Original Article
Effects of Theophylline on Erythropoietin Production in Normal Subjects and in Patients with Erythrocytosis after Renal Transplantation
N Engl J Med 1990; 323:86-90July 12, 1990
- Abstract
- Abstract
Background.
Erythrocytosis occurs in 10 to 15 percent of renal-transplant recipients, and there is in vitro evidence that the production of erythropoietin is modulated by adenosine.
Methods.
We prospectively evaluated the effects of theophylline, a nonselective adenosine antagonist, in eight patients with erythrocytosis after renal transplantation and in five normal controls.
Results.
After an eight-week course of theophylline treatment, the mean (±SEM) serum erythropoietin levels were significantly reduced in both the renal-transplant recipients (from 60±14 units per liter at base line to 9±7 units after treatment; P<0.05) and the normal subjects (from 6.9±0.8 units per liter at base line to 4.7±0.5 units per liter after treatment; P<0.05). Similarly, the hematocrits were reduced in both the transplant recipients (from 0.58±0.04 at base line to 0.46±0.03 after treatment; P<0.05) and the normal subjects (from 0.43±0.01 at base line to 0.39±0.01; P<0.05). In the renal-transplant recipients, red-cell mass was also reduced after eight weeks of theophylline (from 3197±82 ml at base line to 2273±69 ml after treatment; P<0.05). The previous requirement of weekly phlebotomy was eliminated in all recipients. Plasma and urinary cyclic AMP levels were not increased. These effects were reproducible when the subjects were rechallenged with theophylline after a recovery period.
Conclusions.
Theophylline attenuates the production of erythropoietin in both normal subjects and patients with erythrocytosis after renal transplantation and may be useful in the treatment of the latter condition. (N Engl J Med 1990; 23:86–90.)
Media in This Article
Figure 1
Effect of Theophylline Treatment on the Frequency of Phlebotomy, the Serum Erythropoietin Level, and the Hematocrit in Eight Renal-Transplant Recipients.Figure 2
Effect of Theophylline Treatment on the Serum Erythropoietin Level and the Hematocrit in Five Normal Subjects.Article Activity
- Article
ERYTHROCYTOSIS (an elevation in red-cell mass with normal plasma volume) is well known to occur after renal transplantation.1 2 3 4 5 This complication is estimated to affect 10 to 15 percent of renal-transplant recipients.3 Various causes have been suggested for this phenomenon (e.g., allograft rejection, renal-artery stenosis, and hydronephrosis),5 6 7 most of which have included abnormally high production of erythropoietin.1 2 3 4 5 6 7 The mechanism for the increased production of erythropoietin in this clinical setting is thought to be either autonomous production or defective feedback regulation of erythropoietin production by the remaining native kidney.4
Adenosine is known to stimulate the activity of both A1 and A2 adenosine receptors. The selective stimulation of A2 receptors is known to increase the activity of adenylate cyclase.8 The selective A2-receptor agonist 5′-N-ethyl-carboxamide adenosine has been shown to increase both erythropoietin production and adenylate cyclase activity.8 9 10 This effect is not observed with selective A1-receptor agonists.9 , 10 Ueno et al. demonstrated that the increase in erythropoietin production could be attenuated by the nonselective adenosine antagonist theophylline.9 We undertook the present study to evaluate the hypothesis that adenosine modulates the production of erythropoietin in recipients of renal transplants who have erythrocytosis. This hypothesis was tested prospectively with the use of theophylline in eight such recipients and five normal subjects.
Methods
Subject Selection
A review of more than 100 recipients of renal allografts at the Ochsner Clinic and the University of Tennessee Medical Center between 1986 and 1988 identified 8 male recipients between 48 and 55 years of age who had erythrocytosis severe enough to require weekly phlebotomy. To be enrolled in the study, each recipient had to satisfy the following criteria: four consecutive weekly hematocrits equal to or higher than 0.55, with weekly or biweekly phlebotomy needed for the hematocrit to be maintained at this level or lower; four consecutive weekly serum erythropoietin levels that were consistently above the upper limits of normal (6.58±0.39 units per liter), performed at the same time as the complete blood counts and determined by a sensitive radioimmunoassay that has been described elsewhere11 , 12; one determination, made during the final week of the four-week base-line period, of a normal plasma volume as measured by radioiodinated albumin, and an increased red-cell mass as determined by chromium-51—labeled red cells; a single measurement of the oxygen content of arterial blood that was within the normal range (partial pressure of oxygen, ≥ 10.6 kPa), as assessed by arterial-blood gas measurements with correction for age; the absence of obstructive or restrictive pulmonary disease, as assessed by pulmonary-function studies; a normal chest film; the absence of allograft rejection with normal renal function (creatinine clearance, ≥ 1.32 ml per second); the absence of cancer or polycythemia vera; the absence of renal-artery stenosis, as assessed by renal scanning with and without captopril; and stable arterial-blood pressures of 140/90 mm Hg or less. In addition, the urinary and plasma levels of cyclic AMP were measured for four consecutive weeks before drug treatment. Cyclic AMP levels were determined by a competitive protein-binding assay (Diagnostic Products, Los Angeles) for which the intraassay and interassay coefficients of variation were 4.5 and 7.1 percent, respectively. Urinary cyclic AMP values were calculated from the plasma and urinary cyclic AMP levels according to the methods of Broadus et al.13
The clinical and demographic characteristics of the recipients studied are summarized in Table 1Table 1
Demographic and Clinical Characteristics of Eight Patients with Erythrocytosis after Renal Transplantation.*. All recipients had been receiving prednisone, cyclosporine, azathioprine, or a combination thereof for months before induction into the study; these drugs were continued throughout the study. No adjustments of medication (e.g., stopping any drug or changing the dosage) were performed before or during the study. Five normal subjects — three men and two women, 27 to 38 years of age — had two consecutive weekly blood collections for the determination of the base-line hematocrit and serum levels of erythropoietin and hemoglobin. Before participation in the study, all normal subjects and transplant recipients signed informed-consent forms approved by the clinical investigation committees of the Ochsner Clinic or the University of Tennessee Medical Center.Study Design and Laboratory Tests
Each renal-transplant recipient was enrolled in the study for a 28-week period. Data were collected in each of four periods during the 28 weeks. The following data were collected weekly throughout the study: hemoglobin level, hematocrit, arterial pressure, pulse, urinary and plasma levels of cyclic AMP, erythropoietin level, and creatinine clearance. Red-cell mass, plasma volume, and serum ferritin levels were determined during the last week of each experimental period. During the periods in which phlebotomy was required, red-cell mass and plasma volume were determined beforehand. After a four-week period of base-line data collection, each subject began treatment with a long-acting preparation of theophylline (Theo-Dur, Key Pharmaceuticals) at a dose of 8 mg per kilogram of body weight per day.14 , 15 The renal-transplant recipients continued to take the drug for eight consecutive weeks, during which time all the previously mentioned weekly laboratory determinations were performed. After data collection was complete, the theophylline treatment was stopped, and an eight-week period of recovery ensued. During the recovery period, all the weekly and supplemental laboratory data mentioned previously were obtained, including measurements of red-cell mass and plasma volume, after which the patients were rechallenged with the drug for another eight weeks.
The five normal subjects received the same oral preparation of theophylline at the same dose as that given to the renal-transplant recipients, and they had four weekly determinations of the hematocrit, the hemoglobin level, and the serum erythropoietin and plasma theophylline levels.
Statistical Analysis
Data are presented as means ±SEM. Comparisons between study periods were assessed by a two-way analysis of variance. Changes in the indexes measured in the presence and absence of theophylline were assessed by a paired Student t-test. Side effects during the initial and rechallenge periods in the renal-transplant recipients were composed by Wilcoxon signed-rank tests.
Results
The data obtained for the eight renal-transplant recipients with erythrocytosis before and after treatment with theophylline are shown in Table 2Table 2
Effects of Theophylline Treatment on Eight Patients with Erythrocytosis after Renal Transplantation.* and Figure 1Figure 1Effect of Theophylline Treatment on the Frequency of Phlebotomy, the Serum Erythropoietin Level, and the Hematocrit in Eight Renal-Transplant Recipients., and those obtained for the five normal subjects are shown in Figure 2Figure 2Effect of Theophylline Treatment on the Serum Erythropoietin Level and the Hematocrit in Five Normal Subjects.. After four weeks of theophylline treatment, the normal subjects all had significant declines in the hematocrit (from 0.43±0.01 at base line to 0.39±0.01 after treatment; P<0.05) and the erythropoietin level (from 6.9±0.8 units per liter at base line to 4.7±0.5 units per liter after treatment; P<0.05). The mean plasma theophylline concentration in the five normal subjects was 49±8 μmol per liter — well below the usual therapeutic level. All the renal-transplant recipients had declines in hematocrit after an eight-week period of theophylline administration, with similar declines at the end of the rechallenge period. The average hematocrit fell within three to four weeks after the administration of theophylline, although the maximal response appeared during the final week of each eight-week study period (Fig. 1). The need for weekly phlebotomy to lower the hematocrit in the transplant recipients was eliminated after one week of treatment with theophylline (Fig. 1). Only three phlebotomies were performed during this study; one recipient underwent the procedure twice during the first two weeks of the rechallenge with theophylline, and another recipient underwent it once during the first week of the initial treatment.Significant declines in erythropoietin levels were noted as early as the end of the first week of treatment with theophylline (from 60±14 units per liter at base line to 18±8 units per liter after one week of treatment; P<0.05). The continuation of theophylline administration resulted in a persistent attenuation of the serum erythropoietin levels at the end of each eight-week period (Table 2 and Fig. 1). Although these levels rebounded as early as one week after the discontinuation of the medication, they never returned to the base-line levels (Table 2 and Fig. 1). The erythropoietin levels measured during the recovery period were lower, albeit not statistically different from the base-line values. The apparent lag between the reduction of the serum erythropoietin level and the reduction of the hematocrit may have had to do in part with the half-life of red cells and other factors not examined in this study.
The serum ferritin level was significantly altered during the study (from 27±12 μg per liter at base line to 271±91 μg per liter after treatment [P<0.05], and from 74±19 μg per liter after the recovery period to 297±71 μg per liter after the rechallenge period [P<0.05]). Five of the eight renal-transplant recipients received iron sulfate (975 mg daily) to correct low serum ferritin levels. Iron sulfate was administered for six weeks during the periods of initial treatment and rechallenge to evaluate whether the correction of iron stores would attenuate the effect of theophylline on erythrocytosis in the presence of lowered serum erythropoietin levels. At the end of the eight-week period of theophylline treatment, there was no difference with respect to the lowering of the hematocrit between those who received iron supplementation and those who did not (change in hematocrit, -0.08±0.02 vs. -0.12±0.03, respectively). However, one of our initial renal-transplant recipients who received iron therapy required two phlebotomies during the period of rechallenge with theophylline. His serum ferritin level at the beginning of this period was 92 μg per liter —well within the normal range. Consequently, iron therapy was discontinued during the recovery period (weeks 13 to 20 of the study) to avoid the need for more phlebotomies.
The urinary and plasma levels of cyclic AMP did not increase significantly during the theophylline period, suggesting that the drug probably had no substantial effect on phosphodiesterase activity (Table 2). The hematocrit and erythropoietin levels, however, were significantly decreased from base line — an effect that would not have been predicted on the basis of the increased adenylate cyclase activity, which is known to increase the serum erythropoietin level.9 , 10 Unfortunately, since there is no selective A2-receptor agonist available for human use, we could not assess the degree of adenosine antagonism by theophylline in these subjects.
The most prominent side effects of theophylline were headache, nervousness, and insomnia. The mean arterial pressure increased during the treatment period in four recipients, but not significantly (from 102±3 mm Hg at base line to 107±5 mm Hg after treatment). This rise in pressure was attenuated by the addition of atenolol (mean dose, 38±12 mg per day) during the rechallenge period (from 103±4 mm Hg during recovery to 94±3 mm Hg after the rechallenge; P<0.05). The frequency of the other side effects, except insomnia, was significantly reduced by the administration of atenolol during the rechallenge period. Insomnia was treated with a benzodiazepine, flurazepam. No recipient had to be withdrawn from the study because of these untoward effects. The side effects observed in the normal subjects were similar to those in transplant recipients.
Discussion
The results of these studies support previous reports that theophylline suppresses the production of erythropoietin by the kidney.9 , 10 All the renal-transplant recipients had rapid and dramatic responses to the administration of theophylline, manifested by a reduction in hematocrit and red-cell mass from both the base-line and the recovery levels. This effect was also seen in the five normal subjects. The reduction in erythrocytosis was lost with the discontinuation of the drug, but it returned when therapy with theophylline was reinstituted.
Sun et al. have recently described the natural history of erythropoietin production after renal transplantation.16 An initial, transient ninefold increase in the serum erythropoietin level after transplantation was followed by a smaller, threefold increase after one month. Thereafter, only a small group of subjects, in whom erythrocytosis would ultimately develop, had erythropoietin levels above normal. Erythrocytosis appeared in these recipients two months after transplantation, with the rise in the hematocrits stabilizing at around 0.57. In our study, the average time after transplantation for the development of erythrocytosis was 12±4 months — within the range described by other investigators.1 2 3 4 A decline in the serum ferritin concentration in these recipients was compatible with the diagnosis of iron-deficiency anemia. The institution of theophylline permitted us to administer iron supplementation to five renal-transplant recipients in order to correct their iron deficiency without blunting the decrease in the erythropoietin level and the hematocrit.
A relative deficiency of erythropoietin is an important cause of anemia in end-stage renal disease.17 Secondary factors, however, such as a shortened life span of red cells, the presence of inhibitors of the marrow response to erythropoietin, and iron deficiency have all been implicated in this process.18 19 20 21 22 23 24 Thus, decreased red-cell mass is primarily due to both a decrease in the production of erythropoietin17 and a secondary reduction of its biologic activity21 or to the response of the marrow to erythropoietin.18 19 20 , 22 , 23 Renal transplantation corrects these pathophysiologic alterations, and after three to five months the hemoglobin concentration returns to normal in the majority of recipients.1 , 4 , 16 In a few, however, the hematocrit continues to rise even after the recipient's anemia has been corrected, resulting in post-transplantation polycythemia.1 2 3 4 , 16 , 21 , 22
In addition to arterial oxygen tension, the production of erythropoietin is modulated by eicosanoids, beta-adrenergic agonists, and adenosine.10 , 11 , 25 26 27 28 29 30 These and other substances are released when the delivery of oxygen to the kidney is reduced.10 , 25 26 27 Any of these factors may contribute to the elevated erythropoietin levels observed after renal transplantation.1 2 3 4 , 21 22 23 24 25 26 27 28 29 30 The administration of adenosine has been shown to increase the incorporation of iron-59 in red cells in formerly hypoxic mice with polycythemia9 and to increase the secretion of erythropoietin in isolated perfused kidneys,10 presumably by increasing the activity of adenylate cyclase through the stimulation of an A2 receptor.14 , 15 Our data provide evidence that theophylline, a nonselective adenosine antagonist, attenuates the production of erythropoietin in humans. Since no selective A2-receptor agonist is available for human use, however, we cannot be sure of the degree of adenosine antagonism in our subjects.
Increased levels of cyclic AMP are known to increase the production of erythropoietin.8 9 10 Intravenous theophylline increases the plasma levels of cyclic AMP.31 The concentration of theophylline required to inhibit the activity of phosphodiesterase in vitro, however, is higher than can be achieved therapeutically in humans.32 33 34 In this study, neither the plasma nor the urinary levels of cyclic AMP were elevated by theophylline. Furthermore, a decrease in the serum erythropoietin level would not be expected to follow the inhibition of phosphodiesterase.
The β-adrenergic receptor antagonist atenolol was used to control elevated arterial pressure and other side effects during the course of the study. Selective β2-receptor agonists increase the activity of adenylate cyclase and subsequently increase the production of erythropoietin.9 , 29 , 30 Thus, β-adrenergic receptor blockade may be predicted to decrease erythropoietin production. We did not observe this in our population, possibly because atenolol is a selective β1-receptor antagonist and the agents used to stimulate erythropoietin production were predominantly β2 agonists.9 , 29 , 30
Some renal-allograft recipients escape the feedback regulation of erythropoietin. In two studies, selective venous catheterization of both native and transplanted kidneys in renal-allograft recipients with polycythemia demonstrated that the mean levels of erythropoietin were significantly higher in the native kidneys.1 , 4 These studies also demonstrated an increase in peripheral-blood levels of erythropoietin. Furthermore, no significant differences in serum erythropoietin levels between native and transplanted kidneys were noted in renal-allograft recipients with normal hematocrits. Wickre et al.3 studied 53 renal-transplant recipients with post-transplantation erythrocytosis and noted that the highest incidence of erythrocytosis was among diabetic smokers with native kidneys. In that study, eight subjects had had bilateral nephrectomies before transplantation. The incidence of post-transplantation erythrocytosis, however, was only 11.3 percent in smokers with bilateral nephrectomies, as compared with 47.2 percent in smokers with native kidneys — a finding that supports the suggestion in previous studies that native kidneys are responsible for the abnormal increase in the production of erythropoietin. Only one of our recipients was a diabetic smoker, and none had bilateral nephrectomies.
It is thought that post-transplantation erythrocytosis is a self-limiting process that requires weekly phlebotomy to avoid thromboembolic complications when the hematocrit rises above 0.55.3 Our study provides an alternative to such phlebotomies that some renal-transplant recipients may prefer.
Supported by a grant (AOMF 6184) from the Alton Ochsner Medical Foundation and a grant (DK 13211) from the National Institutes of Health. Presented in part at a meeting of the American Federation for Clinical Research, Central Society, Chicago, November 8–11, 1989, and a meeting of the American Society of Nephrology, Washington, D.C., December 3–6, 1989.
We are indebted to Joyce Dupre, R.N., for her efforts in the data collection, to Jesse Brookins for his technical assistance in performing the erythropoietin assay, and to Peggy Bourque for assistance in the preparation of the manuscript.
Source Information
From the Department of Medicine. Sections on Nephrology (G.L.B.) and Transplant Surgery (E.R.S., J.L.H.), Ochsner Medical Institutions, New Orleans; the Department of Pharmacology (J.W.F.), Tulane University School of Medicine, New Orleans; and the Department of Transplant Surgery (A.O.G., R.W.), University of Tennessee School of Medicine, Memphis. Address reprint requests to Dr. Bakris at the Ochsner Clinic, Section on Nephrology, 1514 Jefferson Hwy., New Orleans, LA 70121.
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