Spleen phenotype in autosomal dominant polycystic kidney disease.

AIM: To evaluate splenic phenotype in autosomal dominant polycystic kidney disease (ADPKD) including presence of cysts and splenomegaly to determine if these are ADPKD related or represent unrelated incidental findings. MATERIALS AND METHODS: The axial/coronal T2-weighted images of ADPKD patients (n=215) and age/gender-matched controls (n=215) were evaluated for the presence of T2-bright splenic lesions by three blinded observers. Spleen volume (SV) was evaluated in the context of clinical and imaging features as well as results of gene testing for PKD1 and PKD2 mutations. RESULTS: T2-bright splenic lesions were found in 16 of 215 (7%) ADPKD patients compared to 11 of 215 (5%) control patients (p=0.32) and their prevalence was similar in patients with either PKD1 or PKD2 mutations. Median SV was significantly higher in ADPKD patients than controls (236 [182; 313 ml] versus 176 [129; 264 ml], p<0.0001). In multivariable analysis, height-adjusted SV (htSV) was not associated with the presence of liver cysts, haemorrhagic cysts, or infections; however, htSV was directly associated with height-adjusted total kidney volume (htTKV), a biomarker for ADPKD disease severity. CONCLUSIONS: The prevalence of T2-bright splenic lesions is similar in ADPKD patients and non-ADPKD controls, suggesting no relation to the diagnosis of ADPKD; however, splenic enlargement in ADPKD compared to controls could not be explained by liver cystic involvement, by infection/inflammatory conditions, or by haemorrhagic renal cysts. This combined with direct correlation of htSV with htTKV, a biomarker of ADPKD severity, suggests splenomegaly may be related to the pathogenesis of ADPKD.

Management of hypertensive crises: the scientific basis for treatment decisions.

The spectrum of disorders associated with an elevated blood pressure (BP) encompasses chronic uncomplicated hypertension and the hypertensive crises, including hypertensive urgencies and emergencies. Although these syndromes vary widely in their presentations, clinical courses, and outcomes they share pathophysiologic mechanisms and, consequently, therapeutic responses to specifically targeted antihypertensive drug types. Nevertheless, hypertensive crises are often treated with drugs which, in that setting are either unsafe or are of unsubstantiated efficacy. The purpose of this review is to examine the pathophysiology of commonly encountered hypertensive crises, including stroke, hypertensive encephalopathy, aortic dissection, acute pulmonary edema, and preeclampsia-eclampsia and to provide a rational approach to their treatment based upon relevant pathophysiologic and pharmacologic principles. Measurement of plasma renin activity (PRA) level often provides insight regarding pathophysiology and predicts efficacy of antihypertensive treatments in the individual patient. However, in hypertensive crises, drug therapy is initiated before the PRA level is known. Nevertheless, the renin-angiotensin dependence (R-type) or volume dependence (V-type) of hypertension can often be deduced by the BP response to drugs that interrupt the renin system (R-drugs) or that decrease body volume (V-drugs). Based upon these considerations, a treatment algorithm is provided to guide drug selection in patients presenting with a hypertensive crisis.

Renin system activation and delayed function of the renal transplant.

Delayed graft function (DGF), defined as persistent renal failure that requires dialysis within the first week after kidney transplantation, occurs commonly after cadaveric renal transplantation (CRT). This has important implications for long-term outcome because the 1-year allograft survival rate is significantly reduced when DGF occurs. The mechanisms contributing to the development of DGF are not well established. However, several lines of evidence indicate that excess renin system activity, in both the cadaver kidney donor and recipient, contributes importantly to the pathogenesis of DGF. If this hypothesis can be verified in clinical studies, then pharmacologic agents that interrupt the renin-angiotensin system (eg, type 1 angiotensin II receptor blockade, angiotensin converting enzyme inhibition, and beta-adrenergic blockade) in the donor and recipient might significantly improve the outcome of cadaveric renal transplants.

Plasma renin activity in the emergency department and its independent association with acute myocardial infarction.

Elevated plasma renin activity (PRA) is associated with increased risk of future myocardial infarction (MI) in ambulatory hypertensive patients. The present study evaluated the relationship of PRA to the diagnosis of acute MI in patients presenting to an emergency department with suspected acute MI. PRA was measured upon entry to the emergency department, before any acute treatment, as part of the standard evaluation of 349 consecutive patients who were hospitalized for suspected MI. Diagnosis of acute MI was confirmed in 73 patients, and ruled out in 276. They did not differ in age (65.9 +/- 2 v 66.1 +/- 1 years), systolic (143 +/- 4 v 140 +/- 2 mm Hg), or diastolic (81 +/- 2 v 81 +/- 1 mm Hg) pressures. Median PRA was 2.7-fold higher in acute MI (0.89 v 0.33 ng/L/s; P < .001). In a multivariate analysis controlling for other cardiac risk factors and prior drug therapy, PRA as a continuous variable was the predominant independent factor associated with acute MI (P < .0001), followed by white race (P = .002) and history of hypertension (P = .047). The height of the PRA level upon entry to the emergency department was directly and independently associated with the diagnosis of acute MI. These new findings extend earlier reports because they encompass acute MI patients, include both hypertensive and normotensive patients, and control for potentially confounding variables. Based on these observations, a randomized clinical trial is warranted to determine whether measurement of PRA in acute MI could refine the process by which treatments are applied.

Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects.

Although beta-adrenergic-blocking drugs suppress the renin system (RAAS), plasma angiotensin II (Ang II) responses during beta-blockade have not been defined. This study quantifies the effects of beta-blockade on the RAAS and examines its impact on prorenin processing by measuring changes in the ratio of plasma renin activity (PRA) to total renin. In normotensive (N = 14) and hypertensive (N = 16) subjects, blood pressure (BP), heart rate, PRA, plasma prorenin, plasma total renin (prorenin + PRA), ratio of PRA to total renin (%PRA), plasma Ang II, and urinary aldosterone were measured before and after 1 week of beta-blockade. Plasma renin activity, Ang II, and urinary aldosterone levels were similar for normotensive and hypertensive subjects. Plasma renin activity correlated with Ang II. Total renin, which is proportional to (pro)renin gene expression, was lower in hypertensive subjects and was inversely related to BP. Beta-blockade decreased BP and heart rate in both groups, with medium- and high-renin hypertensive subjects responding more frequently than those with low renin. Beta-blockade consistently suppressed PRA, Ang II, and aldosterone. Total renin was unchanged, thus, %PRA fell. These results indicate that beta-blockers suppress plasma angiotensin II levels, in parallel with the marked reductions in PRA and urinary aldosterone levels in normotensive and hypertensive subjects. The suppression of Ang II levels was comparable to that produced during angiotensin converting enzyme (ACE) inhibition. However, by reducing prorenin processing to renin, beta-blockers do not stimulate renin secretion, unlike ACE inhibitors and Ang II receptor antagonists. This unique action of beta-blockers has important implications for the treatment of cardiovascular disease.

Diagnosis and treatment of primary aldosteronism.

Disorders of the adrenal cortex and medulla are often associated with hypertension, which can be cured surgically in many cases or may require specific and timely medical treatments. Therefore, knowledge of adrenal physiology, biochemistry, and molecular biology is essential such that an appropriate diagnostic evaluation can be conducted efficiently. The most common hypertensive disorder of the adrenal cortex is primary aldosteronism. Aldosterone-producing adenoma is the most common form of primary aldosteronism and is most likely to be cured by unilateral adrenalectomy when aldosterone production is highly autonomous from renin-angiotensin, lateralizes to one adrenal gland, and is associated with overproduction of 18-hydroxycortiocosterone and C18-methyloxygenated metabolites of cortisol. Variants of adrenal hyperplasia that share these characteristics can also be cured by unilateral adrenalectomy.

Exercise renography in untreated subjects with essential hypertension.

UNLABELLED: Exercise induced renal dysfunction is reported to occur in treated hypertensive patients but not seen normotensive subjects. It is unclear if this phenomenon is related to the disease or to treatment. METHODS: Four normal volunteers and 15 hypertensive subjects (antihypertensive medications were discontinued for more than 4 wk) were studied with upright radionuclide renography at rest and during bicycle exercise. The amount of exercise was sufficient to increase the heart rate at least 20 bpm above the resting value. All subjects were healthy, without evidence of left ventricular hypertrophy renal disease or hypertensive retinal disease. BUN, serum creatinine concentration and urinalysis were normal in all subjects. Renograms were performed for 12-15 min after injection of either 1 mCi[123]orthoidohippurate (OIH) or 2-7 mCi 99mTc-mercaptoacetyltriglycine (MAG3). Visual analysis and mean transit time calculation were performed on the rest and exercise studies. RESULTS: Seven of 14 hypertensive subjects and none of the normal volunteers demonstrated abnormal prolongation in renal transit during exercise which was not seen on the resting renogram. Four of these seven subjects had a history of hypertension for 2 yr or less. CONCLUSION: About 50% of individuals with mild-to-moderate hypertension and normal renal function may have abnormal renal transit of renal excretion agents during exercise, although their baseline studies are normal. This finding is unassociated with therapy and appears to be related directly to the pathophysiology of essential hypertension.

Diagnosis and treatment of primary hyperaldosteronism.

OBJECTIVE: To characterize the clinical and laboratory features of primary aldosteronism and to evaluate which diagnostic tests can discriminate surgically curable forms of this syndrome. DESIGN: Retrospective analysis of the following data from 82 patients with primary aldosteronism: blood pressure, serum electrolytes, urinary aldosterone and electrolytes, computed tomographic scans, plasma renin and aldosterone before and during upright posture, atrial natriuretic peptide, and adrenal vein aldosterone and cortisol. Clinical outcomes assessed after treatment included blood pressure, serum electrolytes, and plasma renin activity. RESULTS: Drug therapy was discontinued before diagnostic tests were done in 56 of 82 patients (34 with adenomas and 22 with hyperplasia). Compared with patients with hyperplasia, those with adenomas had higher systolic (184 mm Hg and 161 mm Hg, respectively; P < 0.001) and diastolic blood pressures (112 mm Hg and 105 mm Hg; P = 0.03), lower serum potassium levels (3.0 mmol/L and 3.5 mmol/L; P < 0.001), and higher serum CO2 (P = 0.001), atrial natriuretic peptide (P = 0.008), and urinary 18-methyl oxygenated cortisol metabolite levels (P = 0.02). In patients with adenomas, aldosterone secretion lateralized to one adrenal gland and did not increase during the postural stimulation test; preoperative urinary aldosterone levels were correlated with diastolic pressures (r = 0.58; P = 0.001). Hypertension was "cured" postoperatively in approximately 35% of patients with adenomas and those with hyperplasia (P > 0.2) but was "improved" more frequently in those with adenomas (P = 0.002). Cured patients from both groups were younger than those not cured (mean ages, 43 years and 54 years, respectively; P = 0.002) and had lower preoperative mean plasma renin activity (0.17 ng/mL per hour and 0.50 ng/mL per hour; P < 0.001). All patients with adenomas in whom aldosterone secretion lateralized were either cured or improved. CONCLUSION: Of the 51 patients with primary aldosteronism who had adrenalectomy (43 patients with adenomas and 8 with hyperplasia), those most likely to be cured were younger and had lower plasma renin activity. In patients with adenomas who were cured or improved, aldosterone secretion was more likely to lateralize. Tests that distinguished adenomas from adrenal hyperplasia included the postural stimulation test, urinary excretion rates of 18-oxocortisol and 18-hydroxycortisol, and adrenal vein sampling.

Deliberate hypotensive epidural anesthesia for patients with normal and low cardiac output.

The use of hypotensive anesthesia is contraindicated in patients with ventricular dysfunction, even though afterload reduction often improves ventricular performance. The purpose of this study was to prospectively assess systemic hemodynamic responses to deliberate hypotension with epidural anesthesia in patients with chronic left ventricular dysfunction. Hemodynamic measurements were performed in 29 patients undergoing total hip arthroplasty under deliberate hypotensive epidural anesthesia using low-dose intravenous epinephrine infusion to maintain mean arterial pressure (MAP) at 50-60 mm Hg. Intraoperative MAP decreased from 100 +/- 16 to 56 +/- 9 mm Hg by 30 min after epidural injection (P < 0.0005). Concurrently, cardiac index (CI) increased from a preanesthetic baseline value of 2.9 +/- 0.5 to 3.3 +/- 0.9 L.min-1.m-2 at 30 min (P < 0.005) after epidural injection and stroke volume index (SVI) increased from 41 +/- 8 to 50 +/- 14 mL.beat-1.m-2 30 min after epidural injection (P < 0.005). Heart rate and central venous and pulmonary artery diastolic pressures were maintained under hypotension with epidural anesthesia in all patients. During deliberate hypotension with epidural anesthesia, patients with a history of congestive heart failure or low preanesthetic CI (< or = 2.5 L.kg-1.m-2) increased their CI and SVI into the normal range. There were no significant perioperative complications in either of these groups. Hypotensive epidural anesthesia can be used successfully in patients with low cardiac output from ventricular dysfunction undergoing total hip arthroplasty.

Adrenergic regulation of renin secretion and renal hemodynamics during deliberate hypotension in humans.

To assess the relative contributions of neural and nonneural stimuli of renin secretion, the effects of an alpha 1-agonist, phenylephrine (Phe), or a beta-agonist, epinephrine (Epi), on plasma renin activity (PRA), renal blood flow (RBF), and glomerular filtration rate (GFR) were compared during sympathetic blockade with epidural hypotensive anesthesia [mean arterial blood pressure (MAP) = 60 and 50 mmHg]. Controls (NaCl) received saline alone to maintain MAP at 50 mmHg. Epi increased PRA (ng.ml-1.h-1) from 0.9 +/- 0.6 to 3.0 +/- 1.5 at 60 mmHg MAP and 4.7 +/- 1.8 at 50 mmHg MAP, with associated decreases in RBF (-33 and -60%, respectively) and GFR (-27 and -53%, respectively). During hypotension with Phe and NaCl, PRA and RBF were unchanged from baseline but GFR decreased. Urinary Na secretion decreased comparably in all three groups. In conclusion, during sympathetic blockade with epidural anesthesia, marked reductions in both renal perfusion pressure and distal nephron Na delivery were insufficient to increase renin secretion. beta-Adrenergic stimulation (e.g., Epi) was required to increase PRA. Epi decreased RBF suggesting an angiotensin II-mediated effect.

The unique steroidogenesis of the aldosteronoma in the differential diagnosis of primary aldosteronism.

18-Hydroxycortisol and 18-oxocortisol have been isolated from the urine of patients with aldosterone producing adrenocortical adenomas, but not from those with idiopathic hyperaldosteronism associated with bilateral adrenal hyperplasia. These C-18 oxygenated cortisols are biosynthesized by the substitution of cortisol for the normal substrate, corticosterone, in the terminal oxidase system required for the biosynthesis of 18-hydroxycorticosterone and aldosterone. To make use of this biochemical difference between the two groups in the preoperative diagnosis of primary aldosteronism, we have developed and utilized a specific primary standard analytical method, stable isotope dilution mass fragmentography, for quantifying 18-hydroxycortisol and the tetrahydro metabolite of 18-oxocortisol in 24-h urine samples. The normal range by this technique of 4.6 +/- 1.8 micrograms/day tetrahydro 18-oxocortisol and 43 +/- 23 micrograms/day 18-hydroxycortisol in urine was lower and narrower than previous estimates using other methods. Excretion of the 18-oxocortisol metabolite ranged from 2-12 micrograms/day in bilateral hyperplasia and 17-1203 micrograms/day in typical adenomas. 18-Hydroxycortisol excretion similarly separated bilateral hyperplasia (23-59 micrograms/day) from typical adenomas (60-2750 micrograms/day). The cortisol C-18 oxidation pathway describes a unique steroidogenic mechanism in the aldosteronoma not present in idiopathic aldosteronism due to bilateral adrenal hyperplasia and as such provides a basis for the biochemical classification of primary aldosteronism and the differentiation of these two groups. This unique biochemistry was also observed in unilateral hyperplasia but not in the renin-dependent aldosteronoma.

Hypertension and adrenal disorders.

Abnormalities of adrenal cortical and medullary function are important causes of hypertension in adults. Mineralocorticoid hypertension, characterized by spontaneous hypokalemia with excessive kaliuresis and low plasma renin activity, is most commonly caused by aldosterone-producing adenoma or, less frequently, by nonadenomatous adrenal hyperplasia. However, recent evidence indicates that this classification oversimplifies the pathophysiologic diversity of this syndrome. Advances in steroid biochemistry and molecular biology have improved our ability to identify patients with various forms of mineralocorticoid hypertension and also provide evidence that they are underdiagnosed. Pheochromocytomas are most commonly located in the adrenal medulla, where they may overproduce norepinephrine or epinephrine. Appropriate screening of norepinephrine, epinephrine, and their metabolites is essential because tumors that secrete epinephrine exclusively may not present with hypertension and, thus, can be overlooked. Extra-adrenal pheochromocytomas are more prevalent than previously considered and pose special problems because they may be multicentric, difficult to locate, and more likely to be malignant than are adrenal pheochromocytomas.

Cortisol inactivation overload: a mechanism of mineralocorticoid hypertension in the ectopic adrenocorticotropin syndrome.

The more severe mineralocorticoid manifestations in the ectopic ACTH syndrome compared to pituitary Cushing's disease have been attributed to hypersecretion of 11-deoxycorticosterone. Another difference between the two forms of ACTH-excess, however, is a more severe degree of hypercortisolism in the ectopic syndrome. Cortisol can become a potent mineralocorticoid if its peripheral metabolism is interfered with as occurs in the syndrome of apparent mineralocorticoid excess. This mechanism also occurs in an experimental model of the apparent mineralocorticoid excess syndrome induced by licorice derivatives. We have tested the hypothesis that cortisol is a major mineralocorticoid in the ectopic ACTH syndrome because of two factors, marked hypersecretion and incomplete peripheral metabolism of cortisol as a result of an overload of metabolizing enzymes. Two measures of the peripheral metabolism of cortisol were found to be markedly decreased in two patients with the ectopic ACTH syndrome. The cortisol turnover quotients were 17.2 and 19.6 (normal = 215 +/- 98) and the ring A reduction constants were 11.8 and 13.8 (normal = 101 +/- 23). These values were comparable to that found in the syndrome of apparent mineralocorticoid excess and consistent with the hypothesis that cortisol is a significant functioning mineralocorticoid in the ectopic ACTH syndrome.

A new circulating hypertensive factor in the plasma of essential hypertensive subjects.

The pressor responses to dialyzed plasma extracts from normotensive (n = 15) and essential hypertensive (n = 14) human subjects were evaluated in anesthetized Sprague-Dawley rats. Hypertensive but not normotensive plasma raised mean arterial pressure (23.6 +/- 3.6 versus -0.5 +/- 2.5 mmHg, P less than 0.0001), and this effect was correlated significantly with its ability to stimulate 45Ca uptake in rat tail artery vascular smooth muscle (r = 0.883, P less than 0.002). These data suggest a humoral contribution to the pathophysiology of essential hypertension in at least some individuals. The time-course and molecular weight distribution of the dialyzed plasma suggest that this effect is not due to known vasopressor substances, but to a factor we tentatively term plasma hypertensive factor.

Characterization of the major brain osmolytes that accumulate in salt-loaded rats.

Previous studies demonstrated an accumulation of "idiogenic osmoles" in the brain with chronic salt loading. Amino acids are known to constitute a portion of these solutes, but the balance of the solutes has yet to be fully characterized. In the present study, 1H-nuclear magnetic resonance (NMR) spectroscopy and biochemical assays of rat brain were used to identify and quantify changes in organic solutes in two different animal models of hypernatremia: hypertonic salt loading and water deprivation. Five days of salt loading increased plasma sodium concentration (PNa) to 165 meq/l and 3 days of water deprivation increased PNa to 151 meq/l, compared with 141 meq/l in controls. Amino acids, methylamines, and polyols were all significantly higher in salt-loaded animals compared with controls. Specifically, higher contents of glutamine (+65%), glutamate (+27%), myo-inositol (+36%), phosphocreatine + creatine (PCr + Cr) (32%), glycerophosphorylcholine (GPC) (+75%), and choline (+114%) were observed. Sorbitol and betaine, osmolytes known to accumulate in the hypertonic inner medulla, were present in low amounts in the brain and were unchanged with salt loading. In contrast to the results with salt loading, no accumulation of brain organic solutes was detected after 3 days of water deprivation. Based on these findings, we propose that amino acids, methylamines, and polyols function as osmoregulatory solutes in the brains of salt-loaded rats in a manner similar to that observed in other biological systems, whereas 3 days of water deprivation is an insufficient stimulus for their accumulation.

Sodium-coupled ion cotransport and the volume regulatory increase response.

In conclusion, maintenance of volume homeostasis is a fundamental requirement of all cells. For many cell types, this process requires expression of ion cotransport mechanisms as well as accumulation of osmotically-active organic compounds. Recent observations have indicated that the cellular mechanisms responsible for modulating hypertonic volume regulation are complex and appear to involve hormonal, biochemical and physico-chemical stimuli. Knowledge of the specific ion-transport mechanisms involved in the initial phase of VRI, the factors that control their expression, and the interrelationships between inorganic and organic solute accumulation will be required before an in depth understanding of hypertonic cell volume regulation in medullary nephron segments can be achieved.