PRA Levels Research Articles

Diurnal rhythm of plasma catecholamines in acromegaly.

We investigated the 24-h profiles of the circulating levels of norepinephrine (NE) and epinephrine (E), blood pressure (BP), and heart rate in 14 acromegalic patients, before (A) and 3-6 months after transsphenoidal surgery (C-A, cured; A-A, active), and in 8 age-matched normal subjects (N). In addition, the responses of NE, E, PRA, and aldosterone to upright posture were investigated. No significant differences in the mean 24-h plasma NE and E levels were observed between either group of acromegalics and the N subjects. Analysis of the 24-h profiles indicated a statistically significant 24-h rhythm of both NE and E in N subjects. No evidence of a 24-h rhythm of plasma NE and E and BP was found in A patients. After surgery, a statistically significant 24-h rhythm of NE was detected in the patients with acrophase (13.54 and 13.45 h in C-A and A-A patients, respectively) and mesor (1019.8+/-45.1 and 1017.8+/-54.7 pmol/L in C-A and A-A patients, respectively) similar to those observed in N subjects (acrophase, 13.21 h; mesor, 942.3+/-42.5 pmol/L). After surgery, the plasma concentration of E clearly fluctuated throughout the 24 h in both C-A and A-A patients, even if cosinor analysis failed to reveal a 24-h significant rhythm. A statistically significant 24-h rhythm of BP was restored only in C-A patients. The mean 24-h heart rate was slightly, but significantly (P<0.05), higher in A than in N subjects and decreased after surgery. No significant differences in upright-stimulated NE, E, and plasma aldosterone levels were observed between each group of acromegalics and N subjects. However, basal and upright-stimulated PRA levels were significantly (P<0.001) lower in A patients. In conclusion, our study demonstrates the lack of a clear circadian variation in catecholamine levels and BP in active acromegaly and the return of a significant 24-h rhythm of NE and BP after pituitary surgery, concomitant with the reduction in GH and insulin-like growth factor I serum levels.

STERIOD AVOIDANCE IN KIDNEY TRANSPLANTATION

306 Previous studies of steriod withdrawal in kidney tx were associated with the occurrence of some late rejection episodes and graft losses. In the current era, the immunosuppression is so effective at preventing acute rejection, that a re-examination of the need for steriods is timely. We describe our experience with 20 kidney tx pts whose maintenance immunosuppression excluded the use of steriods. 19 pts received living donor kidneys: 12 LRD (3 HLA-ID, 6 one-haplo match, 3 zero-haplo match); and 6 LURD, and one recipient of a zero antigen mismatched cadaveric graft. The control group of 25 pts received identical immunosuppression except that it included prednisone. 21 pts received living donor kidneys: 15 LRD (5 HLA-ID, 7 one-haplo match, 3 zero-haplo match); and 6 LURD, and four recipients of cadaveric grafts. Laparoscopic nephrectomy was used for all but one living donor. There was no morbidity in the living donors. All transplants exhibited immediate renal function. All pts were given induction with three doses of solumedrol [500mg, 250mg and 125mg, on days 1, 2, and 3, respectively]; and also basiliximab (N=32) or daclizumab (N=4) (except recipients of HLA-ID grafts). Maintenance immunosuppression was tacrolimus (TAC) and mycophenolate mofetil (MMF; 3 gm/d). TAC was tolerated in all pts, and one was converted from MMF to azathioprine because of GI symptoms. Pt demographics including mean age, duration of dialysis, peak PRA levels, and proportion of recipients of HLA-ID grafts were the same in the two groups. Follow-up has been a median of 61 days (IQ 7-94d) in the steriod avoidance group, and 134 days (IQ 109-218d) in controls. The actuarial pt and graft survivals, and rejection rates were calculated to 120 days. The incidences of bacterial, viral and fungal infection, and occurence PTLD were also determined. (Table) The pt and graft survivals were all 100%. 4 pts in the steriod avoidance group had rejection episodes (1 HLA-ID, 2 one-haplo LRD, 1 LURD), all reversed (3 OKT3, 1 Steriods). 3 control pts had rejection episodes (1 one-haplo LRD, 2 LURD), all reversed (2 OKT3, 1 Steriods). 16 of the pts in the steriod aviodance group remain off prednisone. One pt in each group had a bacterial infection. There have been 0 cases of CMV, fungal infections or PTLD in either group. Longer follow-up is necessary to fully assess risk of graft loss and rejection. These early results suggest that the inclusion of steriods in maintenance immunotherapy may not be necessary in recipients of immediately functioning living donor or zero antigen mismatched cadaveric grafts.Table

COLD ISCHEMIA TIME INCREASES HLA CLASS I ANTIBODIES AFTER REJECTION OF A PRIMARY CADAVERIC RENAL ALLOGRAFT

679 Ischemic injury to kidneys up-regulates many of the molecules, cytokines, and co-stimulatory molecules that may precipitate, or be involved with an immune response to the kidney. Such up-regulation due to ischemic injury may contribute to delayed graft function (DGF) and/or acute rejection. To extend our understanding of the mechanism(s) involved in the injury/stress, inflammation, immunity triad, we measured the production of HLA Class I antibodies (PRA) in 90 recipients of primary cadaveric renal transplants done between 1985 and 1997 who were unsensitized before transplantation (each had at least 3 PRAs, all ≤9%); rejected their first kidney; and had at least three PRA tests performed after this rejection. The data in the table below show the effect of increasing cold ischemia time (CIT) of the rejected primary kidney on Class I antibody production.TableThe data show that Class I PRA levels are lower in the group of patients with CITs of less than 14 hours compared with each of the other CIT groups (< 0.02 for > 14 to ≤ 18; <0.001 for > 18 to ≤ 24; and <0.05 for ≥ 24 hours). The only other major influence on PRA levels was the number of HLA Class I mismatches between donor and recipient, with the 1 to 2 antigen mismatched group having lower PRA levels (28% ± 31; n=39) than those with 3 or 4 mismatches (51% ± 38; n=49) (p< 0.01). Furthermore, multivariate analysis showed that a CIT > 15 hours (odds ratio=3.5; 95% CI=1.2 to 10.1; p=0.01) and an HLA-A & B mismatch >2 (odds ratio=2.9; 95% CI=1.1 to 7.5; p=0.02) independently influenced the risk of developing anti-HLA Class I peak PRA > 20% after rejecting a first cadaveric kidney. Conclusion: These data suggest one additional explanation for the known association between CIT and DGF and/or acute rejection. They are also consistent with the possibility that once certain CIT levels are passed, the immunologic load induces more antibodies to donor HLA Class I antigens.

RENAL TRANSPLANTATION (TXP) IN THE 90'S: ACCESS AND OUTCOMES FOR BLACK AMERICANS AT A SINGLE CENTER

620 In the US, black (B) ESRD patients have had poorer access to transplantation, and poorer graft survival (GS) than Caucasians (W). METHODS: We retrospectively analyzed the demographics of 842 renal transplant recipients at this center between 8/95 and 8/98. We then compared GS between B and W recipients (recs) in two periods. Group 1 included 488 recs (W-232, B-256) of cadaver (CAD) kidneys transplanted between 8/95 and 8/98 (OKT3 or daclizumab induction with cyclosporine/MMF/steroids). Group 2 included 378 recs of CAD kidneys between 1987 and 1995 with OKT3/cyclosporine/azathioprine/steroid therapy. RESULTS: 842 transplants were performed in B or W recipients at this center between 8/95 and 8/98, 286 (34%) from living donors and 556 (66%) CAD. B patients received 350 txps: 65 (19%) from living related donors (LRD), 2 (<1%) from living unrelated donors (LURD), and 283 (81%) CAD. W patients received 492 txps: 169 (34%) LRD, 50 (10%) LURD, and 273 (56%) CAD. Despite comprising 65% of the waiting list, B pts received 51% of CAD kidneys. 40% of W CAD txps had at least 4 HLA ABDR matches, versus only 12% of B CAD txps (p<0.001).(Table)TableThere was no difference in donor characteristics, current or peak PRA levels, delayed graft function, infectious complications, causes of graft loss, or patient survival between races in the Group 1 cohort. CONCLUSIONS: 1) Black txp candidates remain significantly less likely than whites to receive kidneys from living donors, and LURD transplantation is extremely rare among B patients. Thus, B candidates remain relatively more dependent on the CAD donor supply. 2) Both B and W recs of CAD kidneys demonstrated better GS with a protocol substituting MMF for azathioprine. 3) Despite significantly poorer HLA matching for B, GS under both protocols (with aggressive use of anti-T cell induction) was similar in both B and W recipients.

Effect of enalapril on exaggerated erythropoietin response to phlebotomy in erythrocytosic renal transplant patients.

Exaggerated erythropoietin (EPO) response to phlebotomy regardless of the baseline EPO levels have been shown in patients with post-transplant erythrocytosis (PTE) and administration of angiotensin-converting enzyme inhibitors (ACE-1) seems to be effective in controlling PTE. However, the mechanism of this ACE-1 induced reduction in haematocrit (Hct) is not well known. Although some authors have suggested that ACE-1 may reduce EPO secretion, this is still controversial. The aim of the present study was to assess the effect of a single dose ACE-1 on exaggerated EPO response to phlebotomy. In this study, we compared serum EPO and renin (PRA) levels of 10 PTE patients, 10 non-PTE patients and 10 healthy blood donors before and after phlebotomy. The effects of a single dose of ACE-1 (enalapril, 5 mg p.o.) in PTE patients were also evaluated in the second phlebotomy. While the mean basal serum EPO level was significantly higher in the PTE group than the other two groups (P<0.01), the mean basal PRA levels did not differ significantly between these groups. Serum EPO and PRA levels increased significantly after the phlebotomy (P<0.001) and exaggerated EPO response to phlebotomy was suppressed by single dose enalapril (P<0.001) in the PTE patients. The present study has shown that the renin angiotensin system plays an important role in EPO formation and the Hct lowering effect of the ACE-1 is through reduction of EPO in PTE patients.

Differential expression of progestin receptor isoforms in the hypothalamus, pituitary, and endometrium of rhesus macaques.

The progestin receptor exists in at least two isoforms: a long form (PR-B) and a short form (PR-A), which can be separated and detected with Western blot analysis. It has been suggested from in vitro transfection experiments that differential expression of the two isoforms may provide one mechanism for tissue specific actions of progesterone (P). However, more information from in vivo experimentation is needed. It has been reported that P down-regulates the expression of PR in the endometrium and pituitary of E primed macaques. However, PR protein and PR messenger RNA expression in the hypothalamus is maintained with P treatment of E-primed macaques. Thus, there is tissue-specific regulation of PR by its cognate ligand in the nonhuman primate. To gain insight into the tissue-specific regulation of PR by P, we questioned whether differential expression of the isoforms of PR exists in the endometrium, pituitary, and hypothalamus of rhesus monkeys. The expression of PR-A and PR-B was examined after E (28-30 days) and E + P (14 days E + 14 days E + P) treatment in the primate endometrium, pituitary, and hypothalamus. After E or E + P treatment, the levels of PR-A were 5 times higher than PR-B in the endometrium. PR-A was 1.6-fold higher than PR-B in the pituitary. In the hypothalamus, the ratio of A to B ranged from less than 1 (B exceeds A) to unity (A and B equimolar). There was no difference in the ratio of A to B between E-treated and E + P-treated groups in any tissue examined. These observations (a) provide further support of the hypothesis that differential expression of the isoforms of PR may subserve the tissue specific actions of P and (b) also suggest that P does not differentially affect the expression of the isoforms of its cognate receptor in the endometrium, pituitary, or hypothalamus.

Sodium regulating hormones at high altitude: basal and post-exercise levels.

High altitude (HA)-induced diuresis is associated with marked changes in sodium and water regulating hormones, particularly the renin-angiotensin-aldosterone system (RAAS) and atrial natriuretic hormone (ANH). These hormones are also strongly stimulated by physical exercise, which is a major component of daily activity at HA. In spite of the numerous studies in literature, a clear relationship between hormonal changes, HA diuresis, and physical exercise has not yet been established. We therefore evaluated the response of sodium regulating hormones to exhaustive exercise in a group of seven males exposed to prolonged HA hypoxia. The study was divided into four phases: sea level (SL1), after 7 (P1) and after 21 (P2) days at 5050 m (Italian National Research Council Pyramid Laboratory, Nepal), and back at sea level (SL2). At each phase plasma hematocrit (Ht), total body water (TBW), 24-hr sodium excretion (uNa), and urinary volume (uV) were evaluated together with PRA, plasma aldosterone, and ANH, in samples drawn basally from patients in upright position, and at the end of graded step-wise (30 W/2 min) maximal exercise. Levels of uNa and uV were raised at P1 and then declined at P2, with a parallel decrease in TBW and an increase in Ht. Basal PRA and aldosterone levels were suppressed both at P1 and P2 (from 1.9 +/- 0.4 to 0.08 +/- 0.03 and 0.5 +/- 0.1 ng/mL/3 h, and from 7.9 +/- 1.8 to 3.9 +/- 0.4 and 4.5 +/- 0.4 ng/dL, respectively; P < .05). Exhaustive exercise at HA did not induce any significant response in PRA and aldosterone, unlike SL1. Otherwise at P1 ANH levels remained unchanged both basally and during exercise, while at P2 they decreased significantly vs. SL1, both basally and after exercise (from 13.3 +/- 5.7 to 3.5 +/- 1.2 and from 40.2 +/- 10.2 to 17.5 +/- 8.3, respectively; P < .05). Our data show that PRA and aldosterone levels were constantly suppressed at HA and were unresponsive to exercise, whereas the ANH response was significantly stimulated during acute HA exposure, but not during chronic exposure. This suggests that hypoxia-induced chemoreceptor stimulation may cause the natriuretic phenomenon through direct suppression of the RAAS.

Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle

Recent studies suggest that the progesterone receptor isoforms (PR-A and PR-B) activate genes differentially and that PR-A may act as a repressor of PR-B function. Hence, the absolute and relative expression of the two isoforms will determine the response to progesterone. We have measured their relative expression in the uterus of cycling women who underwent endometrial biopsy. PR isoforms were identified on blots of SDS-PAGE gels by reaction with the AB-52 antibody after immunoprecipitation from endometrial extract. Both isoforms were highest in the peri-ovulatory phase, but levels of PR-A were always higher than those of PR-B. The ratio of PR-A to PR-B changed during the menstrual cycle. Between days 2 and 8, PR-B is almost undetectable and the A:B ratio is >10:1. From days 9 to 13, the ratio is about 5:1, and it is about 2:1 between days 14 and 16. Thereafter, PR-B dwindles rapidly and is virtually undetectable at the end of the cycle. In various hypoestrogenic environments, PR-B expression was reduced. However, exogenous estrogens in the follicular phase in the form of oral contraceptives, enhanced PR-B expression. These data support the possibility that progesterone acts through cycle-specific PR isoforms.

Atrial natriuretic peptide in transient puerperal hypertension.

This study is the first approach to evaluate whether human atrial natriuretic peptide (hANP) is involved in the pathophysiology in transient puerperal hypertension (TPH). Five women who were normotensive throughout pregnancy, labor, and delivery developed hypertension between the first and sixth postpartum day. hANP (pg/ml) and plasma renin activity (PRA, ng/ml/h), angiotensin I, II (AI, II, pg/ml), and aldosterone (Aldo, pg/ml) in plasma were quantified by radioimmunoassay. Ten women without hypertension were also studied on hANP, PRA, AI, AII, and Aldo sequentially as the control group. hANP was apparently lower in women with TPH than in normotensive women. The levels of PRA, AI, AII, and Aldo were also clearly decreased in women with TPH, whereas those values in normotensive women were not altered from nonpregnant levels. Maternal natriuresis usually reaches the peak at 3-5 days postpartum. The decrease of hANP and PPA, AI, AII, and Aldo in TPH coincides with this natriuretic period. This observation suggests that hANP may serve an important role in the pathogenesis of TPH.

In familial hyperaldosteronism type I, hybrid gene-induced aldosterone production dominates that induced by wild-type genes.

We compared the aldosterone-producing potency of the angiotensin II-sensitive wild-type aldosterone synthase genes and the ACTH-sensitive hybrid 11 beta-hydroxylase/aldosterone synthase gene by examining aldosterone, PRA, and cortisol day-curves (2-hourly levels over 24 h) in patients with familial hyperaldosteronism type I, before and during long-term (0.8-13.5 yr) glucocorticoid treatment. In 8 untreated patients, PRA levels were usually suppressed, and aldosterone correlated strongly with cortisol (r = 0.69-0.99). Fourteen studies were performed on 10 patients receiving glucocorticoid treatment that corrected hypertension, hypokalemia, and PRA suppression in all. ACTH was markedly and continuously suppressed in 6 studies, 3 of which demonstrated strong correlations between aldosterone and PRA (r = 0.77-0.92). ACTH was only partially suppressed in the remaining 8 studies; aldosterone correlated strongly: 1) with cortisol alone in 5 (r = 0.71-0.98); 2) with cortisol (r = 0.90) and PRA (r = 0.74) in one; 3) with PRA only in one (r = 0.80); and 4) with neither PRA nor cortisol in one. Unless ACTH is markedly and continuously suppressed, aldosterone is more responsive to ACTH than to renin/angiotensin II, despite the latter being unsuppressed. This is consistent with the hybrid gene being more powerfully expressed than the wild-type aldosterone synthase genes in familial hyperaldosteronism type I.

The ratio of progesterone receptor isoforms changes in the monkey corpus luteum during the luteal phase of the menstrual cycle.

Recent evidence suggests that progesterone is required for ovulation, luteinization, and the maintenance of luteal structure and function in primates. Progesterone action is mediated by intracellular progesterone receptors (PRs), and PRs are detectable by immunocytochemistry in the monkey corpus luteum. However, changes in total luteal PR and PR isoform expression have not been quantitated in the corpus luteum during its life span in the menstrual cycle. This study was initiated to identify and quantify PR isoforms in the macaque corpus luteum throughout the luteal phase of the natural cycle by means of Western blotting. Several antibodies generated against the human PR recognized two bands of consistent molecular weights in monkey tissues, and these bands comigrated with PR-A and PR-B from human T47D cells. Taken together, these data suggest that the two proteins identified were macaque PR-A and PR-B. The estimated molecular weights of monkey PR-A and PR-B were approximately 90,000 and 120,000, respectively. PRs were detected in a variety of macaque tissues, including the endometrium, whole ovary, and decidua, but not in spleen, which is PR-negative by other techniques. Whereas PR-A was the predominant isoform observed in endometrium and decidua, PR-B predominated in the ovary without a dominant follicle or corpus luteum as well as in the corpus luteum. In luteal tissue, PR-A levels decreased (p < 0.05) over the course of the luteal phase, while PR-B levels were unchanged. Hence the ratio of PR-B to PR-A (PR-B:PR-A) increased (p < 0.05) from early to very late luteal phase. Since PR-B:PR-A can alter gene expression in response to progestins and antiprogestins in vitro, the temporal changes in PR-B:PR-A in the monkey corpus luteum may contribute to functional differences in luteal responses to progesterone and other steroids in vivo.

Effects of nifedipine treatment on the renin-angiotensin-aldosterone axis.

Nifedipine is a commonly used agent in treating hypertension and angina because of its vasodilator properties. An inhibitory role of nifedipine on aldosterone (Aldo) biosynthesis has been documented in in vitro studies. This study was designed to examine the impact of a sustained release nifedipine formulation on Aldo biosynthesis and its clinical consequences. Early and late effects of nifedipine on Aldo, PRA, and Aldo/PRA ratio levels were studied in a single blind, placebo-controlled, 10-day pilot study. Ten normotensive subjects and 10 patients with hypertension were studied. Blood samples for the measurement of Aldo and PRA were obtained at 2-h intervals for 10 h on a control day and on days 1 and 8 of nifedipine treatment for the determination of baseline, early, and late values. Placebo was administered at 0800 h on the first and second days of the study, whereas nifedipine (60 mg/day) was given for the following 8 days. The Aldo/ PRA ratio was used as a sensitive indirect index of the responsiveness of Aldo secretion to adrenal stimulation with angiotensin. Compared to those on the control day, a significant rise in the integrated PRA levels occurred on the first day of nifedipine treatment, with a further rise observed on the eighth day of the treatment in the normotensive subjects (1.1 +/- 0.6, 1.7 +/- 1.2, and 2.5 +/- 1.8 ng/mL.h on the control day and the first and eighth days of treatment, respectively; P < 0.05) and by the eighth day in the hypertensive subjects (2.2 +/- 2.8 and 4.0 +/- 4.1 ng/mL.h; P < 0.05). A significant rise in integrated Aldo levels occurred in the normotensive subjects on the eighth day of nifedipine treatment (control day, 319 +/- 187; eighth day of nifedipine, 363 +/- 167 pmol/L; P < 0.05) and in the hypertensive subjects (426 +/- 219 and 535 +/- 284 pmol/L; P < 0.05). This was associated with a significant lowering of the Aldo/PRA ratio on the first day of the treatment, with further lowering on the eighth day in the normotensive (435 +/- 454, 269 +/- 209, and 182 +/- 107; P < 0.05) and by the eighth day in the hypertensive subjects (716 +/- 833 and 305 +/- 315; P < 0.05). When individual time points were examined in the normotensive subjects, Aldo/PRA levels were significantly lower on day 8 of nifedipine treatment at 1000, 1200, and 1400 h than corresponding values on the control day. The fall in the Aldo/PRA ratio during nifedipine treatment indicates that the previously reported in vitro inhibition of Aldo biosynthesis in adrenal cells is reproduced in vivo. In the absence of nifedipine, it is likely that Aldo levels would be higher for any given level of PRA. It is probable that the Aldo inhibition and the vasodilatatory effect of nifedipine combine to bring about the lowering of blood pressure. Drugs that inhibit renin-angiotensin axis activity are likely to be particularly effective when additional lowering of blood pressure is required.

The Effects of Insulin on the Juxtaglomerular Apparatus and Plasma Renin Activity

In this study, the effects of insulin on plasma renin activity (RPA), serum sodium, potassium, and blood glucose levels in mice, and the histological and cytological changes occuring in the juxtaglomerular apparatus (JGA) are examined. After injection 250 U/kg of insulin into animals deprived of food overnight, we saw that the levels of blood glucose, sodium, and potassium decreased considerably while PRA levels increased. In the light and electron microscopic sections taken from these animals, the granules decreased in most of the juxtaglomerular granular cells. These cells have developed rough endoplasmic reticulum, increased polysomes, and multivesicular bodies. Granule distribution at various phases showed a noticeable difference in comparison with the control group. Sodium, potassium, and glucose levels decreased following injection of 20 U/kg insulin into animals on normal feeding programs for periods of 10 days, and more (30-60 days); the increase in PRA was unremarkable. The number of juxtaglomerular granular cells increased in JGA following injection of insulin over long periods (30-60 days). Electron micrographs have shown that this to be due to hyperplasia and metaplasia produced in both extramesangial cells and in the smooth muscle cells of the affrent arterioles.

Catecholamines, Renin-Angiotensin-Aldosterone System, and Atrial Natriuretic Peptide at Rest and During Submaximal Exercise in Patients With Congestive Heart Failure

The aim of this study was to determine the responses of plasma catecholamines, renin-angiotensin-aldosterone (RAA) activity, and plasma atrial natriuretic peptide (ANP) to exercise in patients with congestive heart failure (CHF). Cardiac and neurohormonal responses were assessed during submaximal treadmill exercise testing in 23 patients with CHF (New York Heart Association classes I-III) and 13 control subjects (without CHF). Plasma norepinephrine, epinephrine, renin activity (PRA), angiotensin II (ATII), aldosterone, and ANP were measured at rest and immediately after exercise. Exercise duration was shorter in patients with CHF (control, 10.4 +/- 0.9 minute; CHF, 6.2 +/- 0.7 minute; P < 0.01). Heart rate and blood pressure responses were similar except for the smaller peak heart rate (control, 145 +/- 5 beats per minute; CHF, 129 +/- 4 beats per minute; P < 0.05) and higher systolic blood pressure at recovery stage (control, 122 +/- 4 mm Hg; CHF, 142 +/- 4 mm Hg; P < 0.01) in patients with CHF. At rest, plasma norepinephrine levels were insignificantly higher in patients with CHF (control, 110 +/- 10 pg/mL; CHF, 170 +/- 26 pg/mL; P = 0.09), and ANP levels (control, 40 +/- 5 pg/mL; CHF, 94 +/- 17 pg/mL; P < 0.05) and PRA levels (control, 0.77 +/- 0.11 ng/mL/hr; CHF, 4.33 +/- 1.25 ng/mL/hr; P < 0.05) were significantly higher. There were no differences in peak norepinephrine, epinephrine, or ANP between the two groups. Angiotensin II and aldosterone levels were similar between the two groups, although, in patients with CHF, there was a trend toward higher levels of ATII while at rest (control, 12.4 +/- 1.4 pg/mL; CHF, 20.3 +/- 3.3 pg/mL; P = 0.08) and at peak (control, 20.5 +/- 1.8 pg/mL; CHF, 41.0 +/- 9.4 pg/mL; P = 0.10). Peak values of PRA, ATII, and aldosterone positively correlated with respective resting values of PRA (r = 0.88 ng/mL/hr, P < 0.01), ATII (r = 0.63 pg/mL, P < 0.01), and aldosterone (r = 0.99, P < 0.01). Peak norepinephrine and peak ANP also positively correlated with respective resting values of norepinephrine (r = 0.58 pg/mL, P < 0.05) and ANP (r = 0.94, P < 0.01). Analysis of these results showed that patients with CHF had significantly higher levels of PRA and ANP at rest, and a trend toward augmentation in RAA system activity during exercise with less exercise workload. Basal level of neurohormones seemed to be an important determinant for the degree of exercise-induced neurohormonal activation in patients with CHF.

Serum sodium imbalance in the bedridden elderly. Part One: Realities and problem of management

Symptoms and other abnormalities associated with serum sodium imbalance were studied in bedridden elderly and healthy elderly subjects. 1. A significantly higher number of the bedridden elderly suffered from chronic wasting disease. 2. The average serum sodium concentration in bedridden elderly subjects was significantly lower than in healthy subjects, as was the sodium intake and the sodium content in urine, which indicate that the bedridden elderly subjects suffered from chronic sodium deficiency. 3. The bedridden elderly subjects had high levels of plasma PRA and antidiuretic hormone, and their aldosterone levels were low, which indicate that their condition was associated with a decrease in available circulating plasma, hypersecretion of antidiuretic hormone, and a decline in the ability to retain sodium. 4. Measurement of 24-hr creatinine clearance, albumin, and beta 2-microglobulin in urine revealed that bedridden elderly subjects had high levels of renal dysfunction, the result of which may a disturbance in water excretion. Abnormalities in serum sodium levels in the bedridden elderly subjects were related to a chronic deficiency in sodium intake, which reduced their ability to maintain sodium levels and impaired their renal function. Iatrogenic factors are likely to play an important role in the genesis of this condition, and should be taken into account in during management.

Comparison of panel-reactive antibody levels in Caucasian and African American renal transplant candidates.

PRA levels from 58 Caucasian and 70 African American ESRD patients were compared against a panel of cryopreserved lymphocytes from 60 donors (40 Caucasian, 15 African American, 5 others) to determine whether there was significant racial influence on PRA outcome. African Americans were found to have significantly higher mean PRA levels than Caucasians (27% vs. 18%, P = 0.02). Restricting this analysis to only 1 degree transplant candidates showed predictably lower mean PRAs: 6% in Caucasians and 15% in African Americans, but the difference between the two groups remained significant (P = 0.015). The percentage of patients with PRA > or = 10% was also greater among African Americans than Caucasians (43% vs. 24%, P = 0.026). For patients not previously transplanted, the difference between these frequencies remained significant: 11% in Caucasians, 30% in African Americans (P = 0.025). Untransplanted African American patients with positive PRAs (> or = 10%) had significantly higher PRA against African American cell donors (mean = 55%) than against Caucasian cell donors (mean = 44%) (mean difference = 10.6%, P = 0.0056). African Americans were more frequently transfused than Caucasians. The percentage of patients not previously transplanted receiving 0, 1-5, and > 5 transfusions were 69%, 22%, and 9% for Caucasians and 43%, 44%, and 13% for African Americans (P = 0.03). This higher transfusion rate is the most likely contributor to the elevated PRA levels observed in African Americans.

The effects of ibopamine on glomerular filtration rate and plasma norepinephrine remain preserved during prolonged treatment in patients with congestive heart failure.

In acute studies ibopamine, an a selective dopamine agonist, induces moderate increases of GFR and ERPF, and a fall in plasma norepinephrine levels in patients with congestive heart failure (CHF). We evaluated acute and chronic effects of ibopamine on renal haemodynamics, sodium excretion, PRA, plasma aldosterone (ALD) and norepinephrine levels in an open controlled study in 10 patients aged (51-79 years) with mild CHF, NYHA class II-III. All patients used digoxin and frusemide. After a control study day, the second study day involved the administration of 100 mg ibopamine. Subsequently the patients continued to take ibopamine 100 mg three times daily for one month, at which time the chronic effects were measured on the third study day. On the second day ERPF rose from a baseline of 288 +/- 32 to a mean of 308 +/- 32 ml.min-1 x 1.73 m-2 (P < 0.05) during the 4 h after the first administration of ibopamine and GFR rose from 77 +/- 8 to a mean of 84 +/- 8 ml.min-1 x 1.73 m-2 (P < 0.05). The ratio GFR/ERPF, representing the filtration fraction (FF) remained unchanged. On the third study day GFR and ERPF at baseline were similar to those before ibopamine treatment. After the acute on chronic administration we observed an increase in GFR (from 76 +/- 6 to a mean of 85 +/- 7 ml.min-1 x 1.73 m-2 (P < 0.05)), and in ERPF (from 279 +/- 27 to a mean of 293 +/- 29 ml.min-1 x 1.73 m-2 (P < 0.05)). Plasma norepinephrine levels fell from 2.63 +/- 0.48 to 1.92 +/- 0.27 nmol.l-1 (P < 0.05) after the acute administration of ibopamine, and remained unchanged after the acute on chronic ibopamine administration (C: 1.80 +/- 0.42 nmol.l-1). No changes in sodium excretion were observed, either in blood pressure, heart rate, PRA or ALD. We conclude that renal function is preserved during chronic ibopamine treatment and the acute moderate increase of ERPF and GFR after a single dose of 100 mg of ibopamine is still present after one month of treatment with ibopamine in patients with CHF. Ibopamine lowered plasma norepinephrine levels in our patients with CHF, and these values remained unchanged after the acute on chronic administration of ibopamine.

Renin-aldosterone axis in normoalbuminuric insulin-dependent diabetes mellitus patients with glomerular hyperfiltration

The renin-aldosterone axis was evaluated by captopril test in 22 normotensive normoalbuminuric insulin-dependent diabetes mellitus (IDDM) patients with and without glomerular hyperfiltration. Patients were divided into those with glomerular hyperfiltration (Hf-IDDM) and with normal glomerular filtration rate (GFR; Nf-IDDM) according to the upper limit of GFR (134.7 ml/min per 1.73 m 2). Sixteen normal individuals were also studied. GFR was measured by the 51Cr-EDTA single injection method, extracellular fluid volume as the distribution volume of 51Cr-EDTA, and blood volume using 51Cr-sodium chromate-labelled red blood cells. Twenty-five mg of captopril were administered per os and plasma renin activity (PRA; RIA), plasma aldosterone (RIA) and blood pressure were measured at 0 and 120 min post-captopril. PRA at time zero (Hf-IDDM = 2.4 ± 1.7; Nf-IDDM = 2.5 ± 1.9; controls = 1.0 ± 0.6 ng/ml/h) and at 120 min (Hf-IDDM = 9.9 ± 8.3; Nf-IDDM = 11.2 ± 8.9; controls = 5.4 ± 5.7 ng/ml/h) was higher in IDDM patients than in controls ( P = 0.01). The increase of PRA was similar in patients (Hf-IDDM = 7.5 ± 7.3, and Nf-IDDM = 8.7 ± 7.2 ng/ml/h) and controls (4.4 ± 5.3 ng/ml/h). There was no difference in PRA levels between Hf-IDDM and Nf-IDDM patients. PRA did not correlate with GFR, aldosterone, blood pressure, blood volume, duration of diabetes, 24-h urinary sodium and metabolic control indexes. Plasma aldosterone and the magnitude of its decrease after captopril was similar among patients and controls. Captopril induced a greater reduction of systolic blood pressure in patients (Hf-IDDM = 12.3 ± 6.9 mmHg; Nf-IDDM = 11.1 ± 7.3 mmHg) than in controls (5.4 ± 5.2 mmHg) ( P = 0.01). No difference was found between Hf-IDDM and Nf-IDDM patients. In conclusion, normoalbuminuric IDDM patients, irrespective of glomerular hyperfiltration, presented increased levels of PRA and larger blood pressure response to captopril as compared to normal individuals.

969-94 A Prospective, Randomized Steroid-free Maintenance Protocol in Heart Transplant Recipients

Immunosuppressive therapy for orthotopic heart transplant (OHT) recipients should be tailored in an effort to minimize steroid-induced morbidity. Accordingly, to assess the feasibility of and to identify specific predictors of successful steroid-withdrawal following OHT. we prospectively randomized 34 OHT recipients to cyclosporine/prednisone/azathioprine (CPA; n = 19) vs. cyclosporine/azathioprine (CA; n = 15) maintenance therapy. Mean followup was 1.6 ± 0.1 yr. No perioperative Iymphocytolytic induction therapy was used. End-point comparisons between CPA and CA groups included the percent of patients steroid-free at 1 yr, total rejection episodes (≥ IHSLT IIIA). number of major infections. blood pressure. hypercholesterolemia and survival. Total ischemic time. pre-transplant diagnosis. recipient/donor age and gender, and mean PRA levels were similar between the two groups. In the CA group. the mean post-OHT time to steroid-free was 228 d (range 167–356 d) with 9/15 (60%) maintained steroid-free at one-yr. Patients were considered steroid-free failures if they experienced ≥ 2 episodes of moderate-severe rejection requiring augmentation of immunotherapy. No differences in the number or duration of rejection episodes. major infections, systolic/diastolic BP or total cholesterol were observed between the two groups. The univariate predictors of successful steroid-withdrawal included: 1) male donor(p &lt; 0.02); 2) older recipient age (58 ± 2 vs. 48 ± 3 yrs; p = 0.02); and 3) older donor age (34 ± 6 vs. 21 ± 2 yrs; p &lt; 0.06). No difference in 1 yr survival was observed between the CPA vs CA groups. as determined by Kaplan-Meier analysis. Steroid-withdrawal following OHT is not associated with increased morbidity and/or mortality. We believe that this data is of importance for the future rational design of “individualized” immunosuppression following OHT.

Endocrine evaluation of incidentally discovered adrenal masses (incidentalomas)

Since 1989, 45 patients [pts; 26 females and 19 males, aged 19-79 yr (median, 58)] bearing incidentally discovered adrenal masses were studied. The aim of the study was to verify the prevalence of hormone activity in clinically silent adrenal masses. Endocrine work-up included determination of urinary catecholamines and their metabolites, measurement of PRA and aldosterone levels in clino- and orthostatic posture, and basal and dynamic [dexamethasone (dex) suppression and ovine CRH stimulation] evaluation of hypothalamic-pituitary-adrenal axis. The most frequent finding was the reduction of dehydroepiandrosterone sulfate (DHEA-S) levels below the third percentile of controls in 19 (42%) pts. DHEA-S levels were significantly lower in pts than in controls [68 (range, 5-1000) vs. 208 (34-326) micrograms/dL; 1.8 (0.1-27.1) vs. 5.6 (0.9-8.8) mumol/L; P < 0.001]. Three pts (7%) had high 24-h mean serum cortisol levels, and 6 (14%) had blunted day-night amplitude of cortisol rhythm. Defective dex suppressibility was found in 15% of pts vs. 8% of controls (P < 0.05). ACTH and cortisol responses to ovine CRH did not significantly differ between pts and controls, although blunted ACTH responses were found in 22% of the cases. The above-mentioned endocrine alterations could be accounted for by autonomous cortisol secretion by the adrenal nodule at a rate not sufficient to give clinical expression, but able to inhibit to some extent the hypothalamic-pituitary-adrenal axis. These results indicate that silent cortisol hypersecretion is frequently observed in pts with adrenal incidentaloma even if progression to overt Cushing's syndrome seems unlikely. Indeed, the size of the mass and the hormone pattern remained substantially unchanged in 9 pts followed up for 12 months. From merely a cost/benefit ratio, the evaluation of DHEA-S levels and dex suppression has sufficient sensitivity to identify the occurrence of silent hypercortisolism.