Dialysis decision making in Canada, the United Kingdom, and the United States.

This study was designed to determine the extent to which differences in criteria for dialysis patient selection and availability of financial resources cause the wide variation in acceptance rates for dialysis in Canada, the United Kingdom, and the United States. We also sought to determine whether there is agreement among nephrologists in the three countries on which patients should not be offered dialysis. We used a cross-sectional survey of all members of the Canadian Society of Nephrology and the Renal Association of Great Britain, and a randomized sample of 800 members of the American Society of Nephrology. Five case vignettes were presented asking for yes/no decisions on offering or not offering dialysis, together with ranking of factors considered important. We also inquired about dialysis resources and physician demographics. We compared responses by country. More nephrologists from the United Kingdom returned responses (83%) than Canadian (53%) or American (36%) nephrologists. American nephrologists offered dialysis more than Canadian or British nephrologists (three of five cases; P < 0.04 to P < 0.001) and ranked patient/family wishes (three of five cases; P < 0.057 to P < 0.0001) and fear of lawsuit (P < 0.04 to P = 0.0012) higher than British or Canadian nephrologists. Canadian and British nephrologists reported their perception of patients' quality of life as a reason to provide (P = 0.0019) or not provide (P = 0.068 to P = 0.0026) dialysis more often than their American counterparts. Despite these differences, nephrologists from each country did not differ by more than 30% on any decision and ranked factors almost identically. Ten percent and 12% of Canadian and British nephrologists, respectively, but only 2% of American nephrologists, reported refusing dialysis due to lack of resources (P < 0.0001). We conclude that the wide variation in dialysis acceptance rates in the three countries is somewhat influenced by differences in patient selection criteria and withholding of dialysis by nephrologists based on financial constraints, but that other factors, such as differences in rates of patient nonreferral for dialysis, contribute more significantly to the variation. Generally agreed on practice guidelines for dialysis patient selection appear possible.

The effects of posture change and continuous positive airway pressure on cardiac natriuretic peptides in congestive heart failure.

We studied changes in the peripheral plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in seven patients with congestive heart failure (CHF) during four 1-h protocols during which patients maintained either an upright or a supine posture with or without nasal continuous positive airway pressure therapy (N-CPAP) at a pressure of 10 cm H2O (FIO2 = 0.21). The mean plasma ANP concentration of patients increased significantly from baseline at the end of 1 h of recumbency (65.9 +/- 5.8 to 82.6 +/- 8.3 pg/mL (mean +/- standard error); p < 0.05). This increase was prevented by concomitant N-CPAP therapy (72.1 +/- 8.0 to 61.0 +/- 8.8 pg/mL; p = NS). The mean level of ANP decreased significantly (71.9 +/- 9.0 to 62.5 +/- 8.0 pg/mL; p < 0.05) while patients simply maintained an upright posture. A significant reduction was also observed when patients remained upright with accompanying N-CPAP (72.6 +/- 10.9 to 54.6 +/- 4.3 pg/mL; p < 0.05). There were no significant changes observed in the mean level of BNP for any of the protocols undertaken. We conclude that in patients with chronic CHF, (1) an increase in ANP concentration occurs with recumbency, and this can be prevented by N-CPAP therapy; (2) a decrease in ANP occurs with maintenance of an upright posture, and that this reduction may be augmented by N-CPAP; and (3) no net change in BNP concentration occurs with either posture change or N-CPAP.

Chlorotyrosine exerts renal effects and antagonizes renal and gastric responses to atrial natriuretic peptide.

3-Chloro-L-tyrosine (3CT) is an inhibitor of tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis. In vivo inhibition of tyrosine hydroxylase results in lower catecholamine levels. 3CT (0.5 mg/kg), administered as a bolus i.v. to anesthetized uninephrectomized rats, elicited increases of 72% and 44% in urinary sodium concentration and volume, respectively, whereas a dose of 1 mg/kg caused increases of 27% and 29%. 3CT, 1 mg/kg, resulted in a 2-fold increase in plasma aldosterone (ALD); 0.5 mg/kg was without significant effect. At a dose of 1 mg/kg 3CT significantly antagonized the renal effects of atrial natriuretic peptide (ANP) (1.5 micrograms kg-1 min-1 by intrarenal infusion), expressed as an enhanced excretion of urine volume (102 +/- 14 vs. 70 +/- 11 microliters/min) and sodium (16.1 +/- 1.8 vs. 11.5 +/- 1.7 microEq/min) and increased osmolar clearance (171 +/- 12 vs. 144 +/- 13 microliters/min). A dose of 0.5 mg/kg of 3CT did not produce these same responses to ANP. The increased urine flow caused by 3CT may reflect reduced norepinephrine synthesis. The inverse dose-effect relationship of 3CT on urine flow rate may result from concomitant depletion of dopamine (DA) and elevated circulating ALD. The antagonism of 3CT on responses to ANP is not at the receptor level, because 3CT did not compete for [125I] ANP binding or inhibit ANP-stimulated guanylate cyclase in kidney cell membranes. It was proposed that the reduced basal sympathetic and renal DA tone, together with the elevated ALD level, account for this antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased ascitic fluid prorenin in the ovarian hyperstimulation syndrome.

Three patients developed severe ovarian hyperstimulation syndrome (OHS) as a complication of ovarian hyperstimulation for in vitro fertilization. These patients presented with ovarian enlargement, vascular volume depletion, pleural effusions, and exudative ascites. A unique feature of the ascites in OHS was the markedly elevated renin concentration, the majority of which was prorenin. We speculate the renin-angiotensin system (RAS) may play a pathophysiologic role in the localized capillary leak that develops in OHS.

Gender and age as factors in the inhibition of renal clearance of amantadine by quinine and quinidine.

We studied the short-term effect of oral doses of quinine and quinidine on the renal clearance of amantadine in healthy young (age range, 27 to 39 years) and older (age range, 60 to 72 years) adults of both genders in a three-limbed randomized crossover study. Renal clearance of amantadine (13.2 +/- 5.8 L/hr) was significantly inhibited by quinine (9.7 +/- 4.8 L/hr) and quinidine (8.9 +/- 4.0 L/hr) only in male subjects and was not associated with age. The chiral selectivity for the renal clearance of quinidine over quinine was confirmed and extended with the suggestion of both age- and gender-associated changes on the renal clearance ratio for these two diastereomeric drugs. These data support the continued use of amantadine for studies on the renal elimination of organic cationic drugs.

Differing renal effects of activated and nonactivated isoelectric peaks of human prorenin in rats.

Isoelectric species of renin are physically heterogeneous. Recent evidence suggests that they may differ functionally, with some species producing natriuresis and diuresis, whereas others have no effect. A physiological function of secreted prorenin has not been documented in any species. The present study was designed to confirm and describe for the first time the renal effects of certain isoelectric species of prorenin. Anesthetized Sprague-Dawley rats were injected (0.1 ml) with trypsin-activated or nonactivated prorenin obtained from human ovarian follicular fluid. The dose chosen was calculated as sufficient to produce 2,300 ng angiotensin I.h-1.100 g rat body wt-1 in the presence of excess sheep substrate. Blood pressure, creatinine clearance, urine flow rate, and urine sodium, potassium, and osmolar excretion were measured. Activated prorenin from isoelectric peaks at isoelectric points (pI) 5.1, 5.2, 5.4, and 5.6 produced marked increases in urine volume (sixfold) and sodium excretion (7- to 10-fold) compared with the group receiving the vehicle (1% albumin in 0.9% saline). Activated prorenin from peaks at pI 4.9 and 5.8 produced no significant increase over the vehicle-only experiments. Captopril pretreatment (1 mg/kg iv) completely blocked the effects of peaks at pI 5.4 and 5.6. Interestingly, injection of nonactivated prorenin from peaks at pI 5.4 and 5.6 produced effects similar to the injection of activated prorenin from these peaks. Similarly, this effect was blocked by pretreatment with captopril. In summary, only certain isoelectric peaks of human prorenin whether activated, to active renin, or nonactivated produced a marked natriuresis and diuresis.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation and function of prorenin: different viewpoints.

This Symposium includes 15 presentations and an editorial review dealing with prorenin activation and function. It comes 20 years after prorenin was first reported in various contexts and attracted attention because of its connection with renin--angiotensin, its high concentration relative to renin in the blood, and its presence in extrarenal, as well as renal, tissues. Intriguing changes in plasma prorenin have been reported after treatment with antihypertensive and other drugs, following various physiological stimuli, and in pathophysiological states such as Wilms' tumor, Bartter's syndrome, and diabetic nephropathy. Lately, very high prorenin concentrations have been found in human and animal ocular fluid, ovarian follicular fluid, and in association with angiogenesis and microangiopathy. High circulating prorenin concentrations and fulminant hypertension have been reported in rats harbouring the mouse Ren-2 gene. However, what prorenin does in all these extrarenal fluids, tissues, and conditions is not well understood. Among the reasons for this lack of understanding are the difficulties in measuring prorenin and in establishing good animal models. We have not answered the critical question as to whether prorenin itself is bioactive like a hormone, and if so, what its action(s) might be. Nor have we established the main alternative, i.e., whether the function of prorenin is indirect, through renin--angiotensin, be it in the circulation or in the extrarenal tissues. This Symposium provides only partial methodological advances and answers, but we hope it will stimulate the breakthrough work needed to supply more complete answers.

Long-term captopril in young and old patients with mild hypertension.

The decrease in renal blood flow (RBF) observed in patients with hypertension can be increased with converting enzyme inhibition (CEI). It is unknown whether the decrease in RBF observed with age can also be increased with CEI. This study compared the short- and long-term effects of captopril monotherapy in young (less than 50 years) and old (greater than 65 years) hypertensive patients. Captopril effectively decreased blood pressure in both groups (diastolic blood pressure less than 90 mm Hg), with the young patients requiring a lower dose (.7 mg/kg) than the elderly patients (1.2 mg/kg). Creatinine and para-aminohippurate clearances were maintained in both groups, with a decrease in renal vascular resistance being observed in the younger patients. Serum aldosterone levels fell significantly after each dose of captopril at all phases of the study, with no change observed in plasma renin levels. Atrial natriuretic peptide (ANP) level was increased in the elderly patients receiving placebo (48.8 +/- 8 pg/mL) when compared with the young subjects (24 +/- 3.8 pg/mL). Captopril did not alter ANP levels in either group.

Isoelectric heterogeneity of human prorenin (inactive renin) in body fluids.

Using flat bed isoelectric focusing, inactive renins from various body fluids were compared. Normal plasma inactive renin demonstrated six consistent peaks at pH 4.98, 5.14, 5.29, 5.47, 5.63 and 5.91, the largest being 5.29, 5.47 and 5.63. The isoelectric pattern of ovarian follicular fluid inactive renin was similar, with slight shifts at major peaks to a higher pH. Pregnancy plasma had inactive renin patterns like normal human plasma as did pleural fluid, lymphocoele fluid and plasma from anephric humans. Amniotic fluid inactive renin showed a markedly different pattern with major peaks at pH 5.00, 5.16 and 5.30. Fetal plasma (cord blood) also showed differences with only four peaks at 5.24, 5.40, 5.58 and 5.83. We conclude that human prorenin isoelectric patterns are similar for plasma, ovarian and most tissue fluid prorenins, but different for fetal plasma and amniotic fluid suggesting that these forms of renin do not cross the placental barrier.

Atrial-specific granule number and plasma atrial natriuretic peptide in rats: effects of beta-adrenoceptor blockade and sodium intake.

An interrelationship between atrial natriuretic peptide (ANP) and the renin-angiotensin system has been established. Both of these hormonal systems are modulated by sodium balance. The role of the beta-adrenoceptor in the regulation of release of ANP is not clear. We therefore undertook a study to examine changes in atrial-specific granule number and plasma ANP level following beta-adrenoceptor blockade in rats on low and high sodium intakes. A low-sodium diet, as compared with a high-sodium diet, elevated right and left atrial-specific granule number (right atria 54.6 +/- 8.7 vs. 42.3 +/- 5.7; left atria 47.7 +/- 7.7 vs. 30.6 +/- 3.4 granules/unit area) and plasma renin activity (28 +/- 3.7 vs. 5.4 +/- 0.8 ng AI/ml/hr). Plasma ANP levels were lower in the low-sodium animals (98 +/- 34 vs. 345 +/- 38 pg/ml). When treated with the nonspecific beta-adrenoceptor blocker propranolol, the elevated plasma renin activity and atrial-specific granule number in rats on a low sodium intake were significantly less. Neither of these parameters changed in rats on a high sodium intake. Conversely, propranolol treatment resulted in lower plasma ANP levels in rats with high sodium intake. The already-suppressed plasma ANP level in rats on a low-sodium diet was unaltered with beta-adrenoceptor blockade. The results suggest that dietary sodium intake is an important determinant of the response of atrial-specific granule number and plasma ANP levels following beta-adrenoceptor blockade with propranolol.

Smoking, antihypertensive treatment benefit, and comprehensive antihypertensive treatment approach: some thoughts on the results of the International Prospective Primary Prevention Study in Hypertension.

Several major studies investigated the possibility of a primary preventive effect of beta-blockers. The International Prospective Primary Prevention Study in Hypertension (IPPPSH) compared a beta-blocker-containing vs. a non-beta-blocker-containing antihypertensive regimen in 6,357 moderate-severe hypertensive men and women treated over 3-5 years. Blood pressure (BP) control was comparable with either regimen. beta-Blocker treatment was associated with less hypokalemia, earlier electrocardiogram normalization, and fewer withdrawals for uncontrolled hypertension. In agreement with the Medical Research Council (MRC) trial on mild hypertension and the Heart Attack Primary Prevention in Hypertension (HAPPHY) trial, but at variance with the Primary Prevention Metoprolol in Patients with Hypertension (MAPHY) study, cardiac event rates were similar in beta-blocker- and non-beta-blocker-treated patients. With either regimen, in-study BP reduction was associated with a lower rate of stroke as well as of cardiac events. In a subgroup analysis, nonsmokers appeared to derive beta-blocker benefit, the results being similar to those of the MRC. Smokers required higher doses of drugs to achieve diastolic target pressure, had a higher heart rate and hematocrit, and a higher cardiac event rate than nonsmokers at any given level of diastolic pressure. Except for the MAPHY trial, these primary prevention studies do not support the concept of a cardiac primary preventive effect of antihypertensive beta-blockade but stress the importance of good BP control and a comprehensive risk factor prevention approach in the management of hypertensive patients.

Nadolol antihypertensive effect and disposition in young and elderly adults with mild to moderate essential hypertension.

Nadolol was effective and well tolerated as once-daily monotherapy for mild to moderate essential supine diastolic hypertension (SDBP) in 10 young (mean age, 39 years) and 12 elderly (mean age, 68 years) patients in a single-blind, placebo-baseline, escalating-dose study. Doses required to reduce SDBP to 90 mm Hg were not different in young (1.08 +/- 0.21 mg/kg/day) and elderly (0.82 +/- 0.14 mg/kg/day) patients (mean +/- SE). Trough plasma nadolol concentrations at steady state were similar and were linearly related to dose in both groups. More unchanged nadolol was recovered in 24-hour urine samples from young subjects (15.6% +/- 1.9%) than from elderly ones (10.7% +/- 1.1%) (p = 0.028). With increasing nadolol doses, plasma norepinephrine concentration increased and isoproterenol sensitivity decreased in both young and elderly subjects, and creatinine clearance and plasma active renin levels were unchanged; plasma inactive renin levels increased in the young, and aldosterone concentration declined in the elderly with the lowest nadolol dose.

Excessive burden of end-state renal disease among Canadian Indians: a national survey.

Analysis of data from the Canadian National Renal Failure Register indicates that Canadian Natives are at much higher risk for end-stage renal disease (ESRD) than the Canadian population in general. Using two population estimates for the total Native population, the age-standardized incidence rate of newly registered ESRD cases between 1981 and 1986 among Natives was at least 2.5 times (and may be as high as four times) the national rate. Natives were particularly at higher risk for ESRD to diabetes, glomerulonephritis, and pyelonephritis, whereas for the other causes the risk was no different from that of other Canadians. As technologically sophisticated treatment facilities are only available in major urban centers, Native ESRD patients and their families living in remote areas of Canada are faced with major psychosocial disruptions of relocation.

In vivo measurement of thromboxane B2 and 6-keto-prostaglandin F1 alpha in humans in response to a standardized vascular injury and the influence of aspirin.

The effects of smoking, aspirin ingestion, and sex differences on bleeding times and bleeding time thromboxane B2 and 6-keto-prostaglandin (PG)F1 alpha production were examined. Nonsmoking men produced more thromboxane B2 (3.99 +/- 0.76 ng/ml) than nonsmoking women (2.13 +/- 0.24 ng/ml). Female smokers produced more thromboxane B2 (5.01 +/- 0.97 ng/ml) than nonsmoking women. Twenty-four hours after a single dose of 600 mg aspirin, in vitro production of thromboxane B2 in response to collagen fell by 95%, whereas in vivo production of thromboxane B2 and 6-keto-PGF1 alpha in bleeding time blood fell by 87% and 66%, respectively. Subjects with the lowest absolute levels of thromboxane B2 24 hours after aspirin were also those with the longest postaspirin bleeding times. Recovery of 6-keto-PGF1 alpha production was faster than recovery of thromboxane B2 production, but 6-keto-PGF1 alpha production for most subjects was still below basal 72 hours after aspirin. The influence of two different doses of long-term aspirin (80 mg every other day and 325 mg daily) on the in vivo production of thromboxane B2 and 6-keto-PGF1 alpha was studied in normals and diabetics. After 14 days of 80 mg aspirin every other day, thromboxane B2 and 6-keto-PGF1 alpha production were both substantially inhibited (93% and 78%, respectively). After 14 days of 325 mg aspirin daily, thromboxane B2 production was similarly substantially inhibited (93%), whereas 6-keto-PGF1 alpha was significantly less affected (only 45% inhibition). Study of a second group of five normal subjects confirmed that 6-keto-PGF1 alpha production was significantly inhibited 24 hours after the first dose of 325 mg aspirin but was not significantly less than basal after 14 days of 325 mg aspirin. The results suggest that 325 mg aspirin daily is more antithrombotic compared with 80 mg every other day due to the superior preservation of prostacyclin production.

Transplantation in Manitoba.

1. Renal transplantation can be performed at small regional centers as successfully as at large centers. 2. Immunosuppression should be individualized for the patient thereby avoiding the use of costly and often clinically complicated immunosuppressive regimens. 3. Small centers need to participate in large regional pools in order to give highly presensitized patients a reasonable chance of successful transplantation. 4. Long-term patient compliance is a major problem and requires careful surveillance of patients' adherence to their prescribed therapy. Frequent follow-up also allows for the detection of late rejection episodes which can often be reversed.

Inactive renin and aldosterone in Bartter's syndrome.

Studies of plasma samples of 3 subjects with Bartter's syndrome were compared to 8 subjects with other conditions. Despite high levels of active renin initially, with low levels of inactive renin, addition of either human nephrectomized plasma or sheep substrate not only increased active renin (by at least 3-fold) but also led to the appearance of large quantities of inactive renin (10-20 times the concentration originally present, much greater than the small increase seen with other plasmas). The activated inactive renin after substrate addition possibly had a larger and more variable molecular size (42,000-48,000) than normal inactive renin (42,500-44,500). Renin substrate in Bartter's plasma was present in similar amounts and had a normal or supranormal angiotensin generation rate with exogenous human renin. Bartter's substrate had a similar molecular weight (55,000) to that found in normal human plasma. The agent in the exogenous substrate preparations causing the increase in apparent active and inactive renin was not ultrafiltrable. However, an acidification procedure that destroyed exogenous substrate also removed the renin-increasing effect. Captopril increased renin but not aldosterone, while amiloride increased aldosterone but not renin. Neither agent improved serum potassium significantly in these patients on indomethacin.

Inactive renin in peritoneal fluid of the cat: responses to acute stimuli which alter plasma renin.

Active and inactive renin in plasma and peritoneal dialysate were studied in pentobarbitone anesthetized cats during 8 hours of peritoneal dialysis. In control cats, despite a significant rise in plasma active renin from 1.3 +/- 0.22 to 4.4 +/- 0.76 pmoles AI/ml/hr over 8 hours, plasma inactive renin was unchanged. Four-fold rises in plasma active renin after hemorrhage (15 ml/kg) and captopril (1 mg/Kg I.V.) were unaccompanied by significant change in inactive renin. Bilateral nephrectomy resulted in undetectable plasma active renin after 3 hours but plasma inactive renin was 25-30% of initial levels 6 hours post-nephrectomy. In peritoneal dialysate, active renin remained low in control cats but there was a ten-fold rise of inactive renin from 0.06 +/- 0.02 to 0.60 +/- 0.07 pmoles AI/ml/hr. After hemorrhage there was a slight rise of active renin after 3 and 4 hours. Inactive renin was lower than control 6 hours after nephrectomy and captopril, but higher than control 1 and 2 hours after hemorrhage. Dialysate inactive renin accumulation slopes were not different among treatments. Acute changes in plasma active renin have little effect on peritoneal dialysate renin.

Active and inactive renin in the cat.

Pentobarbitone-anesthetized cats underwent peritoneal dialysis and had blood samples removed and kidneys deep frozen at sacrifice. Inactive renin is easily measurable in cat plasma and peritoneal dialysate fluid. Only small amounts are found after acid activation at pH 4.0, but large amounts after trypsin 2 mg/ml at 4 degrees C for 10 minutes. Mean active renin in pentobarbitone-anesthetized cats was 1.8 +/- 0.4 pmoles AI/ml/hr, while inactive renin was 2.3 +/- 0.5 pmoles AI/ml/hr. The increased angiotensin I producing activity after trypsin in peritoneal dialysate was most active at pH 7.0 (plasma and kidney active renin 7.25 and 7.85), and had an apparent molecular weight of 39-40,000. (Plasma active renin had an apparent MW of 33,500 and kidney active renin 36,000. Plasma inactive renin had an apparent MW of 35,500) Cat plasma after cibacron-blue affinity chromatography showed mainly active renin in the breakthrough buffer (30% of total renin eluted), and renin which is almost entirely inactive in the bound peak (70% of total renin eluted). Active renin from plasma and kidney, and activated inactive renin from concentrated peritoneal fluid, showed exactly similar inhibition by the renin inhibitor H77 (IC50 0.3 microM). Cat plasma angiotensinogen had an apparent MW of 53,000.