Hypothalamo-hypophyseal thyroid and gonadal function before and after erythropoietin therapy in dialysis patients.

We examined the effects of administration of two hypothalamic neurohormones, TRH and GnRH, for 3 days in five anemic male dialysis patients and five age-matched normal male volunteers. Patients on chronic hemodialysis have abnormal hypothalamo-hypophyseal thyroid and gonadal functions, including blunted TSH response to TRH, hyperprolactinemia, elevated basal levels of LH with exaggerated response to GnRH, and depressed FSH secretory response to GnRH. After correction of anemia with exogenous erythropoietin, these dialysis patients were given a single injection of the same hypothalamic hormones. The repeat studies after the correction of anemia showed normalization of 1) the TSH response to TRH, 2) basal GH and PRL levels, and 3) the FSH response to GnRH. Although these patients appear to have biochemical evidence of testicular failure, the gonadotropin response (FSH) to GnRH was not exaggerated. In addition, there was no increase in total T4 and free T4 after TRH administration. Although a free T3 response to TRH was present, it was remarkably blunted compared to that of controls. At the present time, it is not known whether these hormonal responses after the correction of anemia are due to better oxygenation or a trophic action of the erythropoietin.

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.

Regulation of aldosterone secretion during hypoxemia at sea level and moderately high altitude.

The aldosterone and cortisol responses to small doses of ACTH (0.125, 0.25, 0.5, and 1.25 micrograms) after dexamethasone administration were measured in normal subjects at sea level while breathing room air (mean O2 saturation, 97 +/- 0.9%) and again while breathing hypoxic gas to lower the O2 saturation to 90%. A population of subjects matched for age and sex adapted to 3000 meters above sea level living in Colombia, South America, was also studied (mean O2 saturation, 94 +/- 0.7%). Hypoxemia, either induced at sea level or as a consequence of high altitude living, resulted in significant inhibition of aldosterone secretion after progressive administration of increasing doses of ACTH, but did not affect the cortisol response to ACTH. In addition, it was associated with higher plasma atrial natriuretic hormone levels. PRA declined only during acute hypoxemia induced at sea level and did not change during sea level normoxemia or high altitude living. Plasma sodium and potassium concentrations were no different in the three experimental conditions. We conclude that hypoxemia inhibits ACTH-stimulated aldosterone secretion and speculate that atrial natriuretic hormone may have mediated this effect.

Effects of dilevalol on rest and supine exercise hemodynamics in mild to moderate systemic hypertension.

Eight mildly to moderately hypertensive subjects free of any antihypertensive medications and on a normal salt diet performed maximal supine arm exercise. Before starting the exercise, a right-sided cardiac catheterization was performed to measure hemodynamic parameters before and during exercise. All patients had normal increases in cardiac output for the level of exercise performed and the peripheral vascular resistance diminished appropriately. An increase in the right atrial and pulmonary artery wedge pressures during exercise could be explained by increased venous return. After the baseline testing, rest and exercise hemodynamics were repeated 2 hours after the administration of 400 mg of dilevalol, a new beta blocker. For the next 2 weeks the patients received 400 mg of the study drug twice a day, with repeat studies obtained thereafter. As with other beta blockers, dilevalol decreases the heart rate and cardiac output on exercise, but, in addition, it induces a decrease in the resting systemic vascular resistance. This action is similar to its isomer, labetalol.

Response to growth hormone-releasing hormone in adult renal failure patients on hemodialysis.

Exogenous synthetic growth hormone-releasing hormone (GHRH [hpGRF-40]), 1 microgram/kg body weight, was administered intravenously (IV) to eight men with chronic renal failure on chronic hemodialysis and to seven men matched for age (control group). Basal and stimulated growth hormone (GH) concentrations following GHRH (hpGRF-40) in renal failure patients were significantly higher than in controls. Basal prolactin and somatomedin C/insulin-like growth factor-1 (SmC/IGF-1) concentrations were significantly higher in the renal failure patients compared with controls. Following GHRH there was no further increase in serum concentration of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, SmC/IGF-1, or cortisol. GH appears to be the only pituitary hormone where there is an exaggerated response to its specific releasing hormone in adults with renal failure.

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.

Blood types in cattle of Iberian ancestry and in Holsteins at various altitudes.

Gene frequencies of RBC antigens were determined in Holsteins and Colombian (criollas) cattle living at 3,000 m, and in cattle descended from fighting bulls (Vacas de lidia) living at 2,500 m. These frequencies were compared with those of Holsteins, cattle native to Florida (scrub cattle), longhorns, and native cattle from Brazil (caracu cattle) living at sea level. The criollas, Vacas de lidia, scrub cows, longhorns, and caracu are descendants of original Iberian stock introduced to the Americas. We found that despite common ancestry (scrub cattle, long-horns, criollas, and caracu), genetic differences may have been derived through years of demographic isolation. The most remarkable blood-group differences were found in the high prevalence of the B system phenogroup (heritable group of antigenic factors) BQA'G'34 in the Vacas de lidia, and of the S system phenogroup U1H' in these cattle and in caracu. Furthermore, the gene frequencies differed in the Holsteins maintained at moderately high altitude (descended from Holsteins kept at sea level), and may have been reflective of the need to adapt to moderately high altitude and chronic hypoxemic conditions. Blood group polymorphism was found in all groups of cattle, although it was reduced in the Vacas de lidia, possibly because their breeding has been carefully controlled and they appear to be highly inbred.

Blood biochemical characteristics of cattle at sea level and at moderately high altitude (3,000 m).

We investigated the biochemical composition of blood from Holstein cows, native breed (criollas), and cows descended from fighting bulls (Vacas de lidia) raised at an altitude of 3,000 m (moderately high altitude, MHA), and compared the results with those from Holsteins and cows of similar genetic ancestry as the criollas (scrub cows), both raised at sea level (SL), to determine blood biochemical values characteristic of adaptation to high altitude. Only potassium and calcium concentrations were similar among groups. Glucose concentration was lower in MHA cows, with the exception of Vacas de lidia. Serum bicarbonate concentration was lower in MHA cows; this finding can be explained by hyperventilation in the hypoxic environment. Serum magnesium concentration was lower in SL and MHA Holsteins than in other groups. Serum phosphate concentration was lower in scrub cows, MHA Holsteins, and criollas than in other groups. Cholesterol concentrations were lower in SL Holsteins, whereas triglycerides were higher in scrub cows and MHA Vacas de lidia. Concentration of high-density lipoprotein was significantly greater in Vacas de lidia and less in MHA criollas than in the other groups. Uric acid and total protein were higher in MHA groups. Using radioimmunoassay for human proteins, thyroxine-binding globulin was undetectable. Total and free thyroxine and free triiodothyronine were higher in scrub cows, followed by Vacas de lidia; lower values were detected in SL and MHA Holsteins and MHA criollas.

Low-dose captopril scintigraphy in the evaluation of renovascular hypertension.

This study compared the results of renal scintigraphy with simultaneous administration of Tc-99m DTPA and I-131 Hippuran (before and after 25 mg of oral captopril) with the results of the renal arteriogram and renal vein renins (before and after the administration of 25 mg of oral captopril) to evaluate the sensitivity and specificity of renal scintigraphy in the diagnosis of renovascular hypertension. The results of 21 consecutive patients suspected of having renovascular hypertension who underwent scintigraphy and renal arteriography were analyzed. Renal scintigraphy postcaptopril detected all the cases of renovascular hypertension (eight patients) plus two additional patients who had significant renovascular stenosis but no renin overproduction. The results indicate that the renal scintigram, before and after the administration of captopril, is an accurate and sensitive test for the detection of renovascular hypertension and should be used as a screening procedure before arteriography is considered.

High altitude living: genetic and environmental adaptation.

High altitude (HA) living produces physiological changes for adaptation to chronic hypobaric-hypoxemic conditions. Although much is known about these physiologic adaptations, no clear separation has been made regarding what is "native" or "genetic" adaptation and what is "acquired." In this review, we describe the genetic vs. acquired adaptation and only include studies performed in a population native to HA and not in an acclimatized population or trekkers. The changes encountered in animals and humans living at HA in terms of hematology, muscular, respiratory, cerebral, cardiovascular, hormonal, fluid and electrolytes and reproduction, strongly suggest that genetics play a very important role in HA adaptation. Unfortunately, the characteristic physiology of HA natives has not been systematically defined to established specific measurable parameters of adaptation in comparison to the acquired ambient adaptation of the non-native population. Once the parameters are established, we can compare non-native populations exposed to HA that must emulate the HA physiology for a definite adaptation to be present. With measurable parameters, especially in the management of fluids and electrolytes, we can define how long it will take for a sea level native to adapt to an HA altitude. Until these studies are performed, speculation will continue and no rational medical intervention can be offered to HA newcomers who may experience HA difficulties.

Hormonal response to exercise in high altitude natives and COPD patients.

Plasma renin activity (PRA) and aldosterone increase with exercise. Acute hypoxia interferes with this hormonal response to exercise, but the effects of chronic or intermittent hypoxia on exercise-induced hormonal changes are not well understood. The hormonal response to exercise was studied in two groups of subjects who were expected to become hypoxic during exercise (high altitude natives at high altitude and patients with moderate to severe chronic obstructive pulmonary disease or COPD), and normal controls. Both the high altitude natives and COPD patients became hypoxic with maximal exercise. The rate of rise of PRA and epinephrine was significantly less in the two study groups than the normal subjects. Changes in aldosterone levels with exercise were similar to PRA but the differences among groups were not significant. Differences between the groups were not seen for changes in atrial natriuretic polypeptide and norepinephrine during exercise. These results support the concept that hypoxia interferes with the renin-aldosterone and adrenal medullary response to exercise.

Partial renal resistance to arginine vasopressin as an adaptation to high altitude living.

BACKGROUND: The normal physiological response to high altitude (HA) is a decrease in total body water (TBW) and plasma and extracellular volume. The present investigation was designed to determine the mechanisms of the decrease in TBW with HA adaptation. METHOD: There were 10 men from the Southern Colombian Andes (2600 m) in Pasto, Colombia, who were compared to age-matched men from sea level (SL), Tampa, FL, in the U.S., with respect to their TBW, ability to handle a water load and response to exogenous arginine vasopressin (AVP). Measurements included circulating AVP, atrial natriuretic peptides [atrial natriuretic factor (ANF) and vessel dilator], and urinary excretion of the AVP sensitive water channel, aquaporin-2 (AQP2). RESULTS: The HA subjects had significantly (p < 0.01) lower TBW (29.37 +/- 0.98 vs 39.71 +/- 1.66 Kg), AQP2 excretion and vessel dilator circulating levels at baseline compared to SL subjects. ANF levels were not significantly different between the two groups. With water loading (20 ml.kg-1 in 15 min) there was a rapid increase in urine volume at 30 min with a decline thereafter in HA subjects while SL subjects had a gradual increment peaking at 120 min. There was a significant (p < 0.05) decrease in plasma AVP in the SL subjects within 30 min after the water load while the HA subjects had no significant decrease in AVP levels. Excretion of AQP2 decreased significantly after the water load only in the SL subjects. Administration of exogenous AVP increased AQP2 3- to 4-fold in the HA in comparison to SL subjects. CONCLUSIONS: Present data demonstrate the following adaptations to HA: decrease in TBW, better ability to handle a water load despite high levels of AVP, a significant decrease in the circulation of vessel dilator, and diminished excretion of AQP2 water channel. These findings indicate an insensitivity of the collecting duct of HA subjects to the actions AVP. However, exogenous administration of AVP caused a marked excretion of AQP2.

Effects of hypoxemia at sea level and high altitude on sodium excretion and hormonal levels.

Acute hypoxemia at sea level is associated with decreased aldosterone secretion. This inhibition is thought to be mediated through secretion of atrial natriuretic factor (ANF). The interaction of these two hormones should result in enhanced renal salt excretion during hypoxemic conditions. This hypothesis was tested by administration of a standardized salt load to seven normal subjects during normoxemia at sea level (SL), acute hypoxemia (AH) at sea level, and high altitude (HA) (3,000 m). Urine and venous blood samples were collected and analyzed. A natriuresis and diuresis was observed only under AH conditions. It was accompanied by a decrease in plasma aldosterone levels, but did not correlate with changes in plasma aldosterone levels, ANF, or other hormones. Increased plasma renin activity (PRA) and increased norepinephrine levels were encountered at HA, suggesting sympathetic nervous system activation. No change in anti-diuretic hormone (ADH) levels with increased plasma osmolality was seen at HA. We conclude that excretion of a salt load during normobaric hypoxemia is enhanced by a decrease in plasma aldosterone levels, unrelated to changes in ANF or other hormones. The differences observed in norepinephrine, PRA, and ADH levels during HA versus AH conditions suggest that hypobaria or chronic hypoxemia may influence these hormonal responses.

Salt loading test in a population adapted to moderately high altitude living (3,000 m).

The sodium excretory capacity of normal subjects acutely mobilized from sea level to moderately high altitude was compared to native subjects adapted to high altitude living (3,000 meters). This study was conducted in order to provide insights into hormonal adaptations associated with acute mobilization to a hypoxemic environment and to try to determine how these variables could influence the renal handling of a salt load. A standard amount of 5% NaCl solution at a volume of 100 ml/m2 BSA was infused over a 30-min period to all subjects. Urine collections were obtained periodically over the next 3 h. Subjects adapted to moderately high altitude living were able to excrete a salt load faster than unadapted subjects (57.1 vs. 32.9 mmol.m-2.h-1, respectively). No change in plasma atrial natriuretic factor (ANF) concentration in either group of subjects was observed during the salt administration period. Adapted individuals had significantly higher baseline levels of antidiuretic hormone (ADH). The high altitude natives enhanced excretory response to a salt load was not explained by any observed hormonal changes and their lack of increased ADH release to serum osmolar changes was unexplained.

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.

Aquaporin-1 expression in proximal tubule epithelial cells of human kidney is regulated by hyperosmolarity and contrast agents.

Primary cells of renal proximal tubule epithelium (S1 segment) of human kidney (HRPTE cells) up-regulate aquaporin-1 (AQP-1) expression in response to hyperosmolarity. NaCl and D(+)-raffinose increased (2-2.5 fold) AQP-1 expression when medium osmolarity was 400 and 500 mOsm/kg.H2O. Urea did not have this effect. Unlike our previous findings with mIMCD-3 cells, vasopressin (10(-8)M) did not affect AQP-1 expression in HRPTE cells in isosmolar or NaCl-enriched hyperosmolar conditions. Furthermore, HRPTE cells increased (3-4 fold) AQP-1 expression when exposed to hyperosmolar Reno-60 and Hypaque-76 (diatrizoates, ionic) contrast agents at 400 and 500 mOsm/kg.H2O. Isosmolar (290 mOsm/kg H2O) Visipaque (iodixanol, non-ionic) at 10% (v/v) concentrations also increased AQP-1 expression, and 25% v/v of Visipaque rendered morphological alterations of HRPTE cells and a 3-fold increase in AQP-1 expression after 24h exposure. Finally, semi-quantitative RT-PCR of HRPTE cells subjected to various isosmolar or hyperosmolar conditions demonstrated up-regulation of AQP-1 mRNA and protein levels. Our results suggest AQP-1 up-regulation in HRPTE cells exposed to environmental stresses such as hyperosmolarity and high doses of isosmolar contrast agents.

Alterations in soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in hemodialysis patients.

Hemodialysis (HD) patients can develop acute reactions during treatment as well as increased long-term susceptibility to infections and malignancies. Abnormalities in leukocyte adhesion may contribute to these processes. Recently, serum levels of soluble adhesion molecules have been detected in circulating blood of normal subjects and in patients with chronic renal failure. We studied the effects of a single dialysis session with new cuprophane membrane on the soluble (s) form of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), two adhesion molecules with a variety of immunologic roles. Significant elevations in both sICAM-1 (523 +/- 61 v 304 +/- 45 [SEM] ng/mL, P < 0.05) and sVCAM-1 (2,055 +/- 270 v 1,189 +/- 149 ng/mL, P < 0.05) were observed in HD patients at baseline compared with controls. Both sICAM-1 and sVCAM-1 levels decreased after a 3-hour HD session (P < 0.001). Early in HD, sICAM-1 levels, though lower than predialysis, were elevated in the exit line of the dialyzer compared with entrance (339 +/- 64 v 259 +/- 53 ng/mL, P < 0.001), whereas sVCAM-1 was decreased on the exit line compared with entrance (639 +/- 90 v 932 +/- 92 ng/mL, P < 0.001). Because ICAM-1 and VCAM-1 are important for many leukocyte functions, alterations in serum levels of sICAM-1 and sVCAM-1 may play a role in the immunologic consequences of uremia and HD treatment.

Cyclosporine-induced alterations in the hypothalamic hypophyseal gonadal axis in transplant patients.

We evaluated the response of 20 male patients, 13 cadaveric kidney and 7 heart transplant recipients, to the administration of 100 micrograms GnRH (gonadotropin-releasing hormone) and 500 micrograms TRH (thyrotropic-releasing hormone). All of the heart transplant recipients and 7 of the kidney transplant patients were receiving a combination of cyclosporine, azathioprine and prednisone; while the 6 remaining kidney transplant patients received azathioprine and prednisone. The patients receiving cyclosporine had decreased plasma levels of prolactin, and manifested a blunted response to TRH administration for prolactin and TSH. The heart transplant patients had a blunted response of LH and FSH to the administration of GnRH. The levels of testosterone were found to be low in all patients regardless of the immunosuppressant therapy. Despite the low testosterone levels, no increment in the concentration of LH or FSH was present. Intramuscular administration of HCG (human chorionic gonadotropin) (Ayerst Laboratories, New York, N.Y.) failed to increase the testosterone concentration in 5 of 6 patients with renal transplants, 3 taking cyclosporine and 3 taking azathioprine. This study suggests that cyclosporine has a selective effect on the hypothalamus and/or hypophysis, resulting in lower baseline levels of plasma prolactin and a pituitary insensitivity to TRH administration. In addition, FSH and LH were low or normal in the presence of low testosterone levels, suggesting that the hypothalamic pituitary gonadal axis is impaired. Furthermore, there may be a direct toxic effect of the immunosuppressant medications on the gonads, manifested as lower testosterone levels and inability to respond to the administration of HCG.

Activated and regulatory T lymphocyte populations in chronic hemodialysis patients.

T lymphocyte activation after leukocyte membrane interaction may play a role in immune dysfunction associated with hemodialysis (HD). Studies of T-lymphocyte activation markers in HD have yielded conflicting results, perhaps due to the use of a limited number of markers and different measurement techniques. We studied the lymphocyte activation markers CD25 (interleukin-2 receptor), CD38, CDw49b (VLA-2), CD71 (transferrin receptor), and HLA-DR, as well as the surface antigens CD3, CD4, CD7, and CD8 by two-color flow cytometry in 23 chronic HD patients before and after a single dialysis session; we also studied 30 normal controls. There was no increase in the percentage of activated T cells in the controls and in the patients pre- and post-HD. Conversely, the percentage of CD3+/CD71+ (transferrin receptor) cells was significantly decreased in the patients pre-HD compared with the controls (3.6% +/- 0.5% [mean +/- SEM] v 5.9% +/- 0.5%; P < 0.005). A single dialysis session did not alter the percentage of activated subsets, but led to significant depletion in the number (x 10(9)/L) of cells that were CD3+ (1.10 +/- 0.10 v 0.97 +/- 0.09; P < 0.05), CD7+ (1.0 +/- 0.09 v 0.85 +/- 0.08; P < 0.0001), and CD8+ (0.50 +/- 0.06 v 0.37 +/- 0.04; P < 0.001), but not CD4+ cells (0.73 +/- 0.08 v 0.69 +/- 0.07; P = NS). These data indicate that the chronic HD patients at baseline "predialysis" do not appear to have an increased percentage of circulating activated T lymphocyte subsets and that the CD3+/CD71+ subset is in fact decreased.(ABSTRACT TRUNCATED AT 250 WORDS)