Erythropoietin Resistance

Erythropoiesis-stimulating agents (ESAs) are used to promote the production of erythrocytes. This medication group includes recombinant human erythropoietin (EPO) derivatives (e.g. epoetin alfa, epoetin beta, and epoetin lambda) and chemically modified forms of EPO (e.g. methoxy polyethylene glycol-epoetin beta and darbepoetin alfa).

Erythropoietin is a hormone that is primarily produced in the kidneys and is essential for regulating the production of erythrocytes. While EPO is constantly secreted at low levels, surges can occur when erythrocyte levels drop. The interstitial peritubular cells of the kidneys detect this relative hypoxia in the blood and respond by increasing EPO release.

Erythropoiesis-stimulating agents are indicated for use in conditions of impaired erythrocyte production, such as anaemia of chronic renal failure and chemotherapy-induced anaemia. They may also be indicated for use in patients with mild-to-moderate anaemia (haemoglobin 100–130 g/L) who are undergoing elective surgery with expected moderate blood loss and to support autologous blood collection before major elective surgery in patients with anaemia.

For patients with chronic kidney disease (CKD), ESAs can effectively manage anaemia and reduce the need for blood transfusions. However, patient response to these agents can vary significantly. Erythropoietin resistance occurs when target haemoglobin (Hb) levels cannot be met or increasingly higher ESA doses are required to maintain Hb targets.

Erythropoietin resistance is associated with a higher risk of death and cardiovascular events in patients with CKD. While the reasons for this have not been fully elucidated, EPO resistance is associated with increased blood pressure, endothelial stress, and a prothrombotic state. Anaemia itself is also strongly associated with cardiovascular issues due to reduced tissue oxygenation, which can lead to tachycardia, vasodilation, increased cardiac workload, and left ventricular hypertrophy. Therefore, it is important to recognise factors that may contribute to EPO resistance and optimise anaemia management in this patient group.

Some potential causes of EPO resistance include:

• Iron deficiency;
• Infection and inflammation;
• Malnutrition;
• Hyperparathyroidism; and
• Inadequate dialysis.

Iron deficiency is the most common cause of EPO resistance in dialysis patients. Iron deficiency may be considered absolute or functional. There are many factors that may contribute to absolute iron deficiency in people with CKD, including gastrointestinal losses, reduced gastrointestinal iron absorption, frequent blood draws, and the impact of dietary restrictions. For patients undergoing haemodialysis, some residual blood loss occurs, which can become significant over time.

In the case of functional iron deficiency, total body iron stores are sufficient, but their bioavailability is reduced. This may be related to systemic inflammation, which results in increasing levels of hepcidin. Hepcidin is an iron regulatory protein that impairs iron transport. Hepcidin levels may rise in CKD due to reduced elimination via the kidneys, increased levels of inflammatory cytokines, and in response to reduced EPO levels.

Malnutrition is a significant issue for patients with CKD. The risk of malnutrition is elevated in this population due to decreased appetite and nutrient intake, intestinal malabsorption, metabolic and endocrine derangements, inflammation, increased catabolism, and dialysate losses. The role of poor nutrition in the development of anaemia is well established, with deficiencies of folic acid, vitamin B12, and iron all contributing. However, studies suggest that a significant effect of malnutrition on EPO resistance is related to malnutrition-inflammation syndrome.

Malnutrition-inflammation syndrome describes the nutritional changes seen in protein-energy wasting as well as the inflammatory changes seen due to uremic toxins and oxidative stress. This inflammatory state may contribute to EPO resistance by reducing EPO production and its effects on erythropoiesis. Inflammation and infection can also increase hepcidin production, which is associated with functional iron deficiency. Evidence suggests that even low-level inflammation can contribute to ESA resistance. Therefore, testing C-reactive protein may be beneficial to detect minor asymptomatic elevations in this inflammation marker that could be significant.

Chronic kidney disease is a common cause of secondary hyperparathyroidism. This condition is a hallmark of end-stage renal disease (ESRD) and is associated with EPO resistance. As CKD progresses, the synthesis and secretion of PTH increases. Rao et al. (1993) first demonstrated an association between higher parathyroid hormone (PTH) levels and greater bone marrow fibrosis in patients with a poor EPO response. There is also evidence to suggest that high levels of PTH increase the osmotic fragility of erythrocytes. These two factors may combine to reduce erythrocyte production as well as their survival.

In CKD, secondary hypoparathyroidism may be driven by hypocalcaemia and hyperphosphataemia. As phosphate complexes with calcium, high levels of serum phosphate lead to reduced levels of ionised calcium. Reduced levels of this physiologically active form of calcium trigger the release of increasing quantities of PTH. Longstanding secondary hyperparathyroidism can lead to tertiary hyperparathyroidism, where the parathyroid glands become unresponsive to plasma calcium levels and autonomously produce high levels of PTH in the presence of hypercalcemia. High levels of phosphate, active vitamin D, and PTH also increase the release of fibroblast growth factor 23 (FGF23). The FGF23 hormone plays a significant role in CKD-related mineral and bone disorders. Evidence suggests that FGF23 may also be important in the development of ESA resistance.

Inadequate dialysis has been shown to increase the risk of ESA resistance in patients receiving dialysis. While the mechanism for this has not been fully elucidated, adequate haemodialysis in CKD patients is associated with lower ESA doses. One study demonstrated that extending the duration of haemodialysis by one hour may reduce the EPO requirement by around 2,000 IU per week.

Lower ESA doses are associated with significant clinical benefits as well as improved cost-effectiveness of treatment. Addressing reversible causes of EPO resistance is important to ensure the optimal use of ESAs. This may include optimisation of iron supplementation, haemodialysis modality, nutritional intake, and other comorbidities.