A ndrogens have been used as treatment for anemia of ESRD since 1970 (1,2). Before the advent of recombinant human erythropoietin, androgens

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1 Androgen versus Erythropoietin for the Treatment of Anemia in Hemodialyzed Patients: A Prospective Study1 Jos#{233}1. Teruei,2 Roberto Marcen, Javier Navarro-Antolin, Abelardo Aguilera, Gemma Fernandez-Juarez, and JoaquIn Ortu#{241}o J.L. Teruel, R. Marcen, J. Navarro-Antolin, A. Aguilera, G. Fernandez-Juarez, J. Ortuno, Department of Nephrology, Hospital lam#{243}n y Cajal, Madrid, Spain (J. Am. Soc. Nephrol. 1996: 7:14-144) ABSTRACT According to this facility s protocol for the treatment of anemia In hemodialyzed patients, androgens were administered to male patients aged over 5 yr and recombinant human erythropoietln was administered to male patients below 5 yr of age and to female patients. In the study presented here, both therapeutic approaches have been prospectively analyzed. Patients were divided Into two groups. Group A was composed of 18 patients, aged 62 ± yr, treated with nandrolone decanoate (2 mg/wk im) for 6 months; Group B was composed of 22 patients (6 men, 16 women) aged 47 ± 15 yr, treated with subcutaneous recombinant human erythropoletln (initial dose, 6 IU/wk) for 6 months. The increases of hemoglobin were similar in both groups; Group A, from 7.3 ±.8 to 1.8 ± 1.7 g/dl (P <.1), and Group B, from 7 ±.6 to 1.4 ± 1 g/dl (P <.1). In Group A, increases of triglycerides (159 ± 71 versus 267 ± 153 mg/dl, P<.1), serum albumin (3.9 ±.3 versus 4.2 ±.3 g/dl, P <.5), and dry weight (62.1 ± 9.8 versus#{243}4.9 ± 1.1 kg, P<.O1)were observed, which remained unmodified in Group B. Blood pressure control worsened in one patient (6%) from Group A, and in ten patients (45%) from Group B (P <.5). In conclusion, androgens produced an improvement In anemia in selected patients, similar to that achieved by use of recombinant human erythropoietin but at a lower cost. Androgens also have an appreciable anabolic effect and did not increase the blood pressure. Key Words: Anemia, nandrolone decanoate, erythropoietin, hemodialysis A ndrogens have been used as treatment for anemia of ESRD since 197 (1,2). Before the advent of recombinant human erythropoietin, androgens Received April 26, Accepted October 6, Coeespandence to Dr. J.L leruel, Servicio de Nefrologia. Hospital Ram#{243}ny calal, Carretera de Colmenar. km 9.1, 2834 Madrid, Spain /71-14$3./ Journal of the American Society of Nephroiogy Copyright 1996 by the American Society of Nephrology were the mainstay of nontransfusional treatment for nonferrogenic anemic patients on dialysis therapy. The availability of recombinant human erythropoietin in the last years of 1 98s has completely modified the treatment of anemia of chronic renal failure, and androgens used as treatment have been abandoned. However, the generalized use of recombinant human erythropoietln is primarily limited by Its high cost. In a retrospective study in hemodialyzed patients treated with nandrolone decanoate, we observed that the anemia response is related to the age of the patients, and that excellent results might be obtained in elderly patients (3). But the vlrilizant effect of androgens (hirsutism and voice change) represented a real inconvenience to its use in women. After our observations, we instituted in 1991 the following protocol for the treatment of anemia in chronic renal failure patients: androgens are to be used in male patients aged above 5 yr and recombinant human erythropoietin is to be used in male patients below this age and in women. In the study presented here, we analyzed the results of this therapeutic protocol. MATERIAL AND METHODS Our protocol of treatment for anemia in nonferrogenic chronic hemodlalyzed patients with a hemoglobin concentration of less than 8 g/dl is the following: in male patients aged 5 or more yr. we Indicate a cycle of nandrolone decanoate, 2 mg given once a week by im injection on a nondlalysis day. for 6 months. The androgens are then withdrawn. Men aged below 5 yr or women are treated with recombinant human erythropoietin, 2 IU subcutaneously, three times a week. This dose Is maintained for 3 months, then may be modified according to the response of the anemia: the goal is to reach a hemoghobin concentration between 1 and 11 g/dl. Among patients with chronic renal failure who received a specific treatment for anemia in our hemodlalysis unit between! 991 and we selected the patients who fulfilled the following conditions: they had completed a cycle of 6 months with androgens (Androgen Group) or received recombinant human erythropoietin for at least 6 months (Erythropoietln Group); they had been stable on chronic hemodialysis for at least 1 month before androgen or recombinant human erythropoietln administration; they had not been previously treated with androgen or recombinant human erythropoietin; their basal hemoglobin concentration was less than 8 g/dl. confirmed at least in three determinations, and; they had not undergone any clinically relevant intercurrent episode such as chronic inflammatory disorders, infection, major surgery, or blood loss during the study period. Patients with asymptomatic chronic hepatitis were included. The Androgen Group was composed of 18 male patients. aged between 5 and 84 yr (62 ± yr. mean ± SD). and on hemodlalysis therapy for 1 to 48 months (mean ± SD, ii ± ; median, 9 months). The primary renal disease was 14 Volume 7 Number

2 Teruel et al chronic glomerulonephritis in four patients. chronic interstitial nephropathy In two patients. nephrosclerosis in four patients, adult polycystic kidney disease in five patients, and unknown etiology in three patients. No patient was anephric. Three patients had been transfused during the 3 months before the start of androgen therapy. In the considered period of time (1991 to 1993), another three male patients, who had started treatment with nandrohone decanoate, were excluded from the study. One patient was transplanted at the fourth month of androgen treatment, another patient was transferred to a different hemodlalysis unit at the second month, and the third patient, diagnosed with adult pohycystic renal disease, suffered from septicemia originating from a cyst at the second month, and was nephrectomlzed. The Erythropoletln Group was composed of 22 patients. Six men and 16 women were included, and were aged between 19 and 77 yr (47 ± 15 yr. mean ± SD) and on hemodialysis therapy for 1 to 69 months (mean ± SD, ± 18; median, 8 monthsl. The primary renal disease was chronic giomerular disease in five patients, chronic interstitial nephropathy in four patients. nephrosclerosis in three patients, adult polycystic kidney disease in three patients, Alport s syndrome in one patient, bilateral nephrectomy by recidivant uroepithehial carcinoma in two patients, and unknown etiology in four patients. Four patients had been transfused during the 3 months before beginning erytlu-opoietin therapy. The patients were dialyzed for 3 to 4 h. three times a week. The dry weight was defined as the lower postdiahysis-tolerated weight level and reevaluated for each patient on a monthly basis. The hematocrit. hemoglobin concentration, and serum levels of triglyceride, cholesterol, albumin. bilirubin, ghutamlc-oxaloacetic transaminase, glutamic-pyruvic transaminase, and alkaline phosphatase were checked monthly before the first hemodialysis session of a week. Serum ferritin was measured every 2 months. If serum ferritin level was 5 ng per ml or below, the patient received an intravenous dose of 1 g of elemental iron (such sodium ferric gluconate). KTIV (calculated as the natural logarithm of predlalysis urea concentration, minus the natural logarithm of postdialysis urea concentration) was measured monthly. The value considered in every patient was the mean of all KT/V values obtained during the 6 months of therapy for anemia. Data are expressed as mean ± SD. Unpaired t test was used to compare patient groups. Analysis of variance and multiple range analysis (Scheff#{233} s Test) were used when indicated. The significance of differences in percentages of events between treatment groups was determined by the chi square and by Fisher s exact tests. Values of P <.5 were considered as significant. RESULTS Both groups were different with respect to age (P <. 1) and sex distribution (P <. 1). Basal values of hematocrit. hemoglobin, triglycerides, cholesterol, albumin, dry weight. and residual renal function were similar in both groups of patients. Basal serum ferritin level was lower in the Androgen Group (Table 1). The evolution of hemoglobin concentration and serum ferritin level in both groups during the 6-month study is expressed in the Table 2. The variation of the serum ferritin level in the Androgen Group had no statistical significance. Except for the serum ferritin TABLE 1. Basal values in Androgen Group and Erythropoietin Group Test Androgen Group (N= 18) Erythropoletln Group (N= 22) P Value Hematocrit 22 ± ± 2.3 NS Hemoglobin (g/dl) 7.3 ±.8 7 ±.6 NS Ferritin (pg/i) 174 ± ± 33 <.5 Triglycerides (mg/dl) 159 ± ± 42 NS Cholesterol (mg/dl) 171 ± ± 38 NS Albumin (g/dl) 3.9 ± ±.3 NS Dry Weight (kg) 62.1 ± ±.7 NS Residual Renal Urea 1.24 ± ± 1.4 NS Clearance (ml/min) #{176}NS. not significant. TABLE 2. Evolution of hemoglobin concentration and serum ferritin level (g/l) in Androgen Group (Group A) and Erythropoietin Group (Group B) Basal 1 Month 2 Months 3 Months 4 Months 5 Months 6 Months Hemoglobin Concentration#{176} (g/dl) Serum Ferritln Levelb (g/l) Group A Group B Group A Group B 7.3 ±.8 7 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 33 3 ± ± ± ± ± ± 229 differences in the hemoglobin concentration with regard to basal value had statistical significance from the first month of therapy in both groups (P <.1 for all time periods, Scheff#{233} stest). #{176}Thedecrease in the serum ferritin level in the Erythropoletln Group with respect to the basai level was statisticaby significant in all time periods (P <.1. Scheff#{233} stest). level at the basal time, there were no differences between the Androgen Group and the Erythropoietin Group at any time during the follow-up. The dose of dialysis during the 6-month study was similar in both groups: KT/V = 1.5 ±.19 in the Androgen Group and 1.9 ±.17 in the Erythropoietin Group (P = not significant). The administration of iron supplements was similar in both groups. In 14 patients from the Androgen Group, it was necessary to give intravenous iron (one dose of 1 g to 11 patients and two doses of 1 g to three patients). In the Erythropoietin Group, 16 patients received intravenous iron ( patients one dose of 1 g. and three patients two doses of 1 g). No patient was transfused during the 6-month therapeutic period. In the Androgen Group, we observed an increment in the serum concentration of triglycerides and albumiii and in the dry weight (Table 3). These parameters did not vary in the Erythropoietin Group (values at 6 Journal of the American Society of Nephrology 141

3 Androgen and Erythropoietin in Hemodialyzed Patients months, triglycerides 159 ± 52 mg/dl; serum albumin, 4,2 ±.3 g/dl; dry weight, 6 ± 1.8 kg). The serum cholesterol concentration did not change in any patients of either group during the 6 months of the follow-up. At the time they began the treatment for anemia, patients in the Androgen Group and patients in the Erythropoietin Group were considered normotensive (predialysis blood pressure less than 14/9 mm Hg, without antihypertensive therapy): the other patients were on antihypertensive therapy and were considered hypertensive. In the Androgen Group, blood pressure only increased in one patient (6%). a previously normotensive patient who needed antihypertensive treatment. In the Erythropoietin Group, blood pressure increased in ten patients (45%, P <.5), six previously normotensive patients needed antihypertensive treatment, and four previously hypertensive patients needed a higher dose of antihypertensive treatment. The increases of blood pressure were mild in all these patients. Furthermore, the blood pressure improved in three patients in each group (Figures 1 and 2). At the start of treatment for anemia, three patients in the Androgen Group and two patients in the Erythropotetin Group had biochemical data of liver disease associated to antibodies of the hepatitis C virus. None of these patients experienced a biochemical worsening of the disease with the administration of nandrolone decanoate or recombinant human erythropoietun. One patient in the Erythropoietin Group presented a mild and transitory elevation of hepatic enzymes at the second month of treatment with negative hepatitis B and C serology. De novo elevation of bilirubin and/or hepatic enzymes was not observed in any patient during the androgen therapy. The initial recombinant human erythropoietin dose was 3 ± 33 lu/kg per wk and at the sixth month was 19 ± 57 lu/kg per week. In our country, the cost of the whole cycle of nandrolone decanoate was $35. TABLE 3. Evolution of serum triglycerides and albumin concentration and dry weight in the Androgen Groupa The cost of erythropoietin therapy for 6 months amounted to between $175 and $575 ($33 ± 1117). Recombinant human erythropoietin treatment was maintained beyond the 6 months of the study in all patients of the Group. The nandrolone decanoate was withdrawn after 6 months of treatment according to our therapeutic protocol. Post-androgen evolution was evaluated in patients. The evolution of hemoglobin after the discontinuation of androgens is shown in Figure 3. In six patients, the hemoglobin decreased when androgen administration was stopped, and they were given a new cycle of androgen between 3 and months thereafter. All patients responded well to androgens again. In seven patients, hemoglobin remained stable after androgens were stopped. Triglycerides returned to basal levels 3 months after the discontinuation of androgens (basal level, 152 ± 79; immediately prior to the last dose of androgens. 262 ± 14; 3 months post-androgens. 173 ± 95 mg/dl). The post-androgen evolution was not evaluated in five patients because the follow-up period was less than three months: one patient was transplanted, one patient suffered gastrointestinal bleeding, one patient was referred to another hemodialysis unit, one patient died by traffic accident, and one patient of acute myocardial infarction. In the last patient, triglyceride concentration did not increase by androgen therapy (basal level, 1 mg/dl; after 6 months, 19 mg/dl). DISCUSSION Previous studies have observed that androgens produce an increase in hematocrit and hemoglobin levels in uremic patients as a consequence of an improvement of red-cell mass (2,4-6). However, other authors considered that the increment of hematocrit by androgens is small and its generalized use is not justified in these patients (7-1). With the advent of successful pathophysiological human recombinant erythropoietin therapy, androgens have been forgotten. In a previous retrospective study in hemodialyzed 14 Test Triglycerides (mg/dl) Albumin (g/dl) Dry Body Weight (kg) Basal 159 ± ± ± Month 22±11 4± ±9.7 2 Months 233 ± ±.3 63 ± Months 219 ± ± ± 1 4 Months 247 ± ±.2 64 ± 1 5 Months 258 ± ± ± Months 267 ± ± ± 1.1 cr11 z 1 -J w I 7 6- NO CHANGE OF BLOOD PRESSURE INCREASE OF BLOOD PRESSURE DECREASE OF BLOOD PRESSURE #{176} differences with regards to the basal values were statistically significant for the triglycerides from the second month (P <.5 at the second and third months, and P <.1 at the fourth. fifth, and sixth months), for the serum albumin from the fourth to sixth months (P <.5). and for the dry body weight from the third to sixth months (P <.1) (Scheff#{233} s Test) MONTHS Figure 1. Evolution of hemoglobin concentration in the Erythropoietin Group. 142 Volume 7 Number

4 Teruel et al V cr11 z 9 w I NO CEANGE OF BLOOD PRESSURE INCREASE OF BLOOD PRESSURE DECREASE OP BLOOD PRESSURE basal MONTHS POST DISCONTINUATION FIgure 3. Evolution of hemoglobin concentration after discontinuation of androgen. NC, new cycle with androgen; RT, renal transplontation. patients, we observed that the response of anemia to the nandrolone decanoate was age related and independent of sex, time on dialysis, or etiology of the renal failure (3). The mechanism of action of androgens and the influence of the age in the response of the anemia are speculative. We have observed that the nandrolone decanoate increases the serum erythropotetin level in hemodialyzed patients, but the variations in the serum erythropoletin concentration were not correlated with the response of the anemia or the age of the patients (11). According to our previous results, we established in 1991 the following protocol for treatment of the anemia in chronic hemodialyzed patients: androgens are recommended for male patients aged 5 or more yr and recombinant human erythropoletln in male patients aged less than 5 yr and in women. We do not use androgens in bilateral nephrectomlzed patients because, according to our experience () and that of the others, they did not appear to benefit from this kind of treatment (8,,14). In this study, we have analyzed the results obtained with this protocol. After 6 months of therapy, the increase in the hemoglobin concentration obtained in 18 patients receiving androgens was similar to that of 22 patients receiving recombinant human erythropoletin, with a lower economical cost. Whereas recombinant human erythropoietln administration was maintained uninterrupted beyond the sixth month, the androgens were discontinued at this time, and in 7 out of evaluated patients, the hemoglobin concentration remained stable at a higher level than the basal. A similar evolution of hemoglobin after the discontinuation of androgens was observed by Neff (14) and by us in a retrospective study (15). MONTHS Basal hemoglobin level and previous blood transfusion requirements (as indicators of the severity of the Figure 2. Evolution of hemoglobin concentration In the Androgen Group. anemia), time on hemodlalysis, and primary renal disease distribution (with exception of two anephrlc cases in the Erythropoietin Group) were similar in both groups of patients. As a consequence of our selection criteria, the composition of both groups was different with respect to age and sex distribution. However, the responsiveness to recombinant human z 11 erythropoietin in chronic renal failure patients is not sex or age dependent. So, we think our results are not conditioned by the differences existing in the composition of groups of patients. It is important to point out that the improvement in anemia by androgens produced an elevation of blood pressure in only one patient. This effect is quite different from that observed in patients treated with human recombinant erythropoietin. which produced an elevation of blood pressure in 45% of our patients. The rate of hemoglobin increase was similar in both groups of patients. In a previous study (16). we studied the course of blood pressure after different forms of correction of anemia (intravenous iron. androgens and human recombinant erythropoietin) in comparable groups of hemodialyzed patients. A rise in blood pressure was observed only in erythropoletin-treated patients. The study presented here confirms our previous results, indicating that the hypertensive effect associated to the human erythropoletln treatment can not be attributed to factors related with the expansion of erythrocyte mass. In contrast to other studies, we observe a higher incidence of hypertension worsening, which could be the result of a different hypertension criterion (17). In addition to the erythropoietic action, androgens had a beneficial anabolic effect. Dry weight and serum albumin concentration Increased in the Androgen Group. These nutritional parameters did not change in the Erythropoletin Group. Androgens are used as treatment of malnutrition in chronic renal failure patients (18) and recently, good results have been obtained with nandrolone decanoate in malnourished patients on chronic ambulatory peritoneal dialysis (19). The main side-effect of androgens was a rise in the concentration of triglycerides. This increment was Journal of the American Society of Nephroiogy 143

5 Androgen and Erythropoietin in Hemodialyzed Patients reversible and disappeared 3 months after the withdrawal of the drug. The relative importance of triglyceride levels as a risk factor for vascular disease seems to be controversial. Triglyceride concentration was not considered as an independent risk factor for vascular mortality neither in general population (2) nor in hemodialysis patients (21). Liver dysfunction. peliosis hepatis. and hepatocellular carcinoma have been reported in patients receiving 1 7-alkylated androgens (7,22-25). Nandrolone decanoate is a 1 9-nortestosterone derivative; it is not a 1 7-alkylated androgen. No cases of hepatic injury has been described with the use of nandrolone decanoate (5, ). In our study, we did not see any case of hepatotoxicity associated to the use of this drug. In conclusion, nandrolone decanoate constitutes a good alternative for the treatment of anemia in elderly male patients on chronic hemodialysis. The results are similar to that of human recombinant erythropoietin, with minimal secondary complications and with lower economical cost. ACKNOWLEDGMENT This work was supported by Grant Number 3 from Fundaci#{243}n LAIR. REFERENCES 1. DeGowin RL, Lavender AR, Forland M, Charleston D, Gottscbalk A: Erythropoiesis and erythropoietin in patients with chronic renal failure treated with hemodialysis and testosterone. Ann Intern Med 197:72: RIchardson JR Jr, Weinstein MB: Erythropoietic response of dialyzed patients to testosterone administration. Ann Intern Med 197:73: GarcIa-Otero G, Aguilera A. Teruel JL, Marc#{233}nR, G#{225}mez C, Ortufio J: Indicaciones actuales de los anabolizantes en el tratamiento de Ia anemia del enfermo dializado. NefrologIa 1993;l3lSuppl 11:4. 4. WillIams JS, Stein JR. Ferris T.H.: Nandrolone decanoate therapy for patients receiving hemodialysis. Arch Intern Med 1974:4: Hendler ED, Goffmet JA, Ross S. Longnecker RE. Bakovic V: Controlled study of androgen therapy in anemia of patients on maintenance hemodialysis. N Engl J Med 1974;291: Buchwald D, Argyres S. Easterling RE, et al: Effect of nandrolone decanoate on the anemia of chronic hemodialysis patients. Nephron 1977;18: Davies M, Muckle TJ, Cassells-Smith A, Webster D, Kerr DNS: Oxymetholone In the treatment of anemia in chronic renal failure. Br J Urol 1972:44: Cattran DC, Fenton SSA. Wilson DR, Oreopoulos D, Shlniizu A, Richardson RM: A controlled trial of nandrolone decanoate in the treatment of uremic anemia. Kidney Int 1977:: NaIk RB, Gibbons AR. Gyde OHB, Harris BR, Robinson BHB: Androgen trial in renal anemia (Abstract]. Kidney mt 1978;14:1O9A. 1. Mirahmadi MK, Vaziri ND, Gorman JT: Controlled evaluation of hemodialysis patients on nandrolone decanoate (ND) vs testosterone enanthate (TE). Trans Am Soc Artif Intern Organs 1979:25: Teruel JL. Marc#{233}nR, Navarro JF, Villafruela JJ, Fern#{225}ndez Lucas M, Liaflo J: Evolution of serum erythropoletln after androgen administration to hemodlalysis patients: A prospective study. Nephron 1995;7: Teruel JL, Quereda C, MartIn E, Orofino L, Lia#{241}oF. Ortu#{241}o J: Tratamiento de la anemia no ferrop#{233}nica en hemodialisis mediante anabollzantes. NefrologIa 1983:3: Fried W. Jonasson. Lang G. Schwartz F: The hematologic effect of androgen in uremic patients: Study of packed cell volume and erythropoietin responses. Ann Intern Med 1973:79: Neff MS. Goldberg J, Shlkin RF, et at.: A comparison of androgens for anemia in patients on hemodialysis. N Engi J Med 198 1:34: Aguilera A, Teruel JL, Navarro-Antolin J. et at.: Has androgen a role in the erythropoletin era? J Am Soc Nephrol 1994:5: Pascual J, Teruel JL, Marc#{233}n R, Liafio F, Ortuflo J: Blood pressure after three different forms of correction of anemia in hemodlalysis. 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Lerner KG, et at.: Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 1972:2: Zevin D, Turanl H, Cohen A, Levi J: Androgenassociated hepatoma in a hemodialysis patient. Nephron 1981:29: von Hartltzsch B, Kerr DNS, Morley G, Marks B: Androgens in the anaemia of chronic renal failure. Nephron 1977:18: Ballal SH, Domoto DT, Polack DC, Marciulonis P Martin KJ: Androgens potentiate the effects of erythropoletln in the treatment of anemia of end-stage renal disease. Am J Kidney Dis 199 1:17: Berns JS, Rudnick MR. Cohen RM: A controlled trial of recombinant human erythropoietin and nandrolone decanoate in the treatment of anemia in patients on chronic hemodlalysis. Chin Nephrol 1992:37: Volume 7 Number