PRA Values Research Articles

Renin gene expression in the adrenal and kidney of patients with primary aldosteronism.

mRNA levels for renin in the adrenal gland and kidney were measured by ribonuclease protection assay (RPA). Renin mRNA was not detected by RPA in aldosteronoma and kidney tissues obtained from two patients with primary aldosteronism (PA). In these patients, the PRA values, plasma concentrations of active renin (ARC), and total renin (TRC = ARC + prorenin) were below the assay limit (less than 0.03 ng/L.s, 2.5 ng/L, and 10 ng/L, respectively). On the other hand, renin mRNA was recognized by RPA in aldosteronoma and kidney tissues obtained from two other patients with PA treated with 50 mg/day spironolactone for more than 2 months. Their TRC values were 49.8 and 16.6 ng/L, but their PRA and ARC were undetectable. Renin mRNA content was greater in normal adrenocortical tissue and in the normal kidneys obtained from three hypertensive patients with renal cell carcinoma. In these patients, the mean values of PRA, ARC, and TRC were 0.28 +/- 0.03 (mean +/- SD) ng/L.s, 18.4 +/- 7.8 ng/L, and 110 +/- 15 ng/L, respectively. This is the first report of the lack of renin gene expression in aldosteronoma and kidney tissues obtained from untreated patients with PA. Furthermore, treatment with spironolactone resulted in an increase in the levels of renin mRNA in the aldosteronoma and kidney tissues of patients with PA.

Multiscreen serum analysis of highly sensitized renal dialysis patients for antibodies toward public and private class I HLA determinants. Implications for computer-predicted acceptable and unacceptable donor mismatches in kidney transplantation.

A multiscreen serum analysis program has been developed that permits a determination of antibody specificity for the vast majority of highly sensitized patients awaiting transplantation. This program is based on a 2 x 2 table analysis of correlations between serum reactivity with an HLA-typed cell panel and incorporates two modifications. One implements the concept of public HLA determinants based on the serologic crossreactivity among class I HLA antigens. The other modification derives from the premise that most highly sensitized patients maintain the same PRA and antibody profiles over many months and even years. Monthly screening results for patients with persistent PRA values can therefore be combined for analysis. For 132 of 150 highly sensitized patients with greater than 50% PRA, this multiscreen serum analysis program yielded information about antibody specificity toward public and private class I HLA determinants. The vast majority of patients (108 of 112) with PRA values between 50 and 89% showed antibody specificity generally toward one, two, or three public markers and/or the more common private HLA-A,B antigens. For 24 of 38 patients with greater than 90% PRA, it was possible to define one or few HLA-specific antibodies. The primary objective of the multiscreen program was to develop an algorithm about computer-predicted acceptable and unacceptable donor HLA-A,B antigens for patients with preformed antibodies. A retrospective analysis of kidney transplants into 89 highly sensitized patients has demonstrated that allografts with unacceptable HLA-A,B mismatches had significantly lower actuarial survival rates than those with acceptable mismatches (P = 0.01). This was shown for both groups of 32 primary transplants (44% vs. 67% after 1 year) and 60 retransplants (50% vs. 68%). Also, serum creatinine levels were significantly higher in patients with unacceptable class I mismatches (3.0 vs. 8.4 mg% [P = 0.007] after 2 weeks; 3.9 vs. 9.1 mg% [P = 0.014] after 4 weeks). Histopathologic analysis of allograft tissue specimens from 47 transplant recipients revealed a significantly higher incidence of humoral rejection (P = 0.02), but not cellular rejection, in the unacceptable mismatch group. These results suggest that the multiscreen program can establish which donor HLA-A,B mismatches must be avoided in kidney transplantation for most highly sensitized patients. For 18 of 150 high PRA renal dialysis patients, the multiscreen program could not define HLA-specific antibody. Most patients had greater than 90% PRA, and many of their sera appeared to contain IgM type nonspecific lymphocytotoxins that could be inactivated by dithioerythreitol (DTE).(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma atrial natriuretic factor in patients with acute myocardial infarction

Plasma atrial natriuretic factor (ANF), renin activity (PRA), aldosterone and antidiuretic hormone (ADH) were determined in 16 patients with uncomplicated acute myocardial infarction (AMI) for 7 days in all patients and in six patients for 8 more days. Echocardiograms were performed and central venous pressure (CVP) was measured on the 2nd, 7th and 15th days. On admission, plasma ANF was higher in patients with AMI (129.8 +/- 70.6 pg ml-1, mean +/- SD) than in healthy volunteers (50.6 +/- 10.0 pg ml-1) (P less than 0.05). Arterial pressure, heart rate, CVP were normal. Left atrial (LAD) and left ventricular diameters (LVDD) were increased in six patients. Ejection fraction (EF) was reduced in all. A significant inverse relationship between ANF and EF was observed. Patients with EF less than or equal to 45%, high LAD and LVDD had the highest plasma ANF and showed steady high plasma ANF for 15 days. Patients with EF greater than 45%, normal LAD and LVDD had elevated plasma levels only for 10 days, rising significantly on days 3-7 after admission. PRA and ADH values were normal throughout the study, whereas aldosterone was above the normal range only on admission. These findings suggest that the reduction in myocardial contractility induced by the infarction may account for the rise in ANF secretion via increased left atrial pressure or left atrial dilatation.

Contributions and clinical significance of IgM and autoantibodies in highly sensitized renal allograft recipients.

The contributions of auto and IgM antibodies in the levels of serologic reactivities of 30 highly sensitized patients were assessed by autologous T cell crossmatches at 4 degrees C and 22 degrees C and dithiothreitol (DTT) reduction of IgM antibodies. The range of panel reactivities of sera from these patients was 30-100%, median 55%. A monthly screen of these sera against a 30-member T cell panel was performed with and without addition of DTT (final concentration = 0.005 M). The results were divided into 3 groups. Group 1 consisted of 17 sera whose PRA values did not change following the DTT treatment. Also none of these sera had autoantibodies, suggesting that these sera contained DTT-resistant (IgG) antibodies, most likely directed against allogeneic targets. Group 2 consisted of 10 sera whose PRA values declined substantially (20-42%) following the DTT treatment, but only 1 serum derived from a patient with systemic lupus erythematosus had autoantibodies. These results suggested that although these sera contained IgM and IgG antibodies, these antibodies were most likely directed at allogeneic target structures with only one exception. Group 3 consisted of 3 sera that became completely unreactive to panel lymphocytes following the DTT treatment. All 3 sera had autoantibodies that were also removed with DTT, suggesting that these sera contained predominantly IgM antibodies directed at autologous target cells. All 3 patients from whom these sera were derived received successful kidney transplants across donor-specific positive T cell crossmatches that became negative following the DTT treatment. We conclude that although 13 out of 30 patients have IgM antibodies, only a small subset of these patients have autoantibodies. Renal transplantation in the presence of auto/IgM antibodies may be safe.

Intraoperative blood transfusions in highly alloimmunized patients undergoing orthotopic liver transplantation.

Intraoperative blood requirements were analyzed in patients undergoing primary orthotopic liver transplantation and divided into two groups on the basis of panel reactive antibody of pretransplant serum measured by lymphocytotoxicity testing. One group of highly sensitized patients (n = 25) had PRA values of over 70% and the second group of patients (n = 26) had 0% PRA values and were considered nonsensitized. During the transplant procedure, the 70% PRA group received considerably greater quantities of blood products than the 0% PRA group--namely, red blood cells: 21.1 +/- 3.7 vs. 9.8 +/- 0.8 units (P = 0.002), and platelets: 17.7 +/- 3.2 vs. 7.5 +/- 1.5 units (P = 0.003). Similar differences were observed for fresh frozen plasma and cryoprecipitate. Despite the larger infusion of platelets, the blood platelet counts in the 70% PRA group were lower postoperatively than preoperatively. Twenty patients in the 70% PRA group received platelet transfusions, and their mean platelet count dropped from 95,050 +/- 11,537 preoperatively to 67,750 +/- 8,228 postoperatively (P = 0.028). In contrast, nearly identical preoperative (84,058 +/- 17,297) and postoperative (85,647 +/- 12,445) platelet counts were observed in the 17 0% PRA patients who were transfused intraoperatively with platelets. Prothrombin time, activated partial thromboplastin time, and fibrinogen levels showed no significant differences between both groups. These data demonstrate that lymphocytotoxic antibody screening of liver transplant candidates is useful in identifying patients with increased risk of bleeding problems and who will require large quantities of blood during the transplant operation.

Embolization of the kidney in secondary renal hypertension as an alternative to surgical nephrectomy. An experimental study.

Embolization of the renal arterial bed with embolization agent Vilan 500 was performed in 13 dogs. Embolized kidneys shrink after the procedure and the functional parenchyma is extinguished. Peripheral PRA values were followed to find out whether renin production by the embolized kidney is extinguished (the non-embolized kidney was surgically removed). In nine of the thirteen dogs peripheral PRA decreased below 0.5 ng/ml/h; this renin activity can be considered extrarenal. Embolization of the kidneys with Vilan 500 can thus substitute surgical nephrectomy in patients with secondary renal hypertension.

The effect of phentolamine on active and inactive renin release in human renovascular hypertension.

SUMMARY1. Phentolamine was infused at low increasing doses (0.2, 0.3, 0.4 and 0.5 mg/min) in five patients with unilateral renal artery stenosis measuring active and inactive (cryoactivable) renin in the renal veins from the stenosed and nonstenosed kidney and in a peripheral vein.2. PRA values from the stenosed kidney (11.59, s.e.m. = 5.79 pmol ang I/ml per h) were higher than those in the peripheral vein (5.19, s.e.m. =2.64) while these latter were similar to those from the contralateral kidney (5.09, s.e.m. =2.93). Phentolamine significantly increased PRA from the stenosed kidney and in the peripheral vein in a dose‐related manner. PRA changes were unrelated both to blood pressure decrements and to heart rate increments induced by the drug.3. Before phentolamine, inactive renin from the stenosed kidney (5.19, s.e.m. = 2.84 pmol ang I/ml per h) did not differ significantly from that on the contralateral side (3.15, s.e.m. = 1.96) and in the peripheral vein (4.40, s.e.m. = 1.96). Phentolamine induced significant (P < 0.005) increments of inactive renin only from the stenosed kidney at the doses of 0.3, 0.4 and 0.5 mg/min. Inactive renin from the contralateral kidney was unchanged and it tended to increase, but not to a significant extent, in the peripheral vein. A highly significant relationship was found between active and inactive renin from the stenosed kidney (r = 0.79, P < 0.001, n= 25) and in peripheral blood (r = 0.71, P < 0.001, n= 25) but not from the stenosed kidney (r = 0.29, n= 25).4. These results suggest that phentolamine, infused at low increasing doses causes an increase of PRA only in the stenosed kidney, an action which does not seem to be wholly explained by either sympathetic nervous system activation or decrease of renal perfusion pressure, and which suggests an action on intrarenal a‐adrenoreceptors. Furthermore, phentolamine stimulated inactive renin release only from the stenosed kidney without evidence of intrarenal conversion of the inactive into the active form.

BODY FLUID VOLUMES AND PRESSOR RESPONSE TO ANGIOTENSIN II AND NOREPINEPHRINE IN PREGNANT RATS

The aims of the present study were to examine the appropriateness of the rat as a model for human pregnancy in distribution of body fluid volumes and pressor response to vasoconstrictor substances. Body fluid volumes and the pressor response to angiotensin II (AII) and norepinephrine (NE) were determined in unanesthetized nonpregnant and pregnant rats, at 6-10 days gestation (early gestation) and 16-20 days gestation (late gestation). The distribution of body fluid volumes was measured by an isotope dilution method; plasma volume (PV), extracellular fluid volume (ECFV), and total body water (TBW) by 131I-radio-iodinated serum albumin, 35S-sodium sulfate, and tritiated water respectively. Late gestation rats had signficantly (p<0.01) increased PV and TBW but only slight increased ECFV when compared to nonpregnant rats, while the pregnant rats had elevated PRA values (p<0.01). The results are almost compatible with the data in human pregnancy. In early gestation, the pressor response to AII tended to decrease, while that to NE was found to be almost the same with that in nonpregnant rats. In late gestation, on the other hand, the pressor response to both AII and NE decreased significantly (p<0.05) compared with nonpregnant rats. The reduced AII pressor response in late gestation decreased further by the treatment with indomethacin (10mg per kg), while response to NE increased significantly (p<0.05) to the normal level in nonpregnant rats. The treatment did not alter the response to AII and NE in either nonpregnant or early gestation of rats. PRA was measured in other groups of unanesthetized pregnant and nonpregnant rats before and after the treatment with indomethacin. PRA values were significantly (p<0.05) elevated both in early and late gestation rats compared with nonpregnant rats before the treatment. The treatment did not change PRA values either in nonpregnant or early gestation rats, but increased them in late gestation rats. These results suggest that the mechanisms of reduced pressor response to AII and NE in late gestation rats might be different : the response to AII is mainly determined by the increased activity of the renin-angiotensin system, and that to NE might be related to increased vasodilator prostaglandins. The rat could serve as another animal model in investigating AII and NE refractoriness in pregnancy.

Hemodynamic effects of [Sar1, Ile8] AII, an angiotensin II analog, in the renin subgroups of essential hypertension.

Hemodynamic effects of [Sar1, Ile8] AII, an angiotensin II analog, were studied in 30 patients with essential hypertension, who were subdivided into 11 low renin, 10 normal renin and 9 high renin groups according to low, normal and high PRA values both before and after furosemide administration (80 mg, orally) plus 4 h of ambulation, respectively. [Sar1, Ile8] AII infusion (600 ng/kg/min) produced significant increases in mean blood pressure (MBP) and total peripheral resistance index (TPRI) in normal renin and low renin groups and significant decreases in MBP and TPRI in high renin group, while the cardiac index and heart rate remained unchanged during the infusion in these three groups. Change in MBP at 30 min of [Sar1, Ile8] AII infusion correlated significantly with alteration in TPRI in 23 patients with essential hypertension, who completed the 30-min infusion. The response of both MBP and TPRI to [SAR1, Ile8] AII also correlated significantly with basal PRA. These results suggest that blood pressure response to [SAR1, Ile8] AII in essential hypertension is primarily due to alteration in total peripheral resistance and that direction and amplitude of the response of both MBP and TPRI are practically dependent on basal PRA levels.

Control of plasma aldosterone (PA) in congenital adrenal hyperplasia, 21-hydroxylase defect (CAH)

We previously found in CAH patients high 8 am PA and 170H-P with normal PRA levels. This discrepancy was further investigated. 1) 17 salt and non salt-losers, aged 5-17 yrs, treated with F alone, were tested. In 6 of 17, high 8 am supine PA and 170H-P were found with normal PRA levels. However, when re-tested at 11 am while standing, they all had increased PRA and PA values. 2) Six children had repeated hormonal determinations during a 24-h period. In 3 patients, PA and 170H-P decreased in the evening, but PRA remained elevated, while the contrary was observed in the early morning. In the 3 others, PA and PRA were low without PA fluctuations. These results indicate that 1) in CAH patients, PA is modulated by ACTH as in normals. 2) 8 am recumbent PRA is not a good index for the mineralocorticoid adjustment which is better based on PRA measured in standing patients.

Significance of renin and aldosterone in cirrhotic patients receiving spironolactone and furosemide

SIGNIFICANCE OF RENIN AND ALDOSTERONE IN CIRRHOTIC PATIENTS RECEIVING SPIRONOLACTONE AND FUROSEMIDE W. W .Faloon, J .Knipp, S .Aroesty. and M .S .Flood. Department of Medicine. Hiehland Hosnitsl and Universitv of Rochester, Rochester; Ne'w York. Elevated plasma renin (PRA) and aldosterone (PA) are characteristic of cirrhotic patients with ascites but the relationship of these to potential response to natriuretic agents is not clear. In 4 ascitic patients receiving constant 15 mEq Na+ diets PRA, PA, urine and serum Nat and K+ were studied during 6 day periods of control, spironolactone (Sp) 150 me/d, control, furosemide (Fu) 40 me/d, control and combined Sp and Fu. All patients had urine Nat less than 5 mEq/d in control periods; 2 patients had good natriuresis (80 and 115 mEq/d) and wt. loss with Sp or Fu or both; 2 patients had poor natriuresis (20 and 5 mEq/d) . Control PRA and PA in responders was PRA 4.0 and 3.3 ng/ml/hr. (normal<%. 5 on low Nat diet), and PA 59 and 108 ng/dl (normal4251 Figures for nonresponders were PRA 7.3 and 11.7. PA 194 and 302. No relationship to Sp or Fu responsiveness was found in serum Nat or K+ or concentration in urine Kt during control periods in these patients. A decrease in PRA and PA was seen in 3 of the 4 patients as the study progressed. Effect of Sp and Fu on PRA and PA was unpredictable and was not related to urine Nat response. Combined Sp and Fu usually (3 of 4 pts ) yielded better natriuresis than Fu but this may have been related to lower PRA and PA values in this period. Continuation of study beyond the periods noted revealed increased PRA and PA after incarcerated umbilical hernia repair (1 pt. ) , after fever due to spontaneous peritonitis (1 pt. ) , and when a patient became “dry” of ascites during diuretic therapy. These observations indicate that slight or moderate elevations of PRA and PA are associated with better responsiveness to natriuretic agents and that induced natriuresis is not consistently followed by an increase or decrease in renin or aldosterone levels. Stressful events may produce elevated renin and aldosterone in the convalescent ascitic cirrhotic.

The circadian rhythm of renin.

The circadian rhythm of plasma renin activity during continuous recumbency was determined fifty-one times in thirty subjects who either slept at night or remained awake for 24 h. Both groups had maximum values between 2400 and 0800 h, despite absence of the expected early morning fall in blood pressure, pulse, and glomerular filtration rate in the awake subjects. Infusion of normal saline between 2300 and 0300 h initially suppressed renin, but did not prevent its subsequent rise regardless of the amount of sodium appearing in the urine. Of thirteen patients tested two to five times, twelve had recurrence of the zenith within a single 4 h period on retesting, despite differences in sodium intake, basal blood pressure, and mean plasma renin activity. Peaks of lesser magnitude were also frequently noted, most commonly at 1000 h and 1800-2000 h. Minimum PRA values were not restricted to a particular time of day and did not generally recur at the same time upon retesting. The mean ratio of maximum to minimum PRA in each study was 246% +/- 18.3% (+/- 1 SEM). The circadian rhythm of renin appears to be independent of known renal mechanisms responsible for regulating renin release. It is possible that this rhythm is controlled by the central nervous system.

Methodologic problems in plasma renin activity measurements

The influence of pH and angiotensinase inhibitors on the in vitro generation of angiotensin I during PRA measurements has been investigated. PRA values obtained at pH 5.7 are higher than those obtained at pH 7.4. At pH 5.7, values obtained using diisopropyl-fluorophosphate (DFP 9 mM) as an angiotensinase inhibitor are higher than values obtained with a mixture of dimercaprol (BAL, 1.6 mM) and hydroxyquinoline (8-OHQ, 3 to 4 mM). Since the two methods for inhibiting angiotensinase are completely and equally efficient, it is suggested that these inhibitors might interfere with the renin angiotensinogen reaction. Significant correlations are observed between the PRA values obtained by the different methods which have been studied. Using an incubation pH of 5.7, and BAL and 8-OH quinoline as angiotensinase inhibitors, the distribution of PRA values in a population of 124 hospitalized hypertensive patients ingesting a normal sodium diet has been studied, and it has been demonstrated that the sensitivity of this method of measurement can detect small changes in PRA in patients with low renin activity.

172: Relationship between PRA and Sodium intake in normal children

In literature a negative correlation between PRA and chronological age has been reported for children. Sodium balance has not been considered in most cases. In adults negative correlation between PRA and Sodium excretion has been clearly documented. A nomogram plotting PRA in normal children, of various ages, in supine and upright positions against the daily rate of urinary Sodium at equilibrium would be desirable. In such a way we investigated a group of normal children, 26 to date; ages 50 days -13 yrs;dieted with constant Kalium (50 mEq/m2/24hrs.) and different-Sodium contents (15-150 mEq/m2/24hrs). Results: regression equations calculated on plotted values show a similar adult-trend. Supine PRA are poorly, whereas upright PRA values are highly related to Sodium intake. A linear correlation is justified in the former; in the latter, a parabolic (or hyperbolic?) correlation consistently reduces the variance. Evidence arises that supine PRA has a limited significance, in individual cases, considering its wide variability also after normalization for Sodium intake.

OUR EXPERIENCE WITH THE RADIOIMMUNOASSAY OF PRA AND ANGIOTENSIN II IN CHILDREN

We determined PRA and Angio II (Kit of CEA-CEN-SORIN) in some hundred cases in two different technical conditions: (A) pH = 7; DFP as inhibitor (B) pH = 5.5 and BAL-IC. Results: in a group of normal children at normal and constant diet PRA was: 0.64 ± 0.46 ng/ml/h. In 30 infants (8 h. – 11 m.) the mean value was: 0.75±0.27. The correlation between PRA and Angio II values (107 children) was highly significant; in spite of this we no longer measure Angio II with the kit because of the cross reactivity with the hepta and hexapeptide. (B) at pH = 5.5 the PRA values were higher. In 10 normal children (5–12 years) at a constant sodium intake of 50 mEq/m2/day, the mean PRA value in supine position after overnight fasting and rest was: 1.11 ± 0.36; after 30–40 min. exercise was: 2.88 ± 0.34. The previous experience (A) of independence of PRA from hypertension, azotemia etc. was confirmed. The sodium intake and position playan overwhelming role in determining the height of PRA values. Finally, the results obtained in some selected conditions or pathological cases are reported.