The role of ACE inhibitors and angiotensin II receptor blockers in the response to epoetin

Iain C. Macdougall

Department of Renal Medicine, King's College Hospital, London, UK

Correspondence and offprint requests to: Dr Iain C. Macdougall, Consultant Nephrologist, Renal Unit, King's College Hospital, East Dulwich Grove, London SE22 8PT, UK.

Introduction

Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers are widely used in renal failure patients in the treatment of hypertension [1], left ventricular dysfunction [2], and diabetic nephropathy [3]. Their efficacy in these conditions is well established, and generally both classes of drugs are well tolerated, with a low incidence of side effects [4]. Thus, ACE inhibitors may induce skin rashes, angioneurotic oedema, diarrhoea, cough, and dizziness [5], while the angiotensin II blockers have a side effect profile not dissimilar to placebo.

Recently, however, much interest has focused on the potential for both classes of drugs to suppress erythropoiesis, and thereby exacerbate anaemia [6,7]. Moreover, much controversy has also been generated over whether these drugs can induce some resistance to erythropoietin therapy, requiring the use of higher dosages with obvious economic implications [818]. Some studies seem to suggest that this is the case [813], while others have found no effect [1417].

The aim of this article is to discuss the possible mechanisms of action for this latter effect, and to review the evidence both for and against a role for ACE inhibitors and angiotensin II blockers causing resistance to epoetin.

Possible mechanisms of action for suppressing erythropoiesis

There does not appear to be a unifying mechanism of action whereby ACE inhibitors or angiotensin II blockers exert their effect on erythropoiesis. It has been known for some time that the renin–angiotensin system is linked intricately with the production of endogenous erythropoietin in the peri-tubular fibroblasts of the kidney. Activation of this system will enhance erythropoietin production [19], hence the reason why patients with renal artery stenosis may become polycythaemic. Similarly, suppression of angiotensin II production by ACE inhibitors may inhibit erythropoietin synthesis, reducing circulating levels of the hormone, and so exacerbating anaemia [6,7,20]. This characteristic of the ACE inhibitors has been put to good use in patients with transplant polycythaemia, a condition which may be partly caused by inappropriately high levels of circulating erythropoietin [2123].

Nevertheless, the small reductions in erythropoietin levels can be overcome easily by the administration of exogenous erythropoietin. Yet, haemoglobin levels can fall quite significantly in patients stable on epoetin in whom an ACE inhibitor is introduced [8,10], suggesting that other mechanisms must be operating. Several possible mechanisms have been described: (i) There is some evidence that angiotensin II can stimulate erythroid progenitor cell growth in vitro [24], and that captopril can inhibit this. (ii) A natural stem cell regulator called Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) has been identified recently which inhibits the recruitment of pluripotent haemopoietic stem cells and normal early progenitors into the S-phase. ACE inhibitors have been found to increase plasma levels of Ac-SDKP markedly, and hence inhibit erythroid growth [25]. (iii) A recent study by Morrone et al. [26] has also suggested that insulin-like growth factor-1 (IGF-1) plays a role in the ACE inhibitor-related decrease in haematocrit in patients with transplant polycythaemia. Serum erythropoietin and IGF-1 levels were significantly higher in patients with this condition than in a control group without transplant polycythaemia. ACE inhibitors significantly reduced haematocrit, IGF-1 and erythropoietin levels, and a direct relationship was found between haematocrit and serum IGF-1 levels, but not between haematocrit and serum erythropoietin levels. (iv) Similarly, ACE inhibitors have been shown to reduce production of interleukin-12, a cytokine known to stimulate erythropoiesis [27]. Thus, it is likely that there are several means by which ACE inhibitors could inhibit erythropoietic activity.

Do ACE inhibitors or angiotensin II blockers inhibit the action of epoetin?

There are studies both supporting and refuting this hypothesis, and these are summarized in Table 1Go [818]. Most of these are small and uncontrolled studies, and many are retrospective.


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Table 1. Studies providing evidence both for and against inhibition of epoetin action by ACE inhibitors or angiotensin II blockers
 
Studies supporting the hypothesis
This article will review only studies which have suggested that either ACE inhibitors or angiotensin II blockers inhibit the action of epoetin, not studies which have suggested that these drugs worsen anaemia in the absence of epoetin. The first report of an interaction between an ACE inhibitor and epoetin was by Walter [8] who retrospectively analysed 43 patients on epoetin, 20 of whom were also on captopril, and the remaining 23 who were not on any ACE inhibitor. The haemoglobin was found to be significantly lower in the captopril-treated patients (6.2±0.2 vs 7.1±0.1 mmol/l; P<0.01). Hess et al. [9] performed a similar retrospective analysis of 40 patients on epoetin (20 on an ACE inhibitor, and 20 not on an ACE inhibitor) and noted that the patients taking ACE inhibitors required significantly higher doses of epoetin at 15 and 18 months. In the same year, Erturk et al. [10] analysed the response rate to epoetin in 23 patients on ACE inhibitors and 24 patients not on ACE inhibitors. In the former group, there were six responders and 17 non-responders to epoetin, and in the latter group there were 19 responders and five non-responders. The group receiving ACE inhibitors also had significantly lower haematocrits than those not on ACE inhibitors (25.8±6.4% vs 32.0±4.2%) and required higher doses of epoetin (194±74 vs 113±73 U/kg/week). Matsumura et al. [11] found that the mean dose of epoetin was higher in 49 patients receiving ACE inhibitor therapy (102±52 U/kg/week) compared with a group of 59 patients not receiving ACE inhibitors (79±38 U/kg/week; P<0.05). All of these studies were retrospective, but more robust scientific data were reported recently by Albitar et al. [12] who conducted a prospective, non-randomized, controlled study of 60 patients with a follow-up period of 12 months. Twenty of the patients received enalapril (dose ranging from 5 to 20 mg per day) as antihypertensive therapy, 20 received nifedipine, and there were 20 controls on no antihypertensive medication. The group of patients on enalapril required significantly higher doses of epoetin compared with the patients on nifedipine or on no antihypertensive therapy [12]. A further prospective study by Erturk et al. [13] approached the problem from the opposite angle, i.e. by assessing the effects of stopping ACE inhibitors on the response to epoetin. Fifteen patients in whom ACE inhibitors were withdrawn were followed-up for 3 years, and an increase in haematocrit and a decrease in epoetin dose were found [13].

Studies refuting the hypothesis
Three retrospective studies in the last 5 years have all suggested that the concomitant use of ACE inhibitors does not cause a lesser response to epoetin therapy [1416]. The first of these was a small study by Conlon et al. [14] who retrospectively analysed 14 patients receiving an ACE inhibitor (eight on captopril, six on enalapril) before and after the ACE inhibitor was started. There were no significant differences in haemoglobin or epoetin dose requirements in the period before the ACE inhibitor was introduced compared with the period on an ACE inhibitor. Sanchez [15] similarly compared the haemoglobin and epoetin dose requirements between 48 patients receiving ACE inhibitors and 204 patients not on ACE inhibitors, and again found no difference between the two groups. Cruz et al. [16] examined 24 patients on an ACE inhibitor (lisinopril, enalapril or fosinopril), and compared the haematocrit and epoetin dose requirements with 24 patients not receiving ACE inhibitor therapy. Again, no difference between the two groups was seen. In this current issue, Chew et al. [17] report on the results of a prospective double-blind placebo-controlled, cross-over study examining the effect of losartan on the action of epoetin. Fourteen patients were recruited, although subsequently five were withdrawn. At a dose of 25 mg per day, there was no difference between the group of patients receiving the angiotensin II blocker and the placebo group [17].

Finally, there is one further study recently reported which is relevant to this issue. Schiffl and Lang [18] compared the effects of captopril and losartan in two groups of 12 dialysis patients using a prospective randomized study design. The group treated with captopril required higher doses of epoetin to maintain the same target haematocrit, in contrast to the group given losartan (mean epoetin dose 2413±157 vs 1685±212).

What can we conclude from these studies?

Despite the uncontrolled nature of most of the studies and the small numbers of patients involved, there does seem to be an inhibitory effect of ACE inhibitors on the action of epoetin. There is a theoretical basis for this effect in view of the known close links between the renin–angiotensin system and erythropoiesis. The data from most of the studies in which an inhibitory effect was seen are reasonably persuasive, particularly from the controlled study by Albitar et al. [12], and one can find criticisms in several of the studies in which no effect was seen. For example, in the small study of an angiotensin II blocker reported in this issue by Chew et al. [17], complete data were available in only nine patients, and the maximum dose of losartan tested was 25 mg daily.

It is becoming apparent, however, that the critical issue regarding this phenomenon does seem to be the dose of ACE inhibitor, and probably also the dose of epoetin. Thus, the effect is most apparent when high doses of an ACE inhibitor are used, particularly if the patient is on low doses of epoetin. This implies that the suppressive effect on erythropoiesis from this class of drugs is nowhere near as potent as the similar effect caused by severe infection or other inflammatory conditions, when it is sometimes impossible to overcome the cytokine-mediated resistance even with extremely high doses of epoetin [28]. It would be unusual, for example, not to be able to overcome the ACE inhibitor-induced suppression of erythropoiesis by increasing the dose of epoetin. Hence, the final conclusion must be that ACE inhibitors may evoke a degree of epoetin resistance particularly at high doses, but that this should be able to be counteracted by a corresponding increase in the dose of epoetin. Although the evidence for angiotensin II blockers producing this effect is less persuasive, this may be due to the paucity of data with this particular class of drugs to date.

Guidelines for managing patients on epoetin and ACE inhibitors/angiotensin II blockers

In the majority of patients, the indications for taking an ACE inhibitor or angiotensin II blocker, whether as an antihypertensive, cardioprotective or renoprotective agent, will almost certainly justify continuing the drug. If the patient is responding well to epoetin, then it would seem reasonable to continue the current management (Figure 1Go). If, however, there is an inadequate response to epoetin (haemoglobin rise <1 g/dl/month, or failure to maintain the target haemoglobin despite a dose of >200 U/kg/week), then other causes of epoetin resistance should be considered and corrected where possible [28]. The indication for the ACE inhibitor or angiotensin II blocker should then be reviewed. If the drug is being used as an antihypertensive, then it may be possible to try reducing the dose or consider changing to an alternative antihypertensive agent. If, however, the drug is being used for left ventricular dysfunction or diabetic nephropathy, then there is no satisfactory alternative. The relative merits of continuing the ACE inhibitor or angiotensin II blocker should be considered in the individual patient. If there are fairly modest arguments for continuing this therapy, then it may be possible to try stopping the drug or reducing the dose. If, however, the arguments are strong, then the options are to try reducing the dose of the drug or to increase the dose of epoetin further. It may be, for example, that a reduction in the dose of ACE inhibitor will improve the response to epoetin while maintaining the clinical benefits of the drug on the heart or kidney. In support of this is the fact that the studies reviewed in this article suggest that the suppressive effects on erythropoiesis are lost at lower doses, while it is known that the benefits of ACE inhibition on the heart and kidney are maintained at lower doses than those required for lowering blood pressure [2]. There should be no indication to stop epoetin therapy in this clinical situation, and indeed the resultant anaemia if this was done would almost certainly negate the benefits of ACE inhibition.



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Fig. 1. Algorithm for the concomitant use of epoetin and ACE inhibitors/angiotensin II blockers.

 
Conclusions

Epoetin therapy and ACE inhibitors/angiotensin II blockers are widely used as therapeutic agents in renal failure patients, and many such patients will find themselves taking both medications. As a result, it is salutary to consider the impact of the potential interaction of both drugs on erythropoiesis, and it does appear that ACE inhibitors or angiotensin II blockers can inhibit the response to epoetin, particularly at high doses. As with most situations in clinical medicine, patients must be treated as individuals, but it is hoped that the comments and suggested guidelines described here will stimulate the clinician to consider the various management options available.

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