Protected: Almost Forty Years of Erythropoietin Therapy: Successes and Limitations

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Lucia Del Vecchio

Lucia Del Vecchio1, Giulio Pucci Bella1, Francesco Locatelli2

1 U.O. Nefrologia e Dialisi, ASST Lariana, Como
2 U.O. Nefrologia e Dialisi, ASST Lecco, Lecco (Past Director)

Corresponding author:
Lucia Del Vecchio
UO Nefrologia e Dialisi, Ospedale Sant’Anna, ASST lariana, Via Ravona 20,
22042 San Fermo della Battaglia, Como, Italia
Tel +390315859552
E-mail: lucia.delvecchio@asst-lariana.it

 

Abstract

Anaemia is a frequent complication of chronic kidney disease; if severe and untreated, it leads to a worsening of quality of life and an increased risk of resorting to haemotransfusions.
Beginning with studies in physio-pathology that began in the late 19th century and continued into the 20th century, the first step was the identification of erythropoietin, then its purification, identification of the gene involved and finally the synthesis of recombinant human erythropoietin and its ‘long-acting’ analogues.
Today, therapy with erythropoiesis-stimulating agents (ESAs), often in combination with martial therapy, is the standard of care for patients with chronic kidney disease and anaemia. Recently, ESAs have been joined by HIF-PHD inhibitors. Unfortunately, both categories of drugs, although effective and well-tolerated in most cases, may be associated with a possible increased cardiovascular and thrombotic risk, especially in particular categories of patients.
For this reason, the choice of therapy with ESA and HIF-PHD must be customised in terms of haemoglobin target, molecule type and dosage to be used.

Keywords: anemia, chronic kidney disease, erythropoietin, erythropoiesis stimulating agents, cardiovascular disease, HIF-PHD inhibitors

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Treating anaemia in patients with chronic kidney disease: what evidence for using ESAs, after a 30-year journey?

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Francesco Locatelli

Francesco Locatelli1, Lucia Del Vecchio2, Luca De Nicola3, Roberto Minutolo3

1 Già Direttore del Dipartimento di Nefrologia e Dialisi, Ospedale Alessandro Manzoni, ASST Lecco
2 Ricercatore indipendente, Como
3 Nefrologia, DU Scienze Mediche e Chirurgiche Avanzate, Università L. Vanvitelli, Napoli

Corrispondenza a:
Prof. Francesco Locatelli
Via Fratelli Cairoli 60, 23900 Lecco
E-mail: francesco.locatelli2210@outlook.it

 

Abstract

Erythropoiesis Stimulating Agents (ESAs) are well-tolerated and effective drugs for the treatment of anaemia in patients with chronic kidney disease.

In the past, scientific research and clinical practice around ESAs have mainly focused on the haemoglobin target to reach, and to moving towards the normality range; more cautious approach has been taken more recently. However, little attention has been paid to possible differences among ESA molecules. Although they present a common mechanism of action on the erythropoietin receptor, their peculiar pharmacodynamic characteristics could give different signals of activation of the receptor, with possible clinical differences.

Some studies and metanalyses did not show significant differences among ESAs. More recently, an observational study of the Japanese Registry of dialysis showed a 20% higher risk of mortality from any cause in the patients treated with long-acting ESAs in comparison to those treated with short-acting ESAs; the difference increased in those treated with higher doses. These results were not confirmed by a recent, post-registration, randomised, clinical trial, which did not show any significant difference in the risk of death from any cause or cardiovascular events between short-acting ESAs and darbepoetin alfa or methoxy polyethylene glycol-epoetin beta. Finally, data from an Italian observational study, which was carried out in non-dialysis CKD patients, showed an association between the use of high doses of ESA and an increased risk of terminal CKD, limited only to the use of short-acting ESAs.

In conclusion, one randomised clinical trial supports a similar safety profile for long- versus short-acting ESAs. Observational studies should always be considered with some caution: they are hypothesis generating, but they may suffer from bias by indication.

Keywords: anaemia, erythropoiesis stimulating agents, ESAs, mortality, chronic kidney disease, long acting, short acting

Sorry, this entry is only available in Italian.

Introduzione

Dalla pubblicazione dello storico lavoro di Eschbach più di 30 anni fa [1], il trattamento dell’anemia con i farmaci stimolanti l’eritropoiesi (Erythropoiesis Stimulating Agents, ESAs) ha rivoluzionato la qualità della vita dei pazienti con malattia renale cronica (Chronic Kidney Disease, CKD). In quegli anni i pazienti erano gravemente anemici e spesso sopravvivevano con livelli di emoglobina anche inferiori a 5 g/dL, ricorrendo a periodiche trasfusioni, con alto rischio di trasmissione di un’epatite allora sconosciuta, definita “non A-non B” (oggi chiamata C) e con conseguente accumulo di grandi quantità di ferro. Nei casi più gravi i nefrologi erano costretti ad intervenire con un trattamento chelante a base di desferriossamina, a sua volta gravato da serie complicanze come la mucoviscidosi. Improvvisamente, grazie all’utilizzo dell’eritropoietina, i pazienti ricominciarono a vivere. Tale era l’entusiasmo dei nefrologi nel poter finalmente correggere efficacemente la grave anemia dei loro pazienti cronici, che si fecero trascinare fino a una correzione troppo rapida dei valori di emoglobina, portando a complicanze come un aumento dei valori pressori sino a severe crisi ipertensive e, a volte, convulsioni. 

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