The effects of corticotropin and growth hormone releasing hormones on their respective secretory axes in chronic hemodialysis patients before and after correction of anemia with recombinant human erythropoietin.

Endocrine abnormalities in chronic hemodialysis patients are in part corrected by control of anemia with recombinant human erythropoietin (rHu-EPO). We further examined the role of rHu-EPO in select hormonal abnormalities thought to be anemia related as well as the GH-insulin-like growth factor 1 (GH-IGF-1) axis that is abnormal in hemodialysis patients. We studied responses to the administration of two hypothalamic hormones, GHRH and ovine corticotropin-releasing hormone (CRH), in five anemic male patients on chronic hemodialysis before and after correction of the anemia with rHu-EPO. For comparison, five age-matched normal male volunteers were tested once. Anemic patients on chronic hemodialysis had high basal GH concentrations, an exaggerated GH response to exogenous GHRH, increased levels of IGF-1, and elevated levels of IGF-1 binding protein-3 in comparison to controls. ACTH response to CRH was comparable in dialysis patients and normal controls, but the cortisol response to endogenous ACTH release was prolonged. The cortisol binding globulin was similar to the controls. After correction of anemia, the basal elevation of GH was no longer present, but the exaggerated response of GH to exogenous GHRH persisted. IGF-1 and IGF-1 binding protein-3 levels remained elevated. The ACTH response to CRH, which was normal before correction of the anemia, became exaggerated in terms of elevated levels. Nevertheless, the prolonged cortisol response persisted. It appears that correction of the anemia in hemodialysis patients with rHu-EPO can partly correct perturbations in the GH secretory axis but may lead to new abnormalities in the CRH-ACTH axis.

Nutritional implications of recombinant human erythropoietin therapy in renal disease.

The treatment of anemia in patients with renal failure has been dramatically changed with the development of recombinant human erythropoietin (r-HuEPO). This review discusses the pathogenesis of the anemia renal failure and the biology of erythropoietin. Causes of poor response to r-HuEPO therapy are outlined, and the importance of adequate available iron is highlighted. Parameters used to measure iron adequacy include serum iron levels, transferrin saturation, and ferritin levels. Other nutritional deficiencies, such as folic acid and vitamin B-12, can also impair r-HuEPO response. Clearly, the advent of r-HuEPO treatment for patients with renal failure and anemia has brought another dimension to the care of these patients. Optimal nutrition management is critical for the success of this new agent.

Salt excretory capacity in natives adapted to moderate high altitude living after acute mobilization to sea level.

The sodium excretory capacity of six normal subjects born and raised at moderately high altitude (2600 m) was evaluated at high altitude (HA), and after acute mobilization to sea level (SL). The ability of these individuals to respond to an acute salt load was evaluated by infusing a volume of 100 ml.m-2 body surface area (BSA) of 5% sodium chloride solution over a 30-min time period in both experimental conditions. HA natives were able to excrete a significantly greater salt load at HA than at SL (41.8% vs. 31.6%, respectively, p < 0.05) in 3 h. No changes in plasma atrial natriuretic factor (ANF) concentration were found in either experimental condition. Despite an increase in serum osmolality, no vasopressin (AVP) response was noted either at HA or SL. No correlation between serum AVP levels and urine c-AMP concentrations was found. The enhanced excretory response to a salt load at HA was not explained by the measured hormonal changes. The lack of AVP response to increased serum osmolality, both at HA and SL, in high altitude adapted subjects is presently unexplainable.

Cell adhesion molecules and the kidney.

Cell adhesion molecules (CAMs) have been implicated in various biologic processes, including morphogenesis, immune response, and thrombosis. There are four major groups: integrins, cadherins, immunoglobulin superfamily members, and selectins. Certain CAMs are differentially expressed in the developing, normal, and cancerous kidney. Other CAMs are altered in glomerulonephritis and transplant rejection. Preliminary studies suggest that blocking CAMs can attenuate tissue damage in human transplant rejection and animal models of glomerulonephritis. The study of CAMs in relation to the kidney is providing further insight into the normal and diseased kidney, and may lead to feasible new treatments for patients with renal diseases.

The role of the leukocyte adhesion molecules VLA-4, LFA-1, and Mac-1 in allergic airway responses in the rat.

Chronic airway inflammation is involved in the pathogenesis of asthma. The leukocyte adhesion molecules VLA-4 of the beta 1 integrin family, and LFA-1 and Mac-1 of the beta 2 family have a demonstrated role in leukocyte-endothelial adherence and may play a role in airway inflammation in asthma. We studied the effects of blocking VLA-4 (CD49d/CD29) and both LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) airway responses and inflammation in rats. BN rats were sensitized with ovalbumin (OA) subcutaneously and were challenged 14 d later with aerosolized OA. Twelve rats were treated prior to challenge with anti-rat VLA-4 monoclonal antibody (mAb), 10 rats received both anti-LFA-1 and anti-Mac-1 mAb, and 14 rats received a control mAb. The pulmonary resistance (RL) was measured for 8 h after challenge. The inflammatory response was evaluated by bronchoalveolar lavage (BAL) and by measuring the lung and airway inflammatory cells retrieved by enzymative dispersion. The early response was significantly decreased in both the anti-VLA-4 group (131% baseline RL) and the anti-LFA-1/Mac-1 group (118%; p < 0.05) compared with the control group (202%). The late response was also significantly decreased in both the anti-VLA-4 (3.7) and anti-LFA-1/Mac-1 (2.6) groups compared with the control group (19.7). The significant differences in bronchoalveolar lavage were a decrease in neutrophils in the LFA-1/Mac-1 group and an increase in macrophages in the anti-VLA-4 group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of haemoglobin and endogenous erythropoietin on hypothalamic-pituitary thyroidal and gonadal secretion: an analysis of anaemic (high EPO) and polycythaemic (low EPO) patients.

OBJECTIVE: Correction of anaemia with recombinant human erythropoietin (rHu-EPO) improves the responsiveness of thyroidal and gonadal axes to exogenous TRH and GnRH in chronic haemodialysis patients, but the mechanisms remain to be fully elucidated. In order to assess the influences of endogenous erythropoietin on the hypothalamo-hypophyseal thyroidal and gonadal axes, we studied the response of polycythaemic and anaemic patients, in comparison to normal controls, after the administration of exogenous TRH and GnRH. DESIGN: Exogenous hypothalamic factors, 500 micrograms TRH and 100 micrograms GnRH, were administered as a bolus and blood samples were obtained over a 3-hour period at 30, 60, 90, 120 and 180 minutes. PATIENTS: Five male polycythaemic patients (low EPO), three male anaemic patients (high EPO) and six normal age and sex matched controls were studied. MEASUREMENTS: Blood samples were centrifuged immediately and the serum was stored at -20 degrees C until assayed for total T4, free T4, free T3, TSH, prolactin, growth hormone (TRH test), and FSH, LH, testosterone (GnRH test). Haematological parameters and biochemical profiles were also measured. RESULTS: After TRH administration, both patient groups showed a normal TSH response; however, their free T4 and free T3 secretion was blunted compared to controls. Normal basal PRL levels increased in an exaggerated fashion, whereas, when compared to chronic renal failure patients on chronic haemodialysis, we did not see a paradoxical GH response or a basal GH increase in these 5 patients. GnRH administration in the study groups elicited a normalization in the LH response without an increase in testosterone levels; however, an exaggerated FSH response was found in the polycythaemic patients (low EPO). CONCLUSIONS: Thus by investigating the role of low endogenous EPO levels in non-anaemic and anaemic patients with high EPO levels, our study suggests that the underlying chronic disease state may be the major contributing factor in the regulation of the hypothalamo-hypophyseal thyroid and gonadal axes, rather than the EPO levels.

The effects of high altitude on hypothalamic-pituitary secretory dynamics in men.

OBJECTIVE: Individuals adapted to high altitude (HA) have abnormalities in endocrine function and specifically in the pituitary-thyroid axis and aldosterone regulation. In this study we assessed hypothalamic-pituitary function in men adapted to high altitude living using exogenous administration of synthetic hypothalamic hormones. DESIGN: Growth hormone releasing hormone (Geref 1-29) 1 microgram/kg, TRH 500 micrograms, GHRH 100 micrograms and ovine corticotrophin releasing hormone (oCRH) 1 microgram/kg were simultaneously administered intravenously to two groups of men: 12 born and raised in the city of Pasto, Colombia, South America, located at an altitude of 2600 m in the southern Colombian Andes (HA group) and 10 men living at sea level (SL) in Tampa, Florida. MEASUREMENTS: The following hormones were measured: GH, IGF-I, TSH, T4, free T4, free T3, PRL, ACTH, beta-endorphin and cortisol. IGF binding protein-3 (IGFBP-3) and cortisol binding globulin (CBG) were also measured. RESULTS: GH response to GHRH in HA men was exaggerated compared to SL men, and IGF-I concentration was also significantly increased in the presence of normal levels of IGFBP-3. No differences in TSH or PRL responses were found following TRH. HA men had lower basal total T4 levels, but higher free T4 and free T3 concentrations. The basal ACTH concentrations in the HA men were significantly lower than SL, although the response to oCRH was still present. beta-Endorphin basal levels were similar at HA and SL but the response to oCRH at HA was blunted. At HA, basal cortisol levels as well as CBG were elevated compared to SL and, in contrast to SL, did not increase significantly after endogenous ACTH secretion. CONCLUSIONS: This study is the first description of exaggerated GH response to the administration of GHRH in HA men and also of a significant increase in IGF-I concentration in the same subjects in the presence of normal levels of IGFBP-3. An altered hypothalamic-pituitary response was found in HA men after administration of oCRH characterized by a significantly lower basal ACTH concentration at HA, although the response to oCRH was present but the beta-endorphin response to oCRH was blunted. At HA, basal cortisol levels, as well as CBG, were elevated and the cortisol levels did not significantly increase after endogenous ACTH secretion. We have characterized the differences in hypothalamic-pituitary dynamics after the administration of TRH, GnRH and oCRH in HA men comparing their response to age/sex matched SL men.