Elevated Plasma Renin Activity Research Articles

The renin-angiotensin system during pregnancy in chronically instrumented, conscious rats

Whether the renin-angiotensin system is activated during rat gestation is controversial. Therefore we serially assessed plasma renin activity in unrestrained, chronically instrumented conscious rats during pregnancy and the postpartum period. Plasma renin activity was 3.26 ± 0.30, 2.80 ± 0.31, and 2.70 ± 0.26 ng · ml -1 · hr -1 on gestational days 6, 12, and 20, respectively. When the same rats were studied after delivery, plasma renin activity was 1.87 ± 0.29, 1.81 ± 0.09, and 2.31 ± 0.35 ng · ml -1 · hr -1 on postpartum days 3, 6, and 11, respectively. Levels measured during pregnancy were significantly greater than in the postpartum period (p<0.05 or <0.01 ). We then evaluated potential functional consequences of the renin-angiotensin system in gravid rats. Near term, renal hemodynamics fall from the peak levels of midgestation; we tested whether angiotensin II mediates this apparent vasoconstriction. Captopril (1.5 mg/kg, 1.5 mg · kg -1 · hr -1) was acutely administered to lower circulating angiotensin II. The drug produced an 80% inhibition of angiotensin I pressor response, a tenfold elevation in plasma renin activity, but caused the same degree of mild renal vasodilation in rats whether they were virgin or pregnant. We also tested whether prior occupancy of receptors by endogenous hormone or receptor downregulation mediates the attenuated pressor response to angiotensin II observed during late pregnancy. Acute administration of captopril failed to augment refractory pressor responsiveness. Chronic treatment with enalaprilat (2.0 mg · kg -1 · day -1 by osmotic minipump) also did not restore pressor responsiveness. But, in our hands, chronic administration of enalaprilat most likely failed to lower plasma angiotensin II. In summary, we suggest that during rat gestation (1) the renin-angiotensin system is activated, (2) angiotensin II does not mediate the apparent renal vasoconstriction observed near term, (3) prior receptor occupancy by endogenous hormone is not responsible for the attenuated pressor response to angiotensin II, and (4) long-term treatment with enalaprilat can produce hypotension without reducing plasma concentrations of angiotensin II.

Calcitonin gene-related peptide is an inhibitor of aldosterone secretion.

This study examined the effects of calcitonin gene-related peptide (CGRP) on aldosterone secretion both in vivo and in vitro. Intravenous administration of CGRP (0.01 micrograms/kg) in 6 conscious dogs produced a significant decrease in plasma aldosterone concentration from 68 +/- 12 pg/ml to 28 +/- 11 pg/ml (p less than 0.05) despite a mild but significant elevation of plasma renin activity. In an in vitro study using isolated rabbit adrenal glomerulosa cells CGRP reduced the basal aldosterone secretion in a dose-related manner and furthermore 10(-9) M CGRP inhibited the aldosterone secretion stimulated by 10(-8) M angiotensin II. From these results it is suggested that CGRP has an inhibitory effect on aldosterone secretion.

Arterial Hypertension as a Paraneoplastic Phenomenon in Hepatocellular Carcinoma

Three South African blacks with hepatocellular carcinoma and arterial hypertension are described. Plasma angiotensinogen (renin substrate) concentrations were increased eightfold to 10-fold in the two patients in whom these concentrations were measured. One of these two patients also showed a 34-fold rise in plasma inactive, active, and total renin concentrations, and an elevated plasma renin activity (2.73 ng.L-1.s-1 angiotensin l/mL/h). Inactive renin (prorenin) constituted 90% of the total plasma renin concentration. In the third patient only plasma renin activity was measured, and this was considerably raised (6.05 ng.L-1.s-1; angiotensin l/mL/h). Thus, the arterial hypertension that rarely complicates hepatocellular carcinoma may be caused either by a combination of eutopic synthesis of excessive quantities of angiotensinogen and ectopic production and secretion of active renin by malignant hepatocytes, or by eutopic production of angiotensinogen alone.

Mechanisms of hypertension during and after orthotopic liver transplantation in children

The aim of this study was to assess the hormonal alterations that may mediate the systemic hypertension that develops in patients during the perioperative period of orthotopic liver transplantation. We studied nine pediatric patients without previous hypertension or renal disease during six time points, starting before transplantation and ending at 48 hours after surgery. Hypertension developed in all patients in association with central venous pressures less than 10 mm Hg. Free water clearance was negative in all nine patients. Vasopressin levels increased intraoperatively but fell as hypertension developed. Atrial natriuretic factor levels increased as systemic blood pressure rose. A high level of plasma renin activity was observed in four patients with renal insufficiency. In six patients, postoperative 24-hour urinary norepinephrine excretion was within the normal age-adjusted range. These findings suggest that the combination of cyclosporine, corticosteroids, and, in some patients, an elevated plasma renin activity prevents the kidney from responding to the acute volume and salt overload with an appropriate diuresis and natriuresis, thus leading to systemic hypertension. The treatment of hypertension after liver transplantation may include salt restriction, diuretics, and, in those patients with a low creatinine excretion index, angiotensin coverting enzyme inhibitors.

Favorable outcome of neonatal aortic thrombosis and renovascular hypertension

Fifteen children with renovascular hypertension as a result of aortic thrombosis were followed for a mean of 26 months (range 5 to 58 months) to determine outcome. As neonates, all patients had hypertension and elevated plasma renin activity. Of 11 patients studied with radionuclide renography and scintigraphy, 10 had abnormal renal blood flow; three had complete absence of unilateral perfusion. On follow-up examination all children were normotensive; five children ages 5 to 24 months required antihypertensive medication. Of 15 children, 14 had normal statural growth; all had normal serum creatinine, plasma renin activity, and calculated glomerular filtration rate values. Patients with complete absence of renal perfusion unilaterally remained functionally anephric; children with less severe perfusion deficits had improved perfusion as shown by radionuclide renography and scintigraphy. We believe that many patients with aortic thrombosis and renovascular hypertension who have had aggressive antihypertensive therapy in the neonatal period will have good renal function and increased perfusion to the affected kidney 2 years later.

Activity of the Unstimulated Renin—Angiotensin—Aldosterone System in Type 1 Diabetic Patients with and without Proteinuria

There have been conflicting reports of the activity of the renin-angiotensin-aldosterone system in diabetes. We studied the activity of the unstimulated renin-angiotensin-aldosterone system in 73 consecutive Type 1 diabetic patients with varying degrees of albuminuria. Patients with elevated albumin excretion rates had elevated median plasma renin activity (macroalbuminuric 2.2, range 0.5-8.2, p less than 0.05; microalbuminuric 2.3, 0.7-7.1, p less than 0.001; vs normoalbuminuric 1.0, 0.2-4.5 nmol l-1 h-1) and higher systolic blood pressure (macroalbuminuric 141 +/- 27 vs normoalbuminuric 116 +/- 13 mmHg, mean +/- SD, p less than 0.01) compared with those with normal albumin excretion rates. Aldosterone secretion and function were normal in all patients studied.

Hypertension in Primary Glomerulonephritis Without Renal Insufficiency

Hypertension is frequently present in glomerulonephritis without renal insufficiency but its pathogenesis is poorly understood. Eighty-five patients with glomerulonephritis and normal renal function, including 55 hypertensive patients, and 24 normal subjects were studied to obtain data on the mechanisms responsible for hypertension. Plasma renin activity (PRA), plasma noradrenaline, total exchangeable sodium, and urinary prostaglandin E (PGE) were determined. Moreover, the autonomic nervous system was explored with the following tests: tilt test, diving reflex, lying down, and deep-breathing tests. In 15 of the 30 normotensive patients with glomerulonephritis, PRA was measured after the administration of propranolol and then indomethacin. No significant differences were found in the mean values of PRA, plasma noradrenaline, total exchangeable sodium, urinary PGE, and autonomic nervous system behaviour between glomerulonephritis patients with and without hypertension or between hypertensive glomerulonephritis patients and control subjects. In many of the normotensive glomerulonephritis patients we found an elevated PRA that was normalised by propranolol but not by indomethacin. In summary, hypertension in glomerulonephritis is not associated with abnormalities in the sodium balance, with renin-angiotensin or with autonomic nervous system abnormalities. A renin hypersecretion seems to be present only in some normotensive patients with glomerulonephritis.

162 SEVERE HYPOLADOSTERONISM DUE TO CORTICOSTERONE METHYL OXIDASE TYPE II (CMO II) DEFICIENCY IN 2 BOYS: METABOLIC AND GAS CHROMATOGRAPHY/MASS SPECTROMETRY (CC-MS) STUDIES

Infection-triggered life-threatening salt loss and hyperkalemia developed in 2 male infants with dystrophy, inappropiately low plasma aldosterone concentrations and elevated plasma renin activity. Sodium supplementation but not short-term high dose oral 9α-fluorcortisol (FF) did revert hyponatremia in one boy (Pat.A) The other boy (Pat.B) is growing normally on a high sodium diet and oral FF (0.1 mg/d). Diagnosis of a defective terminal step of aldosterone biosynthesis was confirmed by measuring urinary excretion of specific mineralocorticoid metabolites:Unknown steroids as candidates responsible for the salt loss could not be identified by GC-MS. In conclusion, CC is mandatory in all cases of unexplained salt loss in infancy and childhood. Short-term response to exogenous mineralocorticoids may not be diagnostic in distinguishing pseudohypoaldosteronism from defects in mineralocorticoid synthesis. (THA: 11-dehydrotetrahydrocorticosterone, a-THB: allo-tetrahydrocorticosterone, C-M: Cortisol metabolites)

Evolving concepts of the renin-angiotensin system. Focus on renal and vascular mechanisms.

The traditional concept of the renin-angiotensin system (RAS) is a circulation-borne endocrine system, the components of which are secreted by various organs. The product of this biochemical cascade, angiotensin II, acts on specific receptors on multiple target organs. Activation of this circulating system has been shown to result in vasoconstriction and hypertension. In addition to this endocrine system, evidence is emerging that the renin-angiotensin system also exists at multiple local tissue sites. Recent data demonstrating that inhibitors of the RAS are capable of lowering blood pressure in the presence of suppressed as well as elevated plasma renin activity (PRA) have given rise to the hypothesis that these inhibitors exert a large part of their effect on angiotensin that is synthesized by and contained in local tissues. The concept implies that local angiotensin concentrations may exceed those of plasma levels and may play an important role in the tonic control of vascular resistance, cardiac and adrenal functions, and intrarenal events. The hypothesis could explain the broad spectrum of activity of angiotensin-converting enzyme (ACE) inhibitors in hypertensives as well as their continuing antihypertensive activity after plasma ACE levels have been restored.

Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis

It has recently been shown that repeated large-volume paracentesis associated with intravenous albumin infusion is a rapid, effective, and safe therapy of ascites in cirrhosis. To investigate whether intravenous albumin infusion is necessary in the treatment of cirrhotics with large-volume paracentesis, 105 patients with tense ascites were randomly allocated into two groups. Fifty-two patients (group 1) were treated with paracentesis (4–6 L/day until disappearance of ascites) plus intravenous albumin infusion (40 g after each tap), and 53 (group 2) with paracentesis without albumin infusion. After disappearance of ascites, patients were discharged from the hospital with diuretics. Patients developing tense ascites during follow-up were treated according to their initial schedule. Paracentesis was effective in eliminating the ascites in 50 patients from group 1 and in 48 from group 2, with the duration of the hospital stay being ~11 days in both groups. Paracentesis plus intravenous albumin did not induce significant changes in standard renal function tests, plasma renin activity, and plasma aldosterone. In contrast, paracentesis without albumin was associated with a significant increase in blood urea nitrogen, a marked elevation in plasma renin activity and plasma aldosterone concentration, and a significant reduction in serum sodium concentration. One patient from group 1 and 11 from group 2 developed renal impairment or severe hyponatremia after treatment, or both (χ2 = 9.19; p < 0.01). The development of these complications could not be predicted by clinical and laboratory data before treatment. Although the probability of survival after entry into the study was similar in patients from both groups, a multivariate analysis identified the development of hyponatremia or renal impairment, or both, following the first paracentesis treatment and the occurrence of other complications during the first hospitalization (encephalopathy, gastrointestinal bleeding, and severe infection) as being the only independent predictors of mortality. These results indicate that intravenous albumin infusion is important in avoiding renal and electrolyte complications and activation of endogenous vasoactive systems in cirrhotics with ascites who are treated with repeated large-volume paracentesis. The development of such complications may impair survival in these patients.

Nephrotoxicity of continuous intravenous infusion of recombinant interleukin-2

Adoptive immunotherapy with recombinant interleukin-2 has been complicated by significant nephrotoxicity of uncertain etiology. Creatinine clearance, effective renal plasma flow, plasma renin activity, aldosterone levels, and urinary prostaglandin excretion were evaluated in a 62-year-old man receiving continuous infusion recombinant interleukin-2. There was a marked decrease in the creatinine clearance and renal plasma flow, accompanied by an elevation in plasma renin activity and aldosterone level. Prostaglandin excretion also decreased, implying a direct effect on renal prostaglandin synthesis. The decrease in renal prostaglandin synthesis at a time of increased plasma renin activity may explain the reduction in renal function seen with recombinant interleukin-2 therapy.

Alterations in erythrocyte Na+,K+-cotransport in normal and hypertensive human pregnancy

Many physiological variables known or thought to affect erythrocyte Na+,K+-cotransport are altered in pregnancy. The interrelationships of Na+,K+-cotransport and pregnancy were therefore examined. Values were elevated by more than 30% in both second and third trimesters with a return towards non-pregnant levels in the postpartum period. Although pregnancy was also associated with elevated plasma cholesterol, renin activity and aldosterone, there was no significant relationship within the pregnant group between Na+,K+-cotransport and any of these factors. No change could be demonstrated in Na+,K+-cotransport values after 7 days of either high (greater than 250 mmol/day) or low (less than 50 mmol/day) sodium intake and values for those who developed pregnancy-associated hypertension (PAH, pre-eclampsia) were not significantly different from those in continuously normotensive women in either the second or the third trimesters of pregnancy.

The Antihypertensive Effects of Calcium Channel Blockade

To study the relation of calcium channel blockade to sodium and calcium metabolism, we measured blood pressure (BP), serum ionized calcium (Ca-io), plasma renin activity (PRA), and 1,25-dihydroxy-vitamin D (1,25D), before and after administration of nitrendipine to essential hypertensive (EH) outpatients on both low and high dietary salt intakes, and on fixed (10 mg b.i.d.) and titrated dose (10-30 mg b.i.d.) schedules. Nitrendipine lowered BP (% delta DBP = -14.9 +/- 3 vs. 1 +/- 3.5, p less than 0.001) and raised Ca-io (0.08 +/- 0.04 vs. -0.04 +/- 0.05 mEq/L, p less than 0.05) in salt-sensitive (SS) but not salt-insensitive (SI) subjects. % delta DBP was related to PRA (r = 0.69, p less than 0.001), to the rise in Ca-io (r = -0.63, p less than 0.01), and to the suppression of circulating 1,25D (r = 0.80, p less than 0.001). Similarly, at doses (10-30 mg b.i.d.) titrated to achieve normotension, nitrendipine uniformly elevated PRA (1.4 +/- 0.3 to 3.5 +/- 0.7 ng/ml/h, p less than 0.05) and Ca-io (2.34 +/- 0.02 to 2.44 +/- 0.02 mEq/L, p less than 0.05). We conclude that the antihypertensive efficacy of nitrendipine appears greatest among SS and lower renin patients, and is related to the drug's ability to alter calcium metabolism. The state of calcium metabolism may thus underlie the sensitivity to calcium blockade and may contribute to its effects.

Male pseudohermaphroditism due to nonsalt-losing 3β-hydroxysteroid dehydrogenase deficiency: Gender role change and absence of gynecomastia at puberty

Adrenal and gonadal functions were evaluated on two adult cousins with male pseudo-hermaphroditism due to congenital 3β-hydroxysteroid dehydrogenase deficiency (3β-HSD) without clinical salt-losing. Both patients had been reared as females since birth. Case 1 presented at age 17 with perineal hypospadias virilization without gynecomastia and a female to male gender role change at puberty. Case 2 had previously undergone bilateral orchidectomy in childhood and presented “primary amenorrhea”, absence of virilization and a female gender role at the age of 24. In the basal state, as well as after ACTH and hCG stimulation, 3β-hydroxy-5-ene-steroid levels were disproportionately elevated, resulting in abnormal 3β-hydroxy-5-ene: 3-oxi-4-ene steroids ratios. Normal basal serum cortisol with inadequate cortisol response to ACTH was observed in both patients. Elevated basal plasma renin activity (PRA) and normal basal serum aldosterone (ALDO) were present in both subjects. After ACTH stimulation serum ALDO rose adequately in Case 1 but subnormally in Case 2. Salt restriction resulted in an increase in serum ALDO and no salt loss in Case 1 whereas in Case 2 the substantial rise in PRA and serum ALDO were unable to prevent slight urinary sodium loss. Case 1 had normal basal serum testosterone with subnormal response to hCG stimulation. Incubation of testicular tissue in vitro with [ 3H]HEA resulted in large Androstenediol production but diminished testosterone conversion confirming the 3β-HSD deficiency in the testes. We conclude that (1) absence of gynecomastia and a female to male gender role change may be observed in the male pubertal presentation of nonsalt-losing 3β-HSD deficiency and (2) the different functional behavior of zona glomerulosa in our patients suggests the presence of variable degrees of 3β-HSD deficiency in the zona glomerulosa of the nonsalt-losing form.

Hormonal and renal responses to converting enzyme inhibition during maximal exercise

The role of angiotensin II in the hormonal and renal responses to maximal exercise was investigated by using the angiotensin-converting enzyme inhibitor captopril. Nine male subjects performed a standardized maximal treadmill test with and without acute captopril treatment (25 mg orally). At rest, captopril elevated plasma renin activity and lowered aldosterone levels. With maximal exercise, captopril treatment reduced the increase in mean arterial blood pressure by 8 mmHg and the increase in plasma renin activity by 3.0 ng ANG I.ml-1.h-1. The responses of adrenocorticotropin (ACTH), cortisol, and vasopressin to maximal exercise were not altered by captopril treatment. Although aldosterone levels were reduced at rest with captopril, during maximal exercise no difference was noted between treatments. Captopril treatment had no effects on the renal handling of salts or water during exercise. In conclusion, angiotensin II plays a role in the increase in mean blood pressure during maximal exercise in normal subjects but has no effect on the exercise responses of ACTH, vasopressin, and aldosterone or on the renal handling of salts and water.

Inhibition of Captopril-Induced Renin Release by Angiotensin II

The angiotensin-converting enzyme inhibitor (CEI) captopril has been shown to elevate plasma renin activity (PRA) and prostaglandin E2 levels, and to lower blood pressure and angiotensin II (AII) levels. Renin is secreted in both active and inactive forms; however, the interrelationship of these forms and responses to captopril are unclear. We proposed to determine if PRA rise induced by captopril is due primarily to release from AII inhibition, and if inactive renin is converted to active renin when PRA increases. Seven normal volunteers were given captopril, 50 mg orally, while on a moderately sodium-restricted diet (35 mEq/day). Changes in PRA and total and inactive renin, as well as prostaglandin E2, were measured. Then, on two different occasions, the captopril dose was preceded or followed by infusion of AII, to negate changes in AII induced by CEI. The dose of AII was obtained by dose-response infusion until a minimal increase in blood pressure occurred. Active renin increased with captopril alone, from 8.2 to 48.3 ng/ml/h by 90 min (p less than 0.01). AII completely blocked the rise in PRA induced by captopril, whether given before or after captopril. Inactive renin did not decline as active renin increased over the 90-min study. Therefore, the PRA rise induced by captopril is mediated through a fall in AII levels and loss of feedback on renin-secreting cells. The rise in PRA comes from secretion of active renin rather than conversion from inactive renin.

Identification of hyponatremia as a risk factor for the development of functional renal insufficiency during converting enzyme inhibition in severe chronic heart failure

To identify patients with severe chronic heart failure who are at greatest risk of developing functional renal insufficiency during converting enzyme inhibition, creatinine clearance was measured in 59 patients before and after long-term therapy with captopril (39 patients) or enalapril (20 patients), while digitalis and diuretic therapy was kept constant. Creatinine clearance increased or remained constant in 33 of the 59 patients (Group I), but declined in the remaining 26 patients (Group II). The two groups were similar with respect to the cause of heart failure, pretreatment renal function and all pretreatment hemodynamic variables. Patients in Group II, however, had lower values for serum sodium concentration (134.8 +/- 1.0 versus 137.0 +/- 0.6 mmol/liter) and higher values for plasma renin activity (10.6 +/- 3.4 versus 3.0 +/- 0.5 ng/ml per hour), received larger doses of furosemide (108 +/- 11 versus 84 +/- 6 mg/day), were more frequently diabetic (42 versus 15%) and were more frequently treated with enalapril (50 versus 21%) than were patients in Group I (all p less than 0.05). By stepwise logistic analysis, only hyponatremia (or an elevated plasma renin activity) and enalapril therapy independently predicted the decline in creatinine clearance during converting enzyme inhibition. These observations could not be explained by changes in systemic blood pressure. In patients with a normal serum sodium concentration (greater than or equal to 137 mmol/liter), creatinine clearance increased with captopril (+21%, p less than 0.05), but not with enalapril (-6%, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Parabrachial lesions increase plasma norepinephrine concentration, plasma renin activity and enhance baroreflex sensitivity in the conscious rat

Electrolytic lesions of the parabrachial nucleus (PBN) caused significant increases in basal plasma renin activity (+433%) and basal plasma norepinephrine concentration (+98%) in conscious rats. Plasma epinephrine concentration, mean arterial pressure, heart rate, hematocrit, plasma osmolality and plasma sodium and potassium concentrations were not significantly affected by the lesions. Atenolol reduced the elevated plasma renin activity in the lesion group to a value similar to that of a control group (sham lesions or lesions in areas adjacent to the PBN). Captopril significantly lowered mean arterial pressure in the lesion group, but it had no effect on arterial pressure in the control group. Lesions of the PBN also increased the baroreflex-mediated bradycardia evoked by an abrupt elevation of arterial pressure. We propose that the PBN tonically inhibits sympathetic activity, sympathetically mediated renin release and baroreflex sensitivity.

Hemodynamic, renal, and hormonal responses to alpha-human atrial natriuretic peptide in patients with congestive heart failure.

Hemodynamic, renal, and hormonal effects of intravenous bolus injection of 50 micrograms synthetic alpha-human atrial natriuretic peptide (alpha-hANP) were studied in eight patients with congestive heart failure. alpha-hANP caused significant reductions in mean blood pressure and systemic vascular resistance. These responses were sustained up to 90 minutes and not accompanied by reflex tachycardia. Cardiac index and stroke volume index increased significantly at 90 minutes and pulmonary capillary wedge pressure, pulmonary arterial pressure, and mean right atrial pressure remained unchanged. Urine volume, urinary sodium excretion, creatinine clearance, and fractional excretion of sodium increased significantly, but fractional excretion of potassium and phosphate did not change. Elevated plasma renin activity, plasma aldosterone, and norepinephrine were suppressed after the injection of alpha-hANP. The bolus injection of this peptide has moderately hypotensive, vasorelaxant, and natriuretic effects in patients with congestive heart failure.

Direct correlation between plasma renin activity and severity of the ovarian hyperstimulation syndrome

Plasma renin activity (PRA) and aldosterone were measured throughout the luteal phase in 21 anovulatory patients who developed ovarian hyperstimulation syndrome (OHSS) during menotropin induction of ovulation. The pattern of PRA in hyperstimulated cycles is characterized by a midluteal peak, which declines to normal in the late luteal phase in nonconceptual cycles, whereas a sustained elevation of PRA occurs in conceptual cycles. Midluteal PRA is significantly (P less than 0.001) elevated in patients with OHSS compared with controls. In the mild form of the disease, the median of PRA is 7.5 (range 6 to 11) ng angiotensin I (AI)/ml/hr, significantly higher than the median for controls, 3.0 ng AI/ml/hr (range, 1.4 to 5). In moderate OHSS, PRA was 24.5 (range, 10 to 40) ng AI/ml/hr, whereas, in the severe form of OHSS, PRA was 55.0 (range, 29 to 95) ng AI/ml/hr. A significant correlation (P less than 0.05) was demonstrated between PRA and either progesterone or 17 beta estradiol (E2). The renin-angiotensin cascade is implicated in new vessel formation. Angiogenesis itself is associated with a rapid increase in capillary permeability. The recent demonstration of high plasma renin-like activity in human follicular fluid and the present observation of high PRA in patients with OHSS may imply that the locally active renin angiotensin system, through induction of new vessel formation and increase in capillary permeability, may have a casual relationship to the ovarian enlargement and extracellular fluid accumulation that are the hallmarks of OHSS.