. Nutritional deficiencies, such as vitamin B12 and folate.
3. CKD patients have exaggerated iron losses, accounting for around 1 to 3 g annually in hemodialysis patients, secondary to chronic bleeding due to uremia-associated platelet dysfunction, blood being trapped in the dialysis apparatus, and frequent phlebotomy. Hemodialysis patients have impaired dietary iron absorption, which is why intravenous iron is a preferred treatment option.
4. In addition to true iron deficiency, CKD patients also have a functional iron deficiency, known as reticuloendothelial cell iron blockade. It is characterised by reduced iron release from body stores unable to meet the requirement for Erythropoiesis.
5. Hepcidin excess is the main factor behind impaired iron regulation and anaemia of chronic renal disease as it affects dietary iron absorption and mobilisation of iron from body stores.
6. ACE inhibitors and ARB have also been known to suppress erythropoiesis.

Clinical evaluation

The clinical presentation of anaemia of chronic renal disease is not different from that of anaemia due to other causes. Common symptoms include:

• Dyspnea
• Fatigue
• Generalised weakness
• Headaches
• Dizziness
• Reduced exercise tolerance

Commonly clinical signs

• Skin and conjunctival pallor
• Respiratory distress
• Tachycardia
• Chest pain (mostly with severe anaemia)
• Heart failure (usually with chronic severe anaemia)

Laboratory evaluation

Common tests required to diagnose the condition include the following:

• Complete blood count (CBC) with differential
• Peripheral smear
• Iron indices (iron, ferritin, total iron binding capacity, transferrin saturation)
• Iron, vitamin B, and folate levels (included in initial workup to rule out other reversible causes of anaemia)
• Thyroid function tests (rule out alternate aetiology of hyperproliferative normocytic anaemia)

Treatment

Treatment of anaemia of chronic renal disease is directed toward improving renal function (when possible) and increasing red blood cell production. Therefore, Erythropoiesis-stimulating agents (ESAs), together with iron supplementation, are the treatment of choice in anaemia of CKD.

Treatment of anaemia in CKD has come a long way. Before the advanced treatment options available today, the main treatment option used to be blood transfusions, which came with numerous complications, including infections, hemosiderosis, fluid overload, transfusion reactions, etc.

It started with the use of androgens in the 1970s to avoid transfusion in patients with CKD. After that, in the 1980s, the development of recombinant EPO, followed by ESAs, revolutionised the management of anaemia in CKD. Although initially instituted to avoid transfusions, they were soon known to have various positive effects, including improved survival and quality of life, improved cardiac function and mortality associated with it, lower hospitalisations, and lower costs.

1. Recombinant human erythropoietin and darbepoetin alfa are the two ESAs generally used in managing anaemia in CKD. They are fairly similar in efficacy and side effect profile, except for the longer half-life of darbepoetin alfa, thus allowing for less frequent dosing.
2. As per KIDGO guidelines, in patients with CKD who are not on dialysis, ESAs are typically considered when haemoglobin level drops below 10 g/dl but are individualised depending on various factors, including symptoms related to anaemia, dependence on transfusions, the rate of drop in haemoglobin concentration, and response to iron therapy. In these patients, erythropoietin (50 to 100 units/kg IV or SC) is usually given every 1 to 2 weeks, and darbepoetin alfa dosing is every 2 to 4 weeks.
3. In patients on dialysis, ESAs are usually avoided unless the haemoglobin level is between 9 and 10 g/dL. In this subset, erythropoietin is given with every dialysis, i.e., three times a week, whereas darbepoetin alfa is dosed once weekly.
4. Generally, the peak rise in RBCs in response to ESAs occurs at 8 to 12 weeks. However, in around 10% to 20% of cases, anaemia can be resistant to ESAs. Common adverse effects of ESAs include seizures, the progression of hypertension, clotting of dialysis access, the progression of malignancy, and higher mortality in cancer patients.
5. In all patients with CKD, regardless of the need for dialysis, the goal of haemoglobin using ESAs is less than 11.5 g/dL. Higher Hb levels have demonstrated higher mortality, thrombosis, and adverse cerebrovascular and cardiovascular events due to higher levels of ESAs when used for target haemoglobin greater than 11 g/dl. These events are likely related to the effect of ESAs on vascular remodelling and causing vasoconstriction.
6. Iron supplementation is the core of the treatment of anaemia in CKD. Due to decreased oral iron absorption, intravenous iron is preferable in hemodialysis patients.
7. KIDGO recommends target transferrin saturation between 20 to 30% and ferritin level 100 to 500 ng/mL in patients with CKD who are not on dialysis. In patients with ESRD on dialysis receiving intravenous iron, goal transferrin saturation of 30 to 50% and ferritin higher than 200 ng/mL.
8. Unlike the general population, high serum ferritin levels do not predict haemoglobin responsiveness in renal failure patients. Finally, no erythropoietin level can be considered adequate for defining renal anaemia. Thus, erythropoietin levels should not be measured regularly in evaluating patients with renal anaemia.
9. Desidustat (Oxemia) a hypoxia-inducible factor prolyl hydroxylase inhibitor is a promising new oral alternative to injectable Erythropoiesis-stimulating agents (ESAs) for the treatment of anaemia in patients with chronic kidney disease (CKD). Desidustat is approved in India for adults with CKD who are either not on dialysis or dialysis. It is administered orally three times a week and dosage should be individualised based on the haemoglobin response of the patient.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Bhavin Mandowara is a practising nephrologist at Zydus Hospital, Ahmedabad.