High-tone external muscle stimulation in end-stage renal disease: effects on symptomatic diabetic and uremic peripheral neuropathy.

OBJECTIVE AND DESIGN: Pain and peripheral neuropathy are frequent complications of end-stage renal disease (ESRD). Because drug treatment is associated with numerous side effects and is largely ineffective in many maintenance hemodialysis (MHD) patients, nonpharmacologic strategies such as electrotherapy are a potential recourse. Among various forms of electrostimulation, high-tone external muscle stimulation (HTEMS) is a promising alternative treatment for symptomatic diabetic peripheral polyneuropathy (PPN), as demonstrated in a short-term study. Based on these novel findings, we performed a prospective, nonrandomized, pilot trial in MHD patients to determine (1) whether HTEMS is also effective in treating diabetic PPN in the uremic state, and (2) whether uremic PPN is similarly modulated. PATIENTS AND INTERVENTIONS: In total, 40 MHD patients diagnosed with symptomatic PPN (25 with diabetic and 15 with uremic PPN) were enrolled. Both lower extremities were treated intradialytically with HTEMS for 1 hour, three times a week. Initially, a subgroup of 12 patients was followed for 4 weeks, and a further 28 patients for 12 weeks. The patients' degree of neuropathy was graded at baseline before HTEMS and after 1 and 3 months, respectively. Five neuropathic symptoms (tingling, burning, pain, numbness, and numbness in painful areas) as well as sleep disturbances were measured, using the 10-point Neuropathic Pain Scale of Galer and Jensen (Neurology 48:332-338, 1997). A positive response was defined as the improvement of one symptom or more, by at least 3 points. Other parameters included blood pressure, heart rate, dry body weight, and a routine laboratory investigation. RESULTS: The HTEMS led to a significant improvement in all five neuropathic symptoms, and to a significant reduction in sleep disturbances for both diabetic and uremic PPN. The response was independent of the patient's age, with a responder rate of 73%. The improvement of neuropathy was time-dependent, with the best results achieved after 3 months of treatment. The HTEMS was well-tolerated by nearly all patients. CONCLUSIONS: This pilot study shows for the first time that HTEMS can ameliorate the discomfort and pain associated with both diabetic and uremic PPN in MHD patients, and could be a valuable supplement in the treatment of pain and neuropathic discomfort in patients who do not respond to, or are unable to participate in, exercise programs during hemodialysis treatment.

Iron metabolism in rhEPO-treated hemodialysis patients.

A number of factors have been shown to limit the response to recombinant human erythropoietin (rhEPO). One major factor appears to be an inadequate iron supply to the bone marrow. Erythropoiesis is dependent upon a continuous supply of iron to the bone marrow. The rate at which iron can be drawn from existing stores may easily limit the rate of delivery for hemoglobin synthesis. This may result in "functional iron deficiency" which is distinct from "absolute iron deficiency" caused by depletion of iron stores. At present there are three main parameters available to clinicians wishing to monitor iron status in their patients: serum ferritin and transferrin saturation (TFS), which are indirect measurements, and the percentage of hypochromic red cells, which directly reflects marrow iron status. Ferritin levels should be measured before starting rhEPO therapy to ensure adequate iron stores (> 200 microg/l), and when patients move from the correction phase to the maintenance phase of therapy (have stores become depleted during the correction phase?). In addition, ferritin levels can give an indication of iron overload following excess parenteral iron administration. The TFS represents a balance between iron supply by the stores and demand by bone marrow. A saturation below 20% probably indicates iron-deficient erythropoiesis. However, this is an indirect measure of marrow iron supply and wide fluctuations have been observed when determined at different time points. The percentage of hypochromic red blood cells is measured by flow cytometry and a hypochromic subpopulation of more than 10% (normal percentage > 2.5%) indicates iron-deficient erythropoiesis. However, not all departments have access to the required equipment. The aim of iron supplementation is to provide sufficient iron for the correction phase and replace iron losses (1,500 - 3,000 mg/year in hemodialysis patients) during the maintenance phase of rhEPO therapy. This amounts to a daily iron need in the range of 5-7 mg, which is well above the normal dietary intake and absorptive capacity of the human intestine. Therefore there is a need for intravenous iron, in particular when the patient ha absolute or functional iron deficiency, is in tolerant of oral iron, or is not complying we with the oral regimen.

Chronic ACE inhibition by quinapril modulates central vasopressinergic system.

OBJECTIVE: The role of the brain as a target for angiotensin converting enzyme (ACE) inhibitors in the treatment of heart failure and hypertension is unclear. To test the hypothesis that ACE inhibitors may modulate other central neuropeptide systems such as the central vasopressin system, we studied the effects of chronic treatment with the ACE inhibitor, quinapril, on ACE activity and on central vasopressin content in specific brain areas in rats. METHODS: 22 rats were chronically treated with quinapril (6 mg.kg-1 BW per gavage daily for 6 weeks; untreated controls, n = 14). ACE density in various brain regions was assessed by in vitro autoradiography using the specific ACE inhibitor, 125I-351A. Vasopressin content was determined in 19 brain areas (micropunch technique) known to be involved in cardiovascular regulation. RESULTS: Following chronic quinapril treatment ACE was significantly decreased in the thalamus (-38%), hypothalamus (-37%), hypophysis (-35%), cerebellum (-36%) choroid plexus (-20%), and locus coeruleus (-35%). Additionally, a marked reduction in serum ACE activity (-97%) was observed. Plasma levels of vasopressin were significantly decreased after quinapril treatment (0.97[s.e.m. 0.11] vs. 1.63[0.24] pg.ml-1 in controls, P < 0.05). Vasopressin content was significantly reduced in 9 of 19 specific brain areas. Regarding the hypothalamic vasopressin-producing nuclei, vasopressin was decreased in the paraventricular (292[197] vs. 2379[585] pg.mg-1 crotein in controls; P < 0.001) and supraoptic nuclei (13618[1979] vs. 24525[3894] pg.mg-1 protein; P < 0.05), but not in the suprachiasmatic nucleus. Vasopressin content was significantly reduced in brain areas connected by vasopressinergic fibres originating in the hypothalamic paraventricular nucleus: namely central gray, subcommissural organ, organum vasculosum laminae terminalis, dorsal raphe nucleus, and locus coerules. Vasopressin content was also significantly reduced in the median eminence (5887[1834] vs. 28321[4969] pg.mg-1 protein, P < 0.001), where the hormone is mainly concentrated in the hypothalamo-hypophysial tract. CONCLUSIONS: Autoradiographic studies in vitro indicate that orally administered quinapril suppresses central ACE activity after chronic treatment. ACE inhibition by quinapril strongly influences vasopressin content in important brain areas which are involved in central cardiovascular regulation. Therefore, central modulatory effects of ACE inhibitors may also contribute to overall therapeutic efficacy.

Alterations in brain atrial natriuretic polypeptide levels in hypophysectomized rats.

Twelve days after hypophysectomy depleted atrial natriuretic polypeptide (ANP) concentrations were measured in the plasma and in 8 of 18 microdissected brain nuclei of rats. Reduced ANP levels were found in brain structures (subfornical organ, organum vasculosum laminae terminalis, preoptic and hypothalamic periventricular nuclei, paraventricular nucleus, lateral hypothalamic area), which are directly involved in the central regulations of salt and fluid homeostasis, as well as in the medial amygdaloid nucleus and the locus ceruleus. ANP concentrations in the median eminence, medial preoptic and arcuate nuclei did not alter by hypophysectomy. Elevated ANP concentrations were measured only in the supraoptic nucleus of hypophysectomized rats.

Parathyroid hormone modulates the release of atrial natriuretic peptide during acute volume expansion.

In this study we investigated the effect of volume expansion on plasma and atrial concentrations of atrial natriuretic peptide (ANP) in the presence and absence of the parathyroid gland and under normocalcemic and hypocalcemic conditions. After volume expansion ANP concentration in plasma was significantly (p < 0.001) higher in intact (702 +/- 86 pg/ml) than in hypocalcemic parathyroidectomized (PTX) (271 +/- 38 pg/ml) rats. Plasma ANP of PTX rats rendered normocalcemic with oral calcium supplementation increased to 402 +/- 85 pg/ml after volume expansion. Results from this study suggest that parathyroid hormone (PTH) is required for augmented ANP secretion in response to acute volume loading and alterations of extracellular calcium may modulate volume-induced ANP release in PTX rats. We would discuss that a parathyroid gland-cardiac atria interaction exists and that changes in serum level of PTH may play a role in the regulation of fluid homeostasis via ANP secretion.

Effects of aldosterone and dexamethasone on atrial natriuretic peptide levels in preoptic and hypothalamic nuclei of adrenalectomized and intact rats.

The effect of aldosterone and dexamethasone on the concentrations of atrial natriuretic peptide (ANP) in preoptic and hypothalamic nuclei was examined in adrenalectomized and intact rats. Five days after adrenalectomy, increased ANP levels in those brain areas which control water intake, i.e. in the subfornical organ, supraoptic nucleus, and in the so-called hypothalamic drinking centers (perifornical nucleus, lateral hypothalamic area) were measured. In contrast to this, adrenalectomy decreased ANP levels markedly in the organum vasculosum laminae terminalis and preoptic periventricular nucleus, which are reportedly involved in the central regulation of salt and water homeostasis. ANP contents of these two preoptic structures were restored almost completely by daily administration of 0.9% sodium chloride or aldosterone but not dexamethasone. The daily administration of aldosterone elevated ANP levels in the supraoptic, paraventricular and perifornical nuclei as well as in the lateral hypothalamus both in control and adrenalectomized rats. Dexamethasone which was without any significant effect on preoptic and hypothalamic nuclei in control rats elevated ANP levels in the supraoptic and perifornical nuclei and in the lateral hypothalamic area of adrenalectomized animals. Since neither adrenalectomy, nor aldosterone or dexamethasone treatment influenced plasma ANP levels, altered ANP contents measured in preoptic and hypothalamic nuclei may represent a direct effect of adrenal corticoids (mainly aldosterone) on brain ANP-containing neurons which may participate in the control of body fluid and electrolyte homeostasis.

Atrial natriuretic peptides in brain nuclei of rats with inherited diabetes insipidus (Brattleboro rats).

The concentration of atrial natriuretic peptides (ANF) was measured radioimmunologically in 18 selected microdissected brain areas of rats with inherited diabetes insipidus (Brattleboro rats) and their control rats (Long-Evans rats). In 7 brain areas known to be involved in the regulation of fluid homeostasis or blood pressure (subfornical organ, organum vasculosum lamina terminalis, periventricular preoptic nucleus, perifornical nucleus, nucleus of the solitary tract, tegmentum pontis, arcuate nucleus) ANF concentration was significantly changed. After restoration of antidiuresis with the V2 receptor agonist 1-desamino-8-D-arginine vasopressin (DDAVP) ANF levels of Brattleboro rats adapted at least partly to those of the control rats in all brain areas except the subfornical organ. Furthermore, ANF was then significantly changed in the supraoptic and paraventricular nuclei of DDAVP-treated diabetes insipidus rats. These data show that the central ANF system is sensitive for changes in electrolyte and fluid homeostasis.

Prostacyclin (PGI2) induces rapid depletion of cyclic AMP levels in brain nuclei of rats.

Intravenous injection of prostacyclin (100 micrograms/kg) in rats resulted in a decrease of systolic blood pressure within 2 minutes. Concentrations of cAMP in 15 brain regions and nuclei were determined by radioimmunoassay. In lower brain stem nuclei, such as the nucleus of the solitary tract and the lateral reticular nucleus (A1 and C1 catecholaminergic cell groups) cAMP levels were depleted significantly, while in others, including the locus coeruleus and the periaqueductal central gray, cAMP levels did not show any alterations. Levels of cAMP were also depleted in some of the hypothalamic nuclei (periventricular, anterior hypothalamic, ventromedial), and in cerebral cortical areas. Lowered cAMP levels in brain areas might indicate lower cellular activity in cells participating in baroreceptor control mechanisms.