Erythropoietin Treatment of Postural Hypotension in Anemic Type 1 Diabetic Patients With Autonomic Neuropathy: A case study of four patients

Postural hypotension (PH) is a feature of autonomic failure that may result from various causes and can be very difficult to treat. Recently, we and others (1, 2, 3) have shown that some patients with severe symptomatic autonomic neuropathy from type 1 diabetes (type 1 DAN) have a normocytic anemia associated with erythropoietin (EPO) deficiency. The treatment of these patients with EPO rapidly corrects their anemia (1) and improves their overall well-being. Preliminary observations by Hoeldtke et al. (3) of the effect of a maximum of 9 weeks of EPO treatment on blood pressure (BP) demonstrated a positive response in four cases of PH in type 1 DAN patients, but evaluation of BP was limited to only two to three readings before and after EPO treatment. These results stimulated the present study, in which we investigated the effect of EPO treatment for 3 months on supine and standing BP in four anemic EPO-deficient type 1 DAN patients.

The patients were treated with recombinant human EPO (25 IU/kg s.c. thrice weekly). All four patients were women (48, 41, 30, and 30 years of age with a duration of diabetes of 13, 24, 19, and 11 years, respectively) and each had normocytic anemia with inappropriately low serum EPO levels. The known causes of anemia were excluded. All of the patients included in the study had pronounced symptomatic PH and at least one other symptom of autonomic neuropathy. The autonomic function tests were severely abnormal. The patients were followed up for 7 months (1-month control phase, 3 months on treatment, and 3 months off treatment). The study was stopped in patient 1 after 3 months on EPO because of serious problems from foot sepsis. Three patients were already on fludrocortisone, the dose of which was kept constant during the study.

During the 7- month study, the patients performed regular BP readings themselves using an automatic sphygmomanometer (Omron 2000) after undergoing several training sessions according to a standardized protocol. The BP recordings were taken before meals and insulin injections at four different times (morning, midday, afternoon, and bedtime) thrice weekly. The supine BP reading was compared with the lowest value within 5 min of standing. Each patient took between 672 and 1,584 BP readings during the course of the study. The statistical significance of the BP response to treatment with EPO was determined by fitting a nonlinear function of time to each patient’s series of mean BP data (4). The applied function modelled a constant BP during the control phase, followed by a gradual increase after EPO administration and a gradual decrease after withdrawal of EPO. This model of assumed BP response was developed on the basis of observations made in patients with chronic renal failure during EPO treatment; it is specific in that it only detects BP responses attributable to the EPO stimulus and therefore excludes measurement errors.

Pronounced symptomatic PH was present in the four patients during the control month (monthly average systolic postural fall: 44.9 ± 3.5, 41.4 ± 6.4, 52.3 ± 5.1, and 21.7 ± 4.9 mmHg, respectively). EPO treatment for 3 months resulted in an increase in standing systolic and diastolic BP in all four patients at all four times throughout the day (Fig. 1). The BP decreased again after EPO withdrawal (Fig. 1). After 3 months of EPO treatment, standing systolic BP in the four patients increased from 5 to 30, 6 to 15, 5 to 13, and 9 to 17 mmHg in the morning, midday, afternoon, and at bedtime, respectively. The standing mean BP in the morning increased significantly in all patients (P = 0.001–0.036). There was also a significant increase in standing mean BP in patients 2–4 (P = 0.001), patients 3 and 4 (P = 0.001 and 0.003), and patients 1, 2, and 4 (P = 0.001–0.025) at midday, in the afternoon, and at bedtime, respectively. There was usually a small and highly variable increase in supine BP, so that the effect of EPO treatment on the actual BP drop was also highly variable. EPO treatment corrected the anemia in all four patients, and hemoglobin increased from 116, 99, 100, and 115 g/l to 140, 131, 124, and 132 g/l, respectively. Hemoglobin decreased to the baseline level by the end of the third month off treatment.

PH in diabetic autonomic neuropathy is extremely variable and difficult to assess. The study of treatment is thus rendered exceptionally difficult. We believe that by using numerous objective measurements of BP (up to 1,584 readings), we have reduced potential bias and present valid results. The greatest benefit to our patients was the increase in standing BP, which was significant at almost all times throughout the day. This was accompanied by a decrease in dizziness on standing, though we appreciate that this was an open study and therefore prone to bias. Of course, some of the improvement in overall well-being might be attributed to the improvement of the anemia in all the patients.

The effect of EPO in raising standing BP might be mediated through a number of different mechanisms. Vasoconstriction might occur after increased norepinephrine levels after injection of EPO (5) or as a result of increased binding of nitric oxide by the greater concentration of hemoglobin, thus reducing its capacity to vasodilate (6). Furthermore, elevated levels of hemoglobin may increase blood viscosity and thereby augment peripheral vascular resistance (7). EPO may also increase vascular sensitivity to angiotensin II, thus further promoting vasoconstriction (5). BP is very sensitive to blood-volume changes, although EPO-increasing red cell mass does not normally increase blood volume (8). Despite the above-mentioned indirect effects of EPO, some authors postulate that EPO exhibits direct pressor effects on vascular smooth muscle cells (9) or enhances DNA synthesis in smooth muscle cells, thereby contributing to vascular hypertrophy (10). EPO might also have a direct trophic effect on the nervous system, as shown recently in neuroblastoma cells (11). These interesting observations need to be developed, and their relevance to effects of EPO on BP in our patients remains speculative.

In summary, we have demonstrated that treatment with EPO increases the standing BP in diabetic patients with severe autonomic neuropathy. This effect, combined with the correction of the anemia, can lead to considerable improvement in the well-being of these severely disadvantaged patients and may provide an additional treatment for seriously affected patients when other measures have failed.