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Ghrelin, the 28 amino acid peptide recently identified as the natural ligand for the growth hormone (GH) secretagogue (GHS) receptor, has multiple activities in addition to stimulation of GH secretion, including stimulation of feeding and weight gain. To utilize these actions for potential therapeutic benefit, we have produced analogs of human ghrelin with enhanced metabolic stability, affinity for the GHS receptor, and efficacy in stimulating weight gain. We have also discovered an analog of ghrelin, BIM-28163, that is an antagonist at the GHS receptor and that fully inhibits GHS receptor activation induced by native ghrelin. In vivo, BIM-28163 does not increase GH secretion but fully blocks ghrelin-induced GH secretion. In contrast, BIM-28163 acts as a full agonist with regard to the ghrelin actions of stimulating weight gain and food intake. These results suggest that a receptor other than the GHS receptor mediates the actions of ghrelin on feeding and weight gain. This concept is strengthened by our observation that at certain hypothalamic sites, BIM-28163 acts as an antagonist of ghrelin-induced neuronal activation, while at other sites, both ghrelin and BIM-28163 induce neuronal activation via the same receptor. Collectively, these results indicate the existence of a novel ghrelin receptor that may regulate the feeding activity of ghrelin. Using BIM-28163 as a tool to define the endogenous role of ghrelin in normal GH secretion, we have demonstrated that antagonism of the GHS receptor in normal rats does not impair the pulsatility of GH secretion but lowers the pulse amplitude and mean GH level. These results demonstrate that endogenous ghrelin acts to amplify the basic pattern of GH secretion established by the interplay of hypothalamic GH-releasing hormone and somatostatin. These studies demonstrate the feasibility of creating ghrelin analogs that are selective for specific activities, as well as their utility in dissecting the role of ghrelin in both normal physiology and specific pathologies.European Journal of Endocrinology 151 S71-S75

Regular intravenous iron supplementation in haemodialysis patients improves the response to Epo therapy.

Continuous haemofiltration with lactate-based replacement fluid is widely used for the treatment of acute renal failure (ARF). In the presence of lactic acidosis, such treatment exacerbates rather than improves the clinical state. Continuous haemofiltration using a locally-prepared bicarbonate-based replacement fluid was performed in 200 patients over 7 years. All the patients had ARF with concomitant lactic acidosis, or demonstrated lactate intolerance after starting haemofiltration with lactate-based replacement fluids. In every case it was possible to correct the acidosis without inducing either extracellular volume expansion or hypernatraemia. In 89 patients (45%), the lactic acidosis resolved while being treated with bicarbonate-based haemofiltration. Fifty-seven patients (28.5%) survived. Significant differences at presentation in the group who survived, compared with those who died, were seen in age (50.8 vs. 57.1), mean arterial pressure (68.5 vs. 60.0 mmHg) and APACHE II score (32.1 vs. 38.9). Neither the severity of the presenting acidosis nor the arterial blood lactate appeared to predict outcome. Patients who developed ARF and lactic acidosis after cardiac surgery had a low survival rate. The combination of ARF and lactic acidosis that cannot safely be treated by haemofiltration using lactate-based replacement fluids can be managed with bicarbonate-based haemofiltration.

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Recombinant human erythropoietin is a successful treatment for the anaemia of renal failure. Its use has however been associated with thromboembolic complications. Changes in platelet number and behaviour in vitro were studied in: (1) 23 haemodialysis patients, and 10 continuous ambulatory peritoneal dialysis patients (CAPD) treated with erythropoietin (EPO); (2) 14 untreated dialysis patients (7 haemodialysis, 7 CAPD), with intrinsically high haemoglobins; and (3) 23 age-matched non-uraemic normal controls. All patients treated with erythropoietin had a significant rise in haemoglobin (23 haemodialysis patients: pre-EPO median (range), 6.9 (5.1-8.1)g/dl; post-EPO, 10.9 (9.0--12.8)g/dl; 10 CAPD patients: pre-EPO, 7.8 (6.7-8.8)g/dl); post-EPO, 12.5 (9.9-14.3)g/dl; p < 0.01). Platelet number was significantly reduced in CAPD patients (pre-EPO: 327 (210-745) & 10(9)/1; post-EPO: 240(198-359) & 10(9)/l; p < 0.01) but not in haemodialysis patients. Spontaneous and collagen-induced whole blood platelet aggregation were significantly increased following erythropoietin treatment, both in haemodialysis (spontaneous platelet aggregation: pre-EPO, 39(12-78)%; post-EPO, 64(27-93)%, p < 0.01, collagen-induced platelet aggregation: pre-EPO, 61(3-95)%; post-EPO, 74(21-93)% p < 0.05), and CAPD patients (spontaneous platelet aggregation: pre-EPO, 38(18-81)%; post-EPO, 71 (41-95)%, p < 0.01, collagen-induced platelet aggregation; pre-EPO, 73(28-95)%; post-EPO, 90(44-95)%, p < 0.05). There was no significant change in aggregation to 1 μM ADP. Spontaneous and collagen-induced platelet aggregation were significantly higher in erythropoietin treated patients and untreated CAPD controls with high haemoglobins compared to age and haemoglobin-matched non-uraemic normal individuals (23 normals: spontaneous platelet aggregation, 37(10-75)%; collagen-induced platelet aggregation, 43(6-94)%, p < 0.001). Enhanced platelet aggregability is associated with vascular disorders. The increased red cell mass due to erythropoietin therapy may have physical and chemical effects on platelet function predisposing to thrombosis in this susceptible group of patients.