Original Article
Relief of Pruritus and Decreases in Plasma Histamine Concentrations during Erythropoietin Therapy in Patients with Uremia
N Engl J Med 1992; 326:969-974April 9, 1992
- Abstract
- Abstract
Background.
The pathophysiologic aspects of pruritus in patients with chronic renal insufficiency are poorly understood, and there is no universally effective treatment. The improvement of pruritus in several patients receiving erythropoietin therapy raised the possibility that erythropoietin affects uremic pruritus directly.
Methods.
We undertook a 10-week placebo-controlled, double-blind, crossover study in a group of patients receiving hemodialysis who had severe pruritus, to investigate the effects of recombinant human erythropoietin on their pruritus and plasma histamine levels. Twenty patients with uremia, of whom 10 had severe pruritus and 10 did not, received erythropoietin (36 units per kilogram of body weight three times weekly) and placebo in random order, each for five weeks. The severity of pruritus was scored weekly, and plasma histamine levels were measured at the beginning and end of each five-week period.
Results.
Eight of the 10 patients with pruritus had marked reductions in their pruritus scores during erythropoietin therapy. The mean (±SE) pruritus score decreased from 25±3 to 6±1 in these patients. The pruritus returned within one week after the discontinuation of therapy. The improvement was not related to the change in hemoglobin level. These eight patients were successfully treated again with low doses of erythropoietin (18 units per kilogram three times weekly), and the effect has persisted for six months. The patients with pruritus had elevated plasma histamine concentrations (20.7±2.7 nmol per liter), as compared with the patients without pruritus (4.2±0.6 nmol per liter; P<0.001) and normal subjects (2.1 ±0.2 nmol per liter; P<0.001). Therapy with erythropoietin induced a decrease in plasma histamine concentrations in both groups of patients with uremia, and recurrences of pruritus after the discontinuation of erythropoietin were accompanied by increases in plasma histamine concentrations.
Conclusions.
Erythropoietin therapy lowers plasma histamine concentrations in patients with uremia and can result in marked improvement of pruritus. (N Engl J Med 1992;326:969–74.)
Media in This Article
Figure 1
Mean (±SE) Daily Pruritus Scores over the Course of the 10-Week Study in the Two Groups of Patients with Uremia Who Had Pruritus.Figure 2
Mean (±SE) Plasma Histamine Concentrations over the Course of the 10-Week Study in the Two Groups of Patients with Uremia Who Had Pruritus.Article Activity
- Article
PRURITUS is one of the most disturbing symptoms in patients with end-stage renal disease, and it occurs in up to 86 percent of patients undergoing maintenance hemodialysis.1 2 3 4 5 The pathogenesis of uremic pruritus is poorly understood. Possible explanations include xerosis of the skin,6 secondary hyperparathyroidism,7 peripheral polyneuropathy,8 and increased plasma vitamin A concentrations.9 Recent studies suggest that histamine, a potent inducer of pruritus in various diseases, may be a cause of uremic pruritus.10 , 11 Because the underlying cause or causes of uremic pruritus are unknown, treatment has largely been empirical. Lidocaine,12 heparin,13 cholestyramine,14 subtotal parathyroidectomy,15 ultraviolet phototherapy,16 , 17 and electric-needle stimulation18 have been effective in some patients but not others. In a recent study of the effects of therapy with recombinant human erythropoietin in patients receiving hemodialysis who had moderate iron overload,19 two patients with severe long-standing pruritus had marked improvement while receiving the hormone. Severe pruritus returned within one week after erythropoietin was discontinued, but it improved again after treatment was resumed. We then undertook a randomized, double-blind study of the effect of erythropoietin on severe pruritus in a group of patients with uremia receiving maintenance hemodialysis.
Methods
Population of Patients
The study subjects were selected from a group of 150 adult patients with end-stage renal disease who were undergoing maintenance hemodialysis. To be eligible for the study, the patients had to have had generalized pruritus for at least one year; pruritus severe enough to disturb sleep and interfere with daytime activities; pruritus unresponsive to commonly used antipruritic drugs; no history of pruritus or dermatologic disease antedating renal failure; and no skin disease except the usual cutaneous findings of uremia, such as xerosis or ecchymoses and lesions due to scratching. Patients with systemic diseases, including diabetes mellitus and collagen disease, were excluded. The 10 patients who fulfilled these criteria (7 men and 3 women) were all studied. Their mean (±SD) age was 55±10 years, and the duration of pruritus ranged from 1 to 5 years. Eight patients dated the onset of pruritus to the time of starting hemodialysis or within three months thereafter; in two patients the onset of pruritus antedated dialysis by approximately one and two months. No patient had had relief with any topical or oral medication, such as lotions, emulsions, ointments, lukewarm baths, antihistaminic or antiserotonin agents, and cholestyramine. Some had been treated with phenothiazines and diazepam in attempts to control symptoms. Two patients had evidence of severe hyperparathyroidism, and another had undergone subtotal parathyroidectomy for severe pruritus without obtaining relief. Another patient had been hospitalized previously to treat severe generalized excoriated skin lesions.
We also studied 10 patients with uremia who had no pruritus. There were six men and four women, and their mean age was 54±9 years. The mean duration of dialysis in the 20 patients with uremia was 49 months (range, 12 to 62). Renal failure was caused by chronic glomerulonephritis in most. None of the patients had evidence of iron overload according to criteria described elsewhere. 19 , 20 The patients were treated with our standard four-hour acetate hemodialysis three times weekly, with use of a dialyzer with a polyacrylonitrile membrane (Filtrai 12, Hospal, Basel, Switzerland) sterilized by gamma irradiation.
Thirty normal subjects (19 men and 11 women; mean age, 49± 13 years) provided blood samples for measurements of plasma histamine. None of the patients or normal subjects had any history or symptoms of allergy.
Study Design
The study was a 10-week randomized, placebo-controlled, double-blind, crossover trial. The patients with pruritus were randomly assigned to receive either erythropoietin (group 1) or placebo (group 2) for five weeks, after which they received the opposite treatment for five weeks. The patients without pruritus were similarly randomly assigned to receive erythropoietin (group 3) or placebo (group 4) and then the other treatment in the same way. Baseline data on pruritus were collected for two weeks before the start of treatment. The erythropoietin was administered intravenously three times weekly at the end of a dialysis treatment, starting with a dose of 36 units per kilogram of body weight. The patients continued to receive this dose until their hematocrits reached or exceeded 0.30, at which time the dose was reduced to 18 units per kilogram. The treatment code was broken only after the completion of the trial. During the base-line period and the 10-week trial, a pruritus score was recorded weekly for all patients with uremia who had pruritus. Scores were assessed in the same way in the patients without pruritus, even though they had no pruritus at all.
Plasma histamine concentrations, hemoglobin concentrations, hematocrit, and serum concentrations of creatinine, calcium, phosphate, magnesium, uric acid, alkaline phosphatase, and parathyroid hormone were measured in all patients before and at the end of each five-week treatment period. All blood samples were taken immediately before dialysis. The diet of the patients was not modified during the study. They were instructed to stop using medications that might alter their plasma histamine concentrations or interfere with their measurement.21 , 22 Phosphate-binding agents were continued at the same dose in each patient as before the study. None of the patients received sedatives, antihypertensive drugs, or vitamin D. The study was conducted in accordance with the principles of the Declaration of Helsinki of the World Medical Association, and all the subjects gave informed written consent.
Measurement of Pruritus
We measured the severity of pruritus with the scoring system proposed by Duo18 and modified by Mettang et al.,23 with minor additional modifications. This system is based on the severity, frequency, and distribution of pruritus; the frequency of scratching; and the number of times the patient was awakened because of pruritus during the night. Each patient kept a diary. Once a week an investigator scored the symptoms after interviewing the patients and examining their diaries. A single investigator who was unaware of the treatment assignments evaluated all the patients. Severity, frequency, distribution, and sleep disturbance were monitored as follows. In the scoring of severity, pruritus without the need to scratch received one point; pruritus with the need to scratch but without excoriations, two points; pruritus that was unrelieved by scratching, three points; pruritus accompanied by excoriations, four points; and total restlessness, five points. In the scoring of distribution, pruritus at a single location received one point; scattered pruritus, two points; and generalized pruritus, three points. Frequency was determined by the number of episodes of pruritus and their duration in a 24-hour period. Each four short episodes (less than 10 minutes each) or one long episode (more than 10 minutes) of pruritus received one point, with a maximum of five points. In the scoring of sleep disturbance, each episode of awakening due to pruritus received 2 points, with a maximum of 14 points. For severity, distribution, and frequency, separate scores were recorded for the morning (from the time of awakening until noon) and the afternoon (from noon until bedtime), so that a maximum of 26 points could be achieved during the day. The score for disturbances during sleep was then added to determine the final score. The highest possible score for a 24-hour period was therefore 40, with 35 percent of the points (14 of 40) attributed to the nighttime period.
Laboratory Investigations
Blood samples for the determination of plasma histamine concentrations were drawn before dialysis from an antecubital vein into cold tubes containing tripotassium EDTA and were cooled immediately on ice. After centrifugation at 4°C, the plasma was stored at —40°C until the time of analysis. Plasma histamine concentrations were measured by radioimmunoassay (Immunotech International, Marseilles, France). The combination of sample acylation and the use of monoclonal antibodies make this histamine assay highly sensitive and specific.24 , 25 The sensitivity of the assay was 0.2 nmol per liter. The intraassay and interassay coefficients of variation were less than 10 percent. The histamine assays were performed by an investigator who was unaware of the clinical status of the patients. All the samples from an individual subject were analyzed at the same time. Serum concentrations of calcium, phosphate, magnesium, uric acid, creatinine, and alkaline phosphatase and blood urea nitrogen were measured by AutoAnalyzer (Technicon Instruments, Basingstoke, United Kingdom). Serum parathyroid hormone was measured by radioimmunoassay with an antiserum that reacted with the midregion of the hormone as described elsewhere.26 Blood cell counts were performed with a Coulter counter.
Statistical Analysis
Results are expressed as means ±SE unless otherwise indicated. Differences between treatments were tested for significance by analysis of variance. The within-group and between-group comparisons were done with the Wilcoxon—Mann—Whitney rank-sum test or with Student's t-test, as appropriate. Differences were considered significant when the P value was less than 0.05.
Results
Effects on the Pruritus Score
During the two-week base-line period, all 10 patients in groups 1 and 2 reported severe pruritus. The mean daily pruritus scores during this period did not differ between the two groups (Table 1Table 1
Mean (±SE) Daily Pruritus Scores, Plasma Histamine Concentrations, Hemoglobin Levels, and Hematocrits in the Four Groups of Patients Receiving Hemodialysis, before and after Each Five-Week Period of the Study.*). During the five-week course of erythropoietin therapy in group 1, there was a significant decrease (P<0.05) in the mean daily pruritus score, whereas the score did not change in the patients who received placebo (group 2) (Fig. 1Figure 1Mean (±SE) Daily Pruritus Scores over the Course of the 10-Week Study in the Two Groups of Patients with Uremia Who Had Pruritus.). Four of the five patients who received erythropoietin had marked reductions in pruritus, which became mild, intermittent, and localized; their sleep disturbances diminished; and their excoriations disappeared. The mean daily pruritus score in the four patients who responded to erythropoietin decreased from 22±3 to 6±3 (P<0.001). In all four of these patients, the pruritus started to improve within one week after therapy was started, and improvement was maximal after three to four weeks. In one patient the mean daily pruritus score did not change appreciably during erythropoietin therapy (it was reduced from 36 to 34). This patient had severe hyperparathyroidism, for which a recommendation of surgical parathyroidectomy had been made that the patient had declined. In this patient the product of the serum calcium concentration and the serum phosphate concentration was 5.2 mmol per liter. In group 2 only one patient had slight improvement in the pruritus score (from 28 to 24) while receiving placebo.During the second study period, after the crossover, the four patients in group 1 who had responded to erythropoietin had severe pruritus within seven days, and at the end of the five-week period the mean daily pruritus score in this group did not differ from the mean base-line value. In all four of these patients, treatment with erythropoietin was resumed at a low dose (18 units per kilogram three times weekly) for six months, with benefit. (The patient who did not respond to erythropoietin did not consent to further treatment at higher doses.) In group 2 the five-week course of erythropoietin therapy induced a significant decrease (P<0.01) in the mean daily pruritus score, as compared with that at the end of the first period, during which the patients received placebo. Four of the five patients in this group had marked reductions of pruritus when they received erythropoietin that were very similar to those in the four patients in group 1 when they received erythropoietin. The mean daily pruritus score in the four patients in group 2 who responded to treatment decreased from 27±4 to 6±1 (P<0.005). In these patients, the improvement began within one week and reached its maximum after three to four weeks. These four patients continued to receive erythropoietin (18 units per kilogram three times weekly) after the end of the study and remained in remission. The patient who did not respond to erythropoietin (daily pruritus scores before and after the period of treatment, 26 and 24, respectively) had severe hyperparathyroidism, with an elevated value for the product of the serum calcium concentration and the serum phosphate concentration (5.8 mmol per liter).
For the combined groups of patients who responded to therapy, the mean pruritus score decreased from 25±3 before erythropoietin therapy to 6±1 at the end of the five-week period.
Effects on Plasma Histamine Concentrations
The plasma histamine concentrations in the normal subjects ranged from 1.5 to 2.9 nmol per liter (mean, 2.1 ±0.2). The patients with uremia who had severe pruritus had a significantly higher mean plasma histamine concentration than either the patients without pruritus (20.7±2.7 vs. 4.2±0.6 nmol per liter, respectively; P<0.001) or the normal subjects (P<0.001). Although the patients with uremia who did not have pruritus had a significantly lower mean plasma histamine concentration than the patients with pruritus, this concentration was still significantly higher than that in the normal subjects (P<0.001).
In the patients with uremia who had pruritus, there was no difference between groups 1 and 2 in the mean base-line plasma histamine concentration (Fig. 2Figure 2
Mean (±SE) Plasma Histamine Concentrations over the Course of the 10-Week Study in the Two Groups of Patients with Uremia Who Had Pruritus.). In group 1 this value decreased from 20.8 to 4.2 nmol per liter during treatment with erythropoietin (P<0.005), but not to the level found in the normal subjects (2.1 nmol per liter, P<0.001). The value in group 1 then increased progressively to 23.2 nmol per liter at the end of the five weeks of placebo. In group 2, the mean plasma histamine concentration did not change during the first period, when the patients received placebo, but it decreased to 5.8 nmol per liter (P<0.02) during treatment with erythropoietin. As in group 1, the value at the end of the period of erythropoietin treatment in group 2 was significantly (P<0.001) higher than the value in the normal subjects. In the two patients whose pruritus scores did not decrease, plasma histamine concentrations decreased to the same extent during erythropoietin therapy as in the eight patients who responded to erythropoietin therapy.The mean base-line plasma histamine concentrations in the two groups of patients with uremia who did not have pruritus were similar (Table 1). In group 3, erythropoietin induced a significant decrease in the mean plasma histamine concentration (P<0.05), to a value (2.6 nmol per liter) similar to that in the normal subjects. The value increased to 5.0 nmol per liter during the placebo period. In group 4 the mean plasma histamine concentration did not change during the initial period of placebo but then decreased to 2.5 nmol per liter at the end of the treatment with erythropoietin (P<0.05).
Effects on Laboratory Investigations
The serum concentration of parathyroid hormone was increased in all the patients receiving hemodialysis, and the mean values in the patients with uremia who had and who did not have pruritus were similar (560±167 vs. 486±199 pmol per liter; normal range, 20 to 95). The two patients with pruritus who did not respond to erythropoietin had severe hyperparathyroidism, as indicated by markedly elevated serum concentrations of parathyroid hormone (2288 and 1804 pmol per liter) and radiologic evidence of osteitis fibrosa. There was no significant difference between the patients with and those without pruritus in the mean serum concentrations of calcium, phosphate, magnesium, uric acid, creatinine, alkaline phosphatase, and ferritin or in the values for blood urea nitrogen, hemoglobin, and the hematocrit. The values for hemoglobin and for the hematocrit in the four groups of patients before and during each treatment period are shown in Table 1. Erythropoietin therapy induced a significant increase (P<0.05) in the mean hemoglobin and hematocrit values but no significant change in any of the biochemical values.
Discussion
Erythropoietin was effective treatment for pruritus in patients with uremia who were receiving hemodialysis. Overall, 8 of 10 patients with severe pruritus had marked improvement during erythropoietin treatment, whereas none improved during the administration of placebo. The pruritus in these eight patients became mild, intermittent, and localized, their excoriations disappeared, and their sleep disturbances diminished. The benefit was readily evident from the fall in the daily pruritus score. Although pruritus in patients with uremia is a highly subjective symptom, with wide variations in threshold and intensity, and it has been difficult to assess its expression and the response to treatment,1 2 3 4 5 the patients' weekly scores improved progressively during erythropoietin therapy. It is noteworthy that these patients had severe, long-standing pruritus.
The response to erythropoietin was not immediate, but it was evident within one week and reached its maximum after three to four weeks. This pattern of response was similar to that in patients treated with ultraviolet phototherapy16 17 18 and electric-needle stimulation.18 In patients treated with the latter two methods, however, improvement persisted for months after the end of therapy, whereas in our patients severe pruritus invariably returned within seven days after the cessation of erythropoietin therapy. All the patients who later received further treatment with erythropoietin improved, and none have had a relapse with continued treatment for six months at a low dose (18 units per kilogram three times weekly). There is a discrepancy between the half-life of erythropoietin in patients with uremia who are treated by hemodialysis and the duration of the remission of pruritus after therapy ends. The half-life of erythropoietin before and during long-term treatment in such patients is approximately five to seven hours, and long-term treatment does not alter these values.27 The persistence of relief of pruritus for a few days after the discontinuation of erythropoietin suggests that it is acting as an antipruritic agent in a compartment from which its egress is slow. A similar mechanism has been proposed to explain the long-lasting relief of pruritus in patients receiving hemodialysis after the intravenous administration of lidocaine.12 , 28
The pathophysiologic features of uremic pruritus are poorly understood. Many different disorders, such as xerosis of the skin,6 secondary hyperparathyroidism,7 peripheral polyneuropathy,8 and increased plasma vitamin A concentrations,9 have been connected with the pathogenesis of pruritus in uremia. Stockenhuber et al.10 reported that patients receiving hemodialysis who had pruritus had increased plasma histamine concentrations, suggesting that histamine, a potent mediator of pruritus in a number of diseases, could cause pruritus in patients with uremia. Several studies have subsequently been undertaken to evaluate the pathogenetic role of histamine11 , 23 in uremic pruritus, but the results are conflicting, and the causative role is uncertain.
The patients with uremia and severe pruritus whom we studied had elevated plasma histamine concentrations as compared with the patients without pruritus and the normal subjects. The patients with uremia who did not have pruritus also had a higher mean plasma histamine concentration than the normal subjects. These results confirm those of Stockenhuber et al.,10 , 11 and are consistent with the possibility that histamine may be involved in the pathogenesis of pruritus in patients with uremia. Erythropoietin induced a fall in plasma histamine levels in all patients with severe pruritus, and in most of them the decrease was associated with marked improvement of pruritus. However, at the end of the five-week treatment period, the mean plasma histamine concentration was still increased, as compared with that of the normal subjects, and the pruritus had not completely disappeared. Furthermore, the recurrence of severe pruritus after the discontinuation of erythropoietin was invariably accompanied by an increase in the plasma histamine concentration. Erythropoietin also induced a significant decrease in plasma histamine concentrations in the patients with uremia who did not have pruritus. Even more intriguing is the fact that the plasma histamine concentrations also decreased in the two patients whose pruritus did not improve during erythropoietin therapy. Both these patients had evidence of severe hyperparathyroidism and high values for the product of the serum calcium and serum phosphate concentrations, suggesting that hyperparathyroidism with elevation of the calcium-phosphate product may cause uremic pruritus7 , 15 independently of the plasma histamine concentration.
It seems likely, therefore, that the mechanism of the antipruritic action of erythropoietin may be related to the hormone's lowering effect on plasma histamine concentrations. The origin of the increased plasma histamine concentrations in these patients is obscure. It may be, at least in part, the consequence of the liberation of histamine from basophils and mast cells,11 which are increased in the skin and other organs in patients with uremia.29 However, the mechanism leading to the possible increase in histamine liberation is unknown. In other conditions, such as food hypersensitivity30 and atopic dermatitis,31 the increased spontaneous release of histamine is mediated by a histamine-releasing factor produced by mononuclear cells. Evidence of direct effects of erythropoietin on T and B lymphocytes is now emerging. Schaefer et al.32 demonstrated enhanced basal and mitogen-stimulated production of immunoglobulin by cultured peripheral-blood mononuclear cells from patients receiving dialysis. Kalechman et al.33 reported an increased production of cytokines by the peripheral-blood mononuclear cells of patients receiving hemodialysis. These and other studies34 , 35 suggest that the administration of erythropoietin to patients with uremia may affect both the cellular and the humoral components of the immune system. Therefore, a working hypothesis might be that the histamine-lowering effect of erythropoietin is mediated by the inhibitory modulation of mononuclear cells, with a fall in the release of the histamine-releasing factor.
Although our results are preliminary, they suggest that there is a strong association between severe pruritus and elevated plasma histamine concentrations in patients with uremia and that erythropoietin is effective therapy for uremic pruritus.
Source Information
From the Department of Internal Medicine, University of Udine Medical School, Udine (S.D.M., E.C., E.B.); the Department of Immunology, Santa Maria degli Angeli Hospital, Pordenone (D.V., G. Santini); and the Dialysis Unit, General Hospital, Cividale del Friuli (G. Sepiacci); all in Italy. Address reprint requests to Dr. De Marchi at Via Tartagna, 39, 33100 Udine, Italy.
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