Management of the Anaemia of Chronic Renal Failure with Recombinant Erythropoietin

Transcription

1 Quarterly Journal of Medicine, New Series 73. No pp December 1989 Management of the Anaemia of Chronic Renal Failure with Recombinant Erythropoietin JOHN W. ADAMSON* and JOSEPH W. ESCHBACHf From *The New York Blood Center, New York, NY 10021, and fdivision of Hematology, Department of Medicine, University of Washington, Seattle, WA 98195, U.S.A. ANAEMIA AND CHRONIC RENAL FAILURE Anaemia is an almost invariable consequence of progressive renal failure. The anaemia is hypoproliferative in nature as determined by a low reticulocyte count when corrected for the anaemia, reduced ratio of erythroid to granulocytic elements in the marrow, and low values for quantitative iron kinetics [1]. Most investigators believe that inadequate erythropoietin production is the prime cause of the anaemia. However, several other factors may contribute to the anaemia of uncomplicated chronic renal failure: (i) a mild to moderate shortening of red cell survival [2]; (ii) gastrointestinal and other blood loss associated with platelet dysfunction [3]; and (iii) the possible effect on erythropoiesis of inhibitors which are retained in chronic renal failure [4]. Other factors which may contribute to the anaemia are associated with specific complications and/or treatment of the dialysis patient. These factors include residual blood loss in the dialyser, erythroid suppression from aluminum toxicity (brought about by the chronic ingestion of aluminum-containing phosphate binders), osteitis fibrosa from severe secondary hyperparathyroidism, and, rarely, acute or chronic haemolysis [5]. While all of these mechanisms have at one time or another been raised as significant contributors to the anaemia, deficiency of erythropoietin remains foremost. Consequently, one of the long-standing goals of both haematologists and nephrologists has been the application of erythropoietin to the treatment of the anaemia of chronic renal failure. Animal studies in both rodents [6] and sheep [7] suggested that this treatment should be effective, although it was acknowledged that the methods by which animals were made uraemic and, to a variable degree, anaemic, might not properly reflect the pathophysiology of renal disease in man. Nevertheless, these models did result in established anaemia and, in the sheep, renal failure which required dialysis. In addition, the experience with the sheep model suggested that erythropoietin worked equally well in the uraemic and normal condition, predicting that it would be effective in uraemic humans [7]. ERYTHROPOIETIN IN CHRONIC RENAL FAILURE Correction of the anaemia Since erythropoietin concentrations in serum are insufficient to be a source to treat patients with the anaemia of chronic renal failure, the application of recombinant DNA technology to the problem has answered the need. The first published reports of the successful isolation, T, Oxford University Press 1989

2 1094 J. W. A damson and J. W. Eschbach cloning and expression of the human erythropoietin gene appeared in 1985 [8, 9]. This was rapidly confirmed and extended [ 10] and large amounts of recombinant human erythropoietin (rhuepo) became available for clinical trials. Such clinical trials were initiated in December, 1985 in Seattle [11] and in March, 1986 in London [12], and were targeted to anaemic patients on haemodialysis. The results of these trials [11, 12], and the accumulating numbers of patients which form the basis of multicentre trials in the United States [13], western Europe [14], and Japan [15], have supported the concept that erythropoietin deficiency is the major mechanism responsible for the anaemia. In the initial trial in the United States, rhuepo was given in increasing doses to groups of haemodialysis patients. It was administered as an intravenous bolus injection three times a week immediately following dialysis. Erythropoiesis was monitored by measurements of the reticulocyte count, quantitative ferrokinetics, transfusion requirements and haematocrit [11]. The lowest doses used (1.5 and 5 U/kg body weight) were ineffective. Initial responses were seen at 15 U/kg/dose and, in some patients, this dose resulted in a cessation of transfusion requirements and a partial correction of the anaemia (Fig. 1). At all doses greater than 15 U/kg, effective responses were observed and the anaemia was corrected. As shown in Fig. 2, the rate of correction of the anaemia was correlated directly with the initial dose. At 45- PATIENT # OI Anephric I I5 J tt t I t t! t 200 ml blood loss \ Transfusions:200ml RBCs rhuepo 15 units/kg 3x/wk 6.0-j ^ Weeks FIG. 1. Response to rhuepo, 15 U/kg, given intravenously three times weekly. Transfusion requirements ceased after the start of treatment. The reticulocyte count, corrected for the anaemia, rose with treatment and returned to baseline levels when it was interrupted for two weeks. The haematocrit subsequently peaked at 25 at this dose.

3 The Anaemia of Chronic Renal Failure and Erythropoietin U/Kg l5ou/kg Weeks of rhuepo therapy FIG. 2. The haematocrit response to various doses of RHuEpo in haemodialysis patients. Each treatment group is comprised of four or five patients and the data represent the mean weekly haematocrit values. (Reproduced from Eschbach JW, el al. N Engl J Med 1987; 316: with permission of the authors and the publishers.) the highest doses employed, increases of as much as 10 haematocrit points were observed within two to three weeks of starting therapy. Over 1000 anaemic haemodialysis patients have now been treated at centres in Canada, the United Kingdom, western Europe, Japan and the United States. Although the dosage protocols have varied, the encouraging findings of the initial studies have been confirmed with a response rate of nearly 100 per cent. In the United States multicentre trial, the rate of rise of haematocrit was shown again to be dose-dependent. In almost all patients, target haemoglobin and haematocrit levels were achieved within eight to 12 weeks after starting therapy. In this multicentre trial, only eight of 309 patients failed to respond and, of those, several had complicating medical conditions which might have predicted a lack of response to the hormone. These included unrecognized iron deficiency, osteitis fibrosa, and infection. In Seattle, some patients have now received rhuepo replacement therapy for three years. Encouragingly, those patients who have entered maintenance therapy have continued to respond to rhuepo without evidence of refractoriness or resistance and, at the time of writing, no patients have been reported who have developed antibodies to rhuepo [13]. Thus, rhuepo is remarkably effective and well tolerated. We have also treated 17 patients with the anaemia (haematocrit < 30) of progressive renal

4 1096 /. W. Adamson and J. W. Eschbach failure not yet requiring dialysis [16]. These patients have responded to rhuepo in a manner similar to haemodialysis patients. While most of the information available has been obtained with the intravenous administration of the drug, results in predialysis patients [16] and from several dialysis centres [17, 18] indicate that subcutaneous dosing with rhuepo may be more effective, although the precise correlation with intravenous dosing and details of pharmacokinetics are unknown. The use of rhuepo has raised three important issues related to management of anaemic patients with chronic renal failure. These include the effect of rhuepo on internal iron metabolism, the effect of the haematocrit on other organ systems such as blood pressure, and the potential role of inflammation in limiting the effectiveness of rhuepo. THE EFFECT OF rhuepo ON INTERNAL IRON METABOLISM With the response to rhuepo, erythropoiesis may be stimulated as much as three to four times more than normal [11] depending upon hormone dose. This imposes a demand to mobilize iron from reticuloendothelial storage sites and to make it available to transferrin for transport to the marrow for incorporation into haemoglobin. Thus, during the initial period of response to rhuepo, there is a one-way shunt of iron from stores, through the circulation, into the marrow and then into the circulating red cell mass. The amount of iron required for an effective response to rhuepo can be calculated easily. If a patient weighing 70 kg raises his/her haematocrit from 18 to 40, the increase in red cell mass will be approximately 1000 ml, equivalent to 1 g of elemental iron. In addition, with rhuepo treatment, iron accumulation from red cell transfusions ceases while iron loss due to residual dialyser blood loss continues. Severely anaemic individuals who begin treatment with rhuepo, and who have iron stores less than 1 g, are at risk of becoming iron deficient during the course of therapy. Currently, recommendations for managing patients during the acute or induction phase of therapy with rhuepo include supplementing the diet with oral iron, or else supplementing reticuloendothelial stores more directly by the administration of iron dextran. It is our practice to administer intravenous iron dextran (0.5 g or more as required) before starting rhuepo in those individuals whose initial serum ferritin levels are less than 100 ng/ml. This will help to guarantee adequate iron availability for the anticipated increase in erythropoiesis. Even when care is taken to maintain an adequate iron supply to the marrow, there will be individuals whose response to rhuepo is so brisk that mobilization of iron from storage sites cannot keep pace with the demand. In this setting, rhuepo may become less effective despite the fact that serum ferritin values clearly indicate that adequate iron stores are present. The condition of 'relative' or 'functional' iron deficiency is one which has been recognized repeatedly. Relative iron deficiency, defined as a transferrin saturation of less than 20 per cent with a normal serum ferritin level, was seen in over 40 per cent of the patients treated with rhuepo in the multicentre trial conducted in the United States. While there are no obvious adverse effects of relative iron deficiency, it is a physiological state which reduces the effectiveness of rhuepo. At this juncture, one of two courses may be followed. The dose of rhuepo may be reduced in order to allow the rate of release of iron from storage sites to catch up with the demands for haemoglobin synthesis, or supplemental iron may be given orally or in the form of intravenous iron dextran. Because some patients are unable to tolerate oral iron and there is an incidence of anaphylaxis from intravenous iron dextran of 11 per cent [19], there is concern that iron deficiency could be a limiting factor in the occasional patient because of the blood loss related to haemodialysis and occasional surgery.

5 The Anaemia of Chronic Renal Failure and Erythropoietin 1097 THE EFFECT OF CORRECTION OF THE ANEMIA IN PATIENTS WITH CHRONIC RENAL FAILURE Correction of the anaemia in patients with chronic renal failure results in better tissue oxygenation. The clinical benefits of this improved oxygenation have been reviewed recently [20], and include improved exercise tolerance, skin circulation, central nervous system function, and increased peripheral vascular resistance. It is the last effect, and its effect on blood pressure, which warrants further review at this time. In the initial group of patients treated with rhuepo, increases in blood pressure, including episodes of hypertensive encephalopathy, were observed with unexpected frequency, both in Seattle [11] and in the United Kingdom [12]. In the United States multicentre trial, 35 per cent of patients experienced an increase in diastolic blood pressure of 10 mmhg or more. In some patients, this increase did not achieve hypertensive proportions. In others, however, the increase exacerbated already existing hypertension or required the initiation of antihypertensive medication. Overall, approximately 25 percent of patients required new or increased treatment for blood pressure as they responded to rhuepo [13]. A similar increase in blood pressure was observed in hypertensive predialysis patients whose anaemia was corrected with rhuepo [16]. The mechanism underlying the increase in blood pressure may be related to an increase in total peripheral vascular resistance [21, 22]. Blood viscosity, which increases as the haematocrit increases, is similar in normotensive and hypertensive patients responding to rhuepo [23], and therefore is not the sole cause. In studies from several centres, the increase in peripheral vascular resistance was associated with a decline in cardiac output [21], although these findings are not universal [24]. Nevertheless, these observations are similar to those published by Neff and co-workers [25] which demonstrated that raising the haematocrit in dialysis patients with red cell transfusions resulted in a progressive increase in diastolic and mean arterial blood pressure. These changes, similar to those found in dialysis patients receiving rhuepo, were mediated by an increase in peripheral vascular resistance which was associated with a decrease in cardiac output. It is believed that the increased vascular resistance results from the correction of the peripheral vasodilatation which accompanies profound, sustained anaemia [22]. The blood pressure changes are not due to a direct pressor effect of rhuepo since hypertension has not been observed in normal volunteers or in other patient groups receiving rhuepo [26]. We have analysed data to determine which factors impose an increased risk for the development or aggravation of hypertension in anaemic patients with chronic renal failure. In an analysis of 63 patients in Seattle, hypertension occurred more frequently if haematocrit was 20 or less at the outset of treatment regardless of whether there was a previous history of hypertension [21]. Of non-hypertensive patients in the Seattle study, 66 per cent developed increased blood pressure while 79 per cent of previously hypertensive patients required an increase in antihypertensive medication [21]. Eighty-nine per cent of patients whose haematocrit measurements were 20 or less at baseline developed increased diastolic blood pressure or frank hypertension as opposed to 57 per cent of those whose haematocrit values were above 20. In the Seattle patients, factors such as age, sex, number of years on dialysis, presence or absence of kidneys, or the disease which led to renal failure, had no relationship with the appearance of hypertension [21]. Thus, the analysis of the Seattle patients indicated that the major risk factor for developing hypertension or an exacerbation in hypertension was severe anaemia and not the rate of rise of haematocrit. An analysis of the multicentre trial results in the United States also failed to show that the rate of rise of haematocrit was a risk factor. Since there is no way, at this time,

6 1098 J. W. A damson and J. W. Eschbach to predict who will develop hypertension or become more hypertensive when treatment with rhuepo is initiated, our recommendation for the anaemic haemodialysis patient is to use a relatively low dose, i.e., 50 to 150 U/kg, thrice weekly, intravenously. As haematocrit approaches 30, the dose should be reduced to reach the target haemoglobin/haematocrit value more gradually. Reducing the dose allows more time to observe the blood pressure response and to initiate appropriate antihypertensive therapy. If, at any time, serious hypertension develops during the acute phase of treatment, rhuepo should be withheld until the blood pressure is controlled. Experience to date indicates that a rising blood pressure during the acute phase of treatment (i.e., when the haematocrit is increasing toward target levels) is more likely to precipitate seizures and/or hypertensive encephalopathy, than similar changes in blood pressure during the maintenance phase (when the haematocrit is relatively stable). THE EFFECT OF INFLAMMATION ON THE EFFECTIVENESS OF rhuepo Considerable interest exists in using rhuepo in patients with anaemia associated with chronic inflammatory or infectious diseases or malignancies. While fragmentary early results #8015 Autologous Transfusions: ti HIP SURGERY I 62.5 I rhuepo U Kg 3x wk Serum Fe % Sal Ferntin ? FIG. 3. The effect of the inflammation of surgery on the response to rhuepo. The haematocrit of this dialysis patient was maintained at approximately 35 with 62.5 U/kg of rhuepo given intravenously three times per week. The dose was increased to 75 U/kg in order to allow the patient to donate three units of red cells for autologous use. Although the patient received 2.5 units during hip-replacement surgery, the haematocrit fell to 18 where it remained forfiveweeks despite a dose of 100 U/kg. Note that the serum ferritin increased and the serum iron decreased at the time of surgery and reversed at the time the patient began to respond again to rhuepo.

7 The Anaemia of Chronic Renal Failure and Erylhropoietin 1099 appear promising [26], there is an added feature of inflammation which predictably would blunt the response to rhuepo. Specifically, chronic inflammatory diseases of many kinds are associated with a reduced release of iron from storage sites and a reduced percentage of transferrin saturation. This characteristic alteration in internal iron metabolism is referred to as reticuloendothelial iron blockade and is one of the major criteria for the diagnosis of the anaemia of chronic disease [27]. Because this relative iron deficiency has been so refractory to simple manipulations such as oral or parenteral iron supplementation, it may be anticipated that rhuepo will be less effective in this setting than in otherwise normal individuals. Figure 3 shows the effect of elective hip replacement in a patient with end-stage renal disease who was receiving rhuepo. The patient's haematocrit had been maintained by thrice-weekly doses of 62.5 U/kg. Before surgery, dose of rhuepo was increased to enable the patient to donate blood for self-use during surgery. The effect of surgery on the response to rhuepo was dramatic in that the haematocrit fell to below 20 and only after four to six weeks had passed was the response to rhuepo re-established. A second patient treated with rhuepo had an identical refractory period after hip replacement surgery. Another patient developed tuberculosis of the sacro-iliac joint. While the patient was febrile, reticulocytes and haematocrit decreased despite the maintenance of a previously effective dose of rhuepo of 125 U/kg, thrice weekly. After appropriate antibiotics were 0> Patient 8120 Tuberculous Arthritis intibkxkt.i rhuepo: 129 U kg. 3iwert I 5.0-4J- * ' 3.0 H } " 0 7/ FIG. 4. The effect of infection on the response to rhuepo. In this haemodialysis patient the haematocrit was increasing slowly on rhuepo, 125 U/kg, intravenously, three times a week. When fever developed, the reticulocyte count and haematocrit decreased. The response to rhuepo was reestablished after appropriate antibiotic therapy was begun.

8 1100 J.W. A damson and J. W. Eschbach begun, the haematocrit rose at an even faster rate than before the development of symptoms (Fig. 4). As more data accumulate in patients with active inflammatory disease, a pattern of relative resistance to rhuepo may emerge, and it is likely that the doses required to maintain target haematocrit in these patients will be higher than the doses required in patients with chronic renal failure. In summary, rhuepo has proved to be an extremely effective and well-tolerated drug. It can be predicted that nearly all patients with uncomplicated anaemia associated with chronic renal failure will respond to rhuepo replacement therapy. Iron availability and blood pressure must be monitored and managed to minimize adverse effects. These management issues in patients with chronic renal failure make it prudent to begin with rhuepo doses that are in the range of 50 to 150 U/kg and to bring the haematocrit gradually to target levels. We believe that the morbidity and impaired quality of life which characterize virtually all patients with chronic renal failure will be markedly improved as a result of treatment with rhuepo. ACKNOWLEDGEMENTS Portions of this work were supported by research grants DK and DK and Clinical Research Center grant, FR-0037, all from the National Institutes of Health, DHHS, and patient support funds from AMGen Corporation, Thousand Oaks, CA. Dr Adamson is a Clinical Research Professor of the American Cancer Society. REFERENCES 1. Adamson JW, Eschbach JW, Finch CA. The kidney and erythropoiesis. A J Med 1968; 44: Shaw AB. Haemolysis in chronic renal failure. Br Med J 1967; 2: Castaldi PA, Rozenberg MC, Stewart JH.The bleeding disorder of uraemia. A qualitative platelet defect. Lancet 1966; 2: Fisher JW. Mechanism of the anemia of chronic renal failure. Editorial review. Nephron 1980; 25: Eschbach JW, Adamson JW. Anemia of end-stage renal disease (ESRD). Kidney Int 1985; 28: Van Stone JC, Max P. Effect of erythropoietin on anemia of peritoneally dialyzed anephric rats. Kidney Int 1979; 15: Eschbach JW, Mladenovic J, Garcia JF, Wahl PW, Adamson JW. The anemia of chronic renal failure in sheep. Response to erythropoietin-rich plasma in vivo. J Clin Invest 1984; 74: Jacobs K, Shoemaker C, Rudersdorf R, et al. Isolation and characterization of genomic and cdna clones of human erythropoietin. Nature 1985; 313: Lin F-K, Suggs S, Lin CH et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 1985; 92: Powell JS, Berkner KL, Lebo RV, Adamson JW. Human erythropoietin gene: High level expression in stably transfected mammalian cells and chromosome localization. Proc Natl Acad Sci USA 1986; 83: Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease withrecombinanthuman erythropoietin: Results of a Phase I and II clinical trial. N Engl J Med 1987; 316: Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986; 2: Eschbach JW, Adamson JW. Correction of the anemia of hemodialysis (HD) patients with recombinant human erythropoietin (rhuepo): Results of a multi-center study. Kidney Int 1988; 33: 189(A). 14. Bommer J, Kugel M, Schoeppe W, et al. Dose-related effects of recombinant human erythropoietin on erythropoiesis: results of a multicenter trial in patients with end-stage renal disease.

9 The Anaemia of Chronic Renal Failure and Erythropoietin 1101 Treatment of renal anaemia with recombinant human erythropoietin. Contr Nephrol 1988; 66' Akizawa T, Koshikawa S, Takaku F et al. Clinical effect of recombinant human erythropoietin on anemia associated with chronic renal failure. A multi-institutional study in Japan. Int J Artif Organs. 1988; 11: Eschbach JW, Kelly MR, Haley NR, Abels Rl, AdamsonJW. Correction of anemia in progressive renal failure with recombinant human erythropoietin (rhuepo). N Engl J Med 1989; 321: Bommer J, Ritz E, Weinreich T, Bommer G, Ziegler T. Subcutaneous erythropoietin. Lancet 1988; 2: Granolleras C, Shaldon S. Experience with daily subcutaneous rhepo in haemodialysis patients maintained on IV rhepo thrice weekly. Contr Nephrol 1989; in press. 19. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA 1980; 243: Eschbach JW, Adamson JW. Recombinant human erythropoietin: Implications for nephrology. Am J Kidney Dis 1988; 11: Buckner FS, Eschbach JW, Haley NR, Davidson RR, Adamson JW. Correction of the anemia in hemodialysis (HD) patients (PTS) with recombinant human erythropoietin (rhuepo): Hemodynamic changes and risks for hypertension. Kidney Int 1989; 35: 190(A). 22. Nonnast-Daniel B, Creutzig A, Kuhn K, et al. Effect of treatment with recombinant human erythropoietin on peripheral hemodynamics and oxygenation. Contr Nephrol 1988; 66: Danielson BG, Gosh J, Linda T, Wikstrom B. Blood viscosity and hypertension in patients treated with erythropoietin. Presented to the Swedish Society of Nephrology 1988; 2 December. 24. Paganini E, Thomas T, Fouad F, Garcia J, Bravo E. The correction of anemia in hemodialysis patients using a recombinant human erythropoietin (rhuepo): Hemodynamic effects. Kidney Int 1988; 33: Neff MS, Kim KE, Persoff M, Onesti G, SwartzC. Hemodynamics of uremic anemia. Circulation 1971; 63: Means RT, Olsen NJ, Krantz SB, et al. Treatment of the anemia of rheumatoid arthritis with recombinant human erythropoietin: clinical and in vitro results. Blood 1987; 70: I39(A). 27. Douglas SW, Adamson JW. The anemia of chronic disorders: Studies of marrow regulation and iron metabolism. Blood 1975; 45:

10