Differential manipulation of the renin angiotensin system and epoietin requirements in maintenance haemodialysis patients

Peter J. Garrett1, Linda Stewart1, Joyce Leary1 and Terence R. J. Lappin2

1 Renal SubRegional Unit Tyrone County Hospital Omagh 2 Haematology Research Laboratory Royal Victoria Hospital Belfast, UK

Sir,

Angiotensin converting enzyme (ACE) inhibitors reduce haemoglobin in haemodialysis [1] and transplant [2] patients and are used in the management of post transplant erythrocytosis [3]. They also increase erythropoietin (Epo) requirements in haemodialysis patients [4]. The mechanism is uncertain.

Newer classes of drug, the angiotensin 1 (AT1) receptor blockers, treat hypertension in a similar manner by interrupting the renin angiotensin system later in the sequence. Their pharmacology, however, differs subtly, with varying effects on angiotensin 2 receptors, bradykinin activity, and angiotensin II levels.

In the Renal SubRegional Unit of Tyrone County Hospital, Omagh, a haemodialysis patient treated for hypertension with an ACE inhibitor ran a haemoglobin of approximately 7 g/dl for some 9 months despite adequate iron stores and Epo treatment. Substitution by the AT1 receptor blocker losartan was followed by a rise in haemoglobin from 7.7 to 9.4 g/dl over 1 month. We therefore designed a study to try to define whether these two drugs could have differential effects on haemoglobin levels and Epo requirements in maintenance haemodialysis patients.

All seven eligible haemodialysis patients on both epoietin therapy and treatment with the ACE inhibitor lisinopril were recruited by fully-informed written consent. All were male and ranged in age from 28 to 76 (mean 57) years. None had clinical or biochemical evidence of aluminium overload.

Clinical data were recorded and blood drawn for full biochemical profile, serum ferritin, serum haematinics, full blood count, reticulocyte count (all measured by standard automated techniques), and baseline serum trough epoietin level by radioimmunoassay. Subjects then either continued lisinopril or changed to losartan according to random selection of hospital numbers and treatment modalities from two envelopes. Losartan dosages were 25 mg for lisinopril 2.5 mg, 50 mg for lisinopril 5 mg, and 100 mg for lisinopril 10 mg or higher.

Blood pressure was checked pre- and post-dialysis two or three times weekly. Blood was drawn fortnightly for full blood count, reticulocyte count, and trough epoietin level. In addition, urea and electrolytes and serum ferritin were assayed every 4 weeks.

Drug dosage was adjusted to maintain mean arterial pressure below 115 mmHg. Epo was administered subcutaneously two or three times weekly pre-dialysis and dosage altered to keep haemoglobin between 9.9 and 13.0 g/dl. All subjects received iron saccharate 20 mg intravenously with dialysis two or three times weekly. Dialysis prescriptions were changed only to maintain adequacy according to standard biochemical criteria.

After 12 weeks, subjects still on lisinopril changed to losartan, while those on losartan reverted to lisinopril. Blood pressure measurements, investigations and therapy adjustments were continued as for the first part of the study, which was terminated after another 12 weeks. Clinical data were again recorded and haemoglobin levels and epoietin dosage at the end of each study period compared using paired t-test or, for non-parametric data, the Wilcoxon matched pairs test, adjusting P values according to the number of probability analyses.

Six patients completed the study, one having withdrawn because of haemorrhage into a polycystic kidney with an acute fall in haemoglobin. Mean haemoglobin was slightly higher and Epo requirements slightly lower on AT1 receptor blockade, but the differences were not significant. Serum intact parathyroid hormone and trough Epo levels showed no significant change.

The proteolytic enzyme renin, produced by the juxtaglomerular apparatus in response to reduced renal blood flow, acts on angiotensinogen to produce angiotensin I (A-I). A-I is in turn converted to angiotensin II (A-II) by ACE, with bradykinin degraded to inactive fragments. A-II increases blood pressure by stimulating AT1 receptors in blood vessels to induce vasoconstriction and the adrenal cortex to promote release of the salt-retaining hormone aldosterone.

ACE inhibitors therefore reduce A-II levels and increase bradykinin whereas AT1 receptor blockers augment A-II without affecting bradykinin. These differential actions could explain variations in observed effects, including perhaps on Epo requirements.

In fact, the literature contains little on the effects of AT1 receptor blockers in haemodialysis patients. Chew et al. [5], in a placebo controlled crossover study in 14 stable haemodialysis patients, have shown no change in haemoglobin or serum Epo levels related to low dose losartan. By contrast, in a multicentre case control study involving 24 anaemic haemodialysis patients not on Epo therapy [6], Schiffl and Lang have reported lower haematocrits and endogenous Epo levels in subjects receiving captopril rather than losartan. In a subsequent phase, exogenous Epo requirements were higher in the captopril group.

These latter results contrast with several reports of a reduction in haemoglobin in renal transplant recipients treated with AT1 receptor blockers, especially in post-transplant erythrocytosis [710]. It is of course possible that different mechanisms are responsible in transplant as opposed to dialysis patients. Furthermore, the possibility of a type 2 statistical error cannot be excluded in either our work or that of Chew et al. [5]. In the group studied, however, we have been unable to prove any differential effect between ACE inhibitors and AT1 receptor blockers on haemoglobin and Epo requirements in maintenance haemodialysis patients.

Acknowledgments

Our thanks are due to Dr Maurice O'Kane, Dr Mary Ryan, Mr John Corey, Mr Denzil Pyne and Mr Charlie Barr for the laboratory assays. We are also grateful to Merck Sharp & Dohme for provision of the trial medications.

References

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