Erythropoiesis stimulating agents (ESA) – the potential risks for patients with Chronic Kidney Disease treated due to anaemia

Since the introduction of recombinant human erythropoietin (rhEPO) to clinical practice it seemed that the problem of anaemia in patients with chronic kidney disease has been brought under control. Further years have produced modifications of particles of rhEPO and led to the synthesis of new medicines – erythropoiesis stimulating agents. These drugs are characterized by longer half-life and the stability of action. However, the results of recent clinical trials carry dangerous conclusions. Despite the improvement of morphological parameters, the reduction of mortality in these patients was not observed.

Therapy with the use of ESA leads to stimulation of the erythrocytes production in the bone marrow, and through this to enhancement of haematocrit, haemoglobin and red blood cells level. The increase in these values translates directly into better quality of patients life and the lack of necessity to perform transfusions – that were previously the primary method of proceeding. It is the reduction of the risk of infection with hepatotropic viruses and the development of hemochromatosis (associated with transfusions) that have led to further research on the ESA improvement.

Target haemoglobin values in patients with chronic kidney disease had been changing with the passage of time. Initially, attempts were made to bring them to physiological values. However, the conclusions of The Normal Haematocrit Study have shown that increasing the morphological parameters too high can be dangerous for patients (in this study the criterion was haematocrit level). In described study patients were divided into two groups. In the first group they reached the normal hematocrit values (42 ± 3%) while in the other patients haematocrit was maintained at the level of 30 ± 3%. After 14 months death or heart attack was observed in 33% of patients with normal haematocrit value, compared to 27% of such observations in patients with a lower haematocrit target level. Similar results were observed by the authors of CHOIR study. Their paper compares the incidence of the composite endpoint in the form of – death, myocardial infarction, hospitalization due to heart failure or stroke. Patients were randomly assigned to two groups in which the haemoglobin concentration was maintained at the target values using ESA at 13.5 or 11.3 g / dl. After 16 months of follow-up in the group with higher haemoglobin levels endpoint occurred in 17.5%, compared to 13.5% in patients with lower haemoglobin level. The biggest differences between these groups have been observed in the number of deaths and hospitalizations because of heart failure.

In the TREAT study, which was the largest in recent years, more than 4000 patients with kidney disease were randomly assigned to 2 groups. It was a placebo controlled study in which patients received one of the ESA medication. After 29 months of follow-up in patients taking the ESA, median haemoglobin level was 12.5 g/dL and in the group treated with placebo 10.6 g/dL. Significantly more often in patients treated with ESA a stroke(5.0% vs 2.6%) and thromboembolic events were observed. Also in this group the incidence of death and cardiovascular events (31.4% vs. 29.7%) were more often reported but the difference was not statistically significant.

As can be seen from these studies, the quest for higher values ​​of morphological parameters may be associated with a higher incidence of complications in patients with chronic kidney disease. It concerns especially cardiovascular complications. Many researchers suppose that the risk of cardiovascular events is related to the rapidity of the increase in haemoglobin concentration, fluctuations in haemoglobin levels, overshoots of the target range, as well as aggressive dosing of ESA. One of the newest concepts that can explain these negative effects is the impact of the ESA on the vascular endothelium and smooth muscle cells, which can also lead to adverse effects in patients with cancers.

To minimize the risks associated with the use of ESA, it is recommended to use these medications when the haemoglobin level drops below 10 g/dl, and to maintain its concentration in the range 10-12 g/dl, (and according to some studies 10-11 g/dl). Frequent measurements of haemoglobin concentration and appropriate dosage of ESA are crucial in order to increase haemoglobin level and decrease patient’s discomfort associated with anaemia and at the same time do not expose them to serious complications. Further studies on larger groups of patients should give us more accurate data on the optimal haemoglobin values for patients with chronic kidney disease, as well as information on whether the different types of ESA have an impact on the incidence of these complications.

Written by: Dominik Cieniawski

Source:
1. Unger EF., Thompson AM., Blank MJ., Temple R.: Erythropoiesis-Stimulating-Agents – time for a reevaluation. N Engl J Med;362:189-192.
2. Rutkowski B.: Aktualne problemy dotyczące rozpoznawania I terapii niedokrwistości nerkopochodnej. Forum Nefrologiczne; 3:291-297.
3. Singh AK., Szczech L., Tang KL. et al.: Correction of anemia with epoetin alfa In chronic Sidney disease. N Engl J Med;355:2085-2098.
4. Pfeffer MA., Burdmann EA., Chen C-Y. et al.: A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med;361:2019-2032.


Would you like to know more? Watch on MEDtube.net: Examination Of The Kidneys And Aorta

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