International Urology and Nephrology 26 (2), pp. 237-243 (1994)

Change in Haemoglobin Concentration, Haematocrit and Vasoactive Hormones in Haemodialysis Patients with Erythropoietin-assoeiated Hypertension I. SASAGAWA, T. NAKADA, t. HASHIMOTO, Y. KUBOTA, H. SUZUKI, T. SAWAMURA

Department of Urology, Yamagata University,School of Medicine, Yamagata, Japan (Accepted September 3, 1993) The changes in haemoglobin concentration, haematocrit, plasma renin activity (PRA) and atrial natriuretie peptide (ANP) were studied in 10 haemodialysis patients with erythropoietin-associated hype~ension. All patients received intravenously 1500 IU of recombinant human erythropoietin (rHuEPO) thrice weekly for 24 weeks. Treatment with rHuEPO induced significant rises in haemoglobin concentration (p<0.001) and haematocrit (p<0.01). However, the difference between post- and pretreatment levels of haemoglobin (AHb) was not correlated with that between postand pre-treatment mean blood pressure (AMBP). No correlation was found between AHt (difference between post- and pre-treatrnent values of haematocrit) mad L~fBP. These results indicate that elevation of the haematocrit and haemoglobin concentration of haemodialysis patients does not necessarily lead to ml increase in blood pressure. In these patients, no significant differences were observed in PRA and AN/), comparing pre-treatment values with those measured 4, 8, 12 or 24 weeks after commencing rHuEPO. This suggests that neither PRA nor ANT play a central role in the pathogenesis of rHuEPO-induced hypertension.

Introduction Anaemia is a common feature in patients with chronic renal failure on regular dialysis. It is mainly due to suboptimal levels of endogenous erythropoiefin (EPO) production [1]. Recombinant human erythropoiefin (rHuEPO) is a major advance in the management of patients with chronic renal failure offering the possibility of reversing the anaemia [2, 31. During treatment with rHuEPO, severe hypertension or hypertensive encephalopathy was noted in some cases [2, 4]. However, the mechanism of blood pressure elevation associated with rHuEPO is still unknown. In the present study, we have investigated the changes in haemoglobin concentration, haematocrit, plasma renin activi~ (PRA) and atrial natriuretic peptide (ANP) in haemodialysis patients who exhibited a rise in blood pressure during rHuEPO treatment.

Patients and methods Ten patients who exhibited a rise in blood pressure during rHuEPO treatment for anaemia due to end-stage renal disease were included in this study. VSP, Utrecht dkad~mtai Klad6, Budapest

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All patients (7 males and 3 females, aged 39--60 years; median 53) had been managed by haemodialysis for 12-103 months (median 42). Specific causes of anaemia such as chronic blood loss, iron deficiency, aluminium overload or deficiency of folio acid and vitamin Bl2 were excluded. None of the patients had severe hyperparathyroidism, a history of vascular or cardiac disease or diabetes. No patient underwent bilateral nephrectomy previously. All patients received intravenously 1500 IU of rHuEPO (Eposin, Chugai Pharmaceutical Inc., Tokyo, Japan) thrice weekly for 24 weeks. Blood pressure was monitored twice weekly during this study. Morning blood pressure was measured by one nurse using a standard mercury sphygmomanometer with the patient in the supine position. Mean arterial pressure was estimated as diastolic pressure plus one third of the difference between systolic and diastolic pressure. Blood samples were obtained before and 4, 8, 12 and 24 weeks after the commencement of rHuEPO therapy. Haematological indices were determined using routine clinical chemistry methods. PRA was measured by a solid phase tube radioimmunoassay method. Plasma level of ANP was estimated by double-antibody radioimmunoassay methods. Results

Changes in blood pressure are illustrated in Fig. 1. During the 24-week period of rHuEPO administration, systolic, mean and diastolic pressures were elevated from 127+13 to 157+11 mm Hg (p<0.001), from 90~8 to 110-~I0 mm Hg

Fig. 1. Change in blood pressure after rHuEPO treatment in haemodialysispatients.Each point representsmean-+.S.D. *p
Sasagawa et aL : Haemodialysis in hypertension

(a)

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(b}

Fig. 2. (a) Change in haemoglobin concentration after rHuEPO treatment in haemodialysis patients. (b) Effect of rHuEPO on haematocrit in haemodialysis patients. Each point represents mean+SD. *p<0.05, **p<0.01, ***p<0.001 compared to pre-treatment values

Fig. 3. Correlation between A mean blood pressure and A haemoglobin in haemodialysis patients (n = 10). Y=I 5.0+1.8X, r=0.24, p>O.05 International Urology and Nephrology 26. 1994

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Fig. 4. Correlation between A metal blood pressure and A haematocrit in haemodialysis patiea~ts (n= I 0). Y=I 3.8+0.8X, r=0.25, p>O.05

Fig, 5, Eflbct of rHu.EPO on PRA in haemodialysis patients. Each point repre~nts mean+SD.

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Fig. 6. Change in plasma ANP level after rHuEPO treatment in haemodialysis patients. Each point represents mean+S. D.

(p<0.001), and from 72i6 to 89~8 mm Hg (p<0.001), respectively. Treatment with rHuEPO induced rises in haemoglobin concentration from 7.0a:0.6 to 9.6~:1.2 g/dl (p<0.001) and haematocrit from 21.8• to 28.6• (p<0.01) by 24 weeks, respectively (Fig. 2). The difference between post- and pre-treatment concentrations of haemoglobin (AHb) was not correlated with that between post- and pre-treatment mean blood pressures (AMBP) (Fig. 3). No correlation was found between AHt (difference between post- and pre-treatment value of haematoerit) and AMBP (Fig. 4). Pre-treatment levels of PRA and ANP were 4.0~3.8 ng/ml/h and 124+71 pg/ml, respectively. Changes in PRA and ANP are shown in Figs 5 and 6. No significant differences were observed in these measurements comparing pretreatment values with those measured 4, 8, 12 or 24 weeks after commencing rHuEPO. Discussion Blood pressure elevation during treatment with rHuEPO is of major concem in patients on haemodialysis. In about 30% of these patients, intravenous administration of rHuEPO induces development or aggravation of hypertenlnternattonal Urologyand Nephrolagy26, 1994

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Fig. 6. Change in plasma ANP level after rHuEPO treatment in haemodialysis patients. Each point represents mean+S. D.

(p<0.001), and from 72i6 to 89~8 mm Hg (p<0.001), respectively. Treatment with rHuEPO induced rises in haemoglobin concentration from 7.0a:0.6 to 9.6~:1.2 g/dl (p<0.001) and haematocrit from 21.8• to 28.6• (p<0.01) by 24 weeks, respectively (Fig. 2). The difference between post- and pre-treatment concentrations of haemoglobin (AHb) was not correlated with that between post- and pre-treatment mean blood pressures (AMBP) (Fig. 3). No correlation was found between AHt (difference between post- and pre-treatment value of haematoerit) and AMBP (Fig. 4). Pre-treatment levels of PRA and ANP were 4.0~3.8 ng/ml/h and 124+71 pg/ml, respectively. Changes in PRA and ANP are shown in Figs 5 and 6. No significant differences were observed in these measurements comparing pretreatment values with those measured 4, 8, 12 or 24 weeks after commencing rHuEPO. Discussion Blood pressure elevation during treatment with rHuEPO is of major concem in patients on haemodialysis. In about 30% of these patients, intravenous administration of rHuEPO induces development or aggravation of hypertenlnternattonal Urologyand Nephrolagy26, 1994

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6. Williams, B., Edmunds, M. E., Thompson, J. P., Burton, P. R., FeehaUy, J. Walls, J.: Does increasing haemoglobin concentration and haematocrit have a pressor effect in dialysis patient? NephroL Dial Transplant., 4, 787 (1989). 7. Bund, S. J., Heagerty, A., Edmunds, M., Walls, J.: Erythropoietin does not induce vasoconstriction directly in human subcutaneous resistance arterioles. Nephron, 53, 173 (1989). 8. Neff, M. S., Kim, K. E., Persoff, M., Onesti, G., Swartz, C.: Hemodynamics of uremic anemia. Circulation, 43, 876 (1971). 9. Capelli, L P., Kasparian, H.: Cardiac work demands and left ventricular function in end-stage renal disease. Ann. Intern. Med., 86, 261 (1977). 10. Verbeelen, D., Bossuyt, A., Smitz, J., tterman, A., Dratwa, M., Jonckheer, M. H.: Hemodynamics of patients with renal failure treated with recombinant human erythropoietin. Clin. NephroL, 31, 6 (1989). 11. Iitake, K., Kimura, T., Matsui, K., Ota, K., Shoji, M., Inoue, M_, Yoshinaga, K.: Effect of haemodialysis on plasma ADH levels, plasma renin activity and plasma aldosterone levels in patients with end-stage renal disease. Acta EndocrinoL, II0, 207 (1985). 12. Schalekamp, M. A., Beevers, D. G., Briggs, J. D., Brown, L J., Davies, D. L., Fraser, R., Lebel, M., Lever, A. F., Medina, A., Morton, J. J., Robert.son, J. I. S., -free, M.: Hypertension in chronic renal failure. An abnomral relation between sodium and the reninangiotensin system. Am..1. Med., 55, 379 (I 973). 13. Hasegawa, K., Matsushita, Y., Inoue, T., Morii, H., Ishibashi, M., Yamaji, T.: Plasma levels of atrial natriuretic peptide in patients with chronic renal failure. J. Clin. Endocrqnol, hletab., 63, 819 (1986). !4. Weidmaim, P., Saxenhofer, H., Ferrier, C., Shaw, S. G.: Atrial natrittretic peptidc in man. Am. J. Nephrol.. 8, 1 (1988).

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