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Secondary Aldosteronism
CLINICAL DISORDERS OF FLUID AND ELECTROLYTE METABOLISM
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SECONDARY ALDOSTERONISM Dalila B. Corry, MD and Michael L. Tuck, MD
Secondary hyperaldosteronism occurs in states of low effective arterial blood volume, which activates the renin-angiotensin-aldosterone axis. The resultant increase in plasma aldosterone (PA) concentration stimulates the distal reabsorption of sodium (Na) by the kidney to restore blood volume. This Na-retaining effect occurs in association with an increase in potassium (K) excretion. As a rule, a loss of K is a consequence of all states of hyperaldosteronism, providing that the kidney is normal. This condition is seen even when the serum K is lower than normal and if the organism is K depleted. The serum K level, however, is not always predictable, because in complex pathophysiologic situations or physiologic conditions such as pregnancy, an array of hormonal and nonhormonal factors can alter aldosterone's effect on blood pressure and electrolytes. Likewise, in certain conditions, paradoxic renal salt losses occur despite secondary aldosteronism. This review analyzes the responses of blood pressure, body fluid, Na, and K to an excess of aldosterone in various clinical conditions. NORMAL ALDOSTERONE FUNCTION
The renin-angiotensin-aldosterone system responds to several factors, including intravascular volume changes, Na, and K.52The primary stimulus is through fluid volume because hypovolemia and hyponatremia increase renin release, which in turn acts as a proteolytic enzyme on angiotensinogen to produce angiotensin I. Angiotensin I, in concert
From the Department of Medicine, Olive View Medical Center, Sylmar; the Veteran's Administration Medical Center, Sepulveda; and the School of Medicine, Department of Medicine, University of California, :>os Angeles, Los Angeles, California
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 24. NUMBER 3 . SEPTEMBER 1995
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with the endothelial form of angiotensin-converting enzyme (ACE), is converted to angiotensin IS (AngII). This octapeptide then exerts its action on the adrenal gland to release aldosterone; this response to AngII is greatly increased by a decrease in Na intake. K is the other major regulator of aldosterone, and the adrenal gland responds to K by stimulating aldosterone release independent of body Na, volume status, or the activity of the renin-angiotensin system. Several new aspects to the renin-angiotensin system cascade of peptide production may be important in the interpretation of states of secondary aldosteronism. In addition to AngII, studies show that the decapeptide angiotensin I also is a substrate for the production of the proposed vasodilator heptapeptide, angiotensin 1-7 (AngIII), mediated by tissue endopeptidases. Administration of AngII receptor blockers favors increased production of AngIII, suggesting that the pathway comes into action to protect against rising levels of AngII. Angiotensin 3-8 is another biologically active product of this system whose action is uncertain. The effect of a given circulating level of aldosterone on overall Na handling by the distal tubule depends on several factors, such as the volume of the filtrate reaching the cortical collecting duct and the composition of the luminal and intracellular fluid. In contrast, in K handling, aldosterone operates in a less complex fashion. Aldosterone acts on renal electrolyte transport in two sequential steps. Early it activates the apical Na conductive pathway and thereby the entry of Na into the principal cells of the cortical collecting duct. An increase in the cytosolic Na concentration increases this cation reabsorption via the basolateral Na+,K+ pumps. Later, continued exposure to aldosterone results in the insertion of additional Na+,K+ pump units into the cortical collecting In a healthy kidney, this increase in Na reabsorption is followed by extracellular volume expansion resulting after a few days of continued aldosterone exposure to an augmentation of glomerular filtration rate (GFR), together with an inability for the proximal tubule to further increase its Na reabsorption. Larger loads of Na then are delivered to the cortical collecting duct, which, despite the constant stimulation of aldosterone, allows more Na to stay in the lumen, therefore an escape phenomenon limits the effects of hyperaldosteronism on retention of Na. Aldosterone excess continues, however, to activate K excretion mechanisms, providing a steady stimulus to K depletion. Patients with high levels of mineralocorticoids have a relatively faster reabsorption of Na in the cortical collecting duct. This electrogenic reabsorption of the cation Na in excess of anions generates a negative lumen charge with increases in the transepithelial potential difference, which favors the movement of K into the tubular lumen. The second process is the movement of K via the conducting channels in the apical membrane of the principal cells of the cortical collecting ducts. The conducting properties of these channels are increased by aldosterone, and this effect is enhanced in the presence of active v a s ~ p r e s s i nMore.~~ over, aldosterone increases the density of these K conductive pathways.62
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Consequently, K secretion and excretion stay high throughout the duration of aldosterone exposure. Thus, regardless of the factors triggering and sustaining the state of secondary hyperaldosteronism, the force for K loss is continuous, threatening K homeostasis, whereas the force for Na reabsorption is transient and balanced by other factors, leaving only mild Na retention and volume excess. In cases of complex electrolyte disorders, calculation of the transtubular K gradient (TTKG) permits a semiquantitative evaluation of the K secretory process and represents an index of aldosterone bioactivity. By reflecting the ratio of the concentration of K in the tubular fluid and the plasma, it allows a rapid analysis of a given disorder in K homeo~tasis.~~ ISCHEMIC HYPERTENSIVE CONDITIONS Renovascular Hypertension
Renovascular hypertension (RVH) is the most common cause of secondary hypertension, with a prevalence rate of 0.2% to 5% of the general p o p ~ l a t i o nThe . ~ ~ blood pressure elevation is secondary to renal ischemia, resulting from a variety of extrinsic or intrinsic lesions of one or both renal arteries or their segmental branches. Although the primary lesion is anatomic, this condition is considered to be an endocrine form of hypertension because the altered renal hemodynamics provide a strong stimulus for the renin-angiotensin-aldosterone system. Clinical features in the classic descriptions of RVH include abdominal bruits, accelerated hypertension (often resistant to antihypertensive agents), renal insufficiency, and hypokalemia. In 1975 reported a 16% incidence rate of hypokalemia (K < 3.5 mmol/L) in RVH based on data from the Cooperative Study for Renovascular Hypertension. Other reports have confirmed the association of hypokalemia with RVH, observing an incidence rate between 10% and 20%.9,56 Despite activation of the renin-angiotensin system in RVH, only moderate secondary hyperaldosteronism occurs. Therefore the findings of hypokalemic alkalosis in a hypertensive patient often direct the diagnostic evaluation toward adrenal causes of mineralocorticoid excess (primary aldosteronism) and away from a diagnostic approach seeking renal parenchymal or renal artery disease. In differentiating between states of primary and secondary aldosteronism, basal measures of renin and aldosterone often are not accurate because of their normal physiologic variability. PA and plasma renin activity (PRA) measured in the basal state have improved in diagnostic accuracy, and expressing them as the PA/PRA ratio to screen primary from secondary hyperaldosteronism has been advocated. McKenna and associates45found that when measured under random conditions, the relation between PA and PRA expressed as a ratio differentiates between primary and secondary hyperaldosteronism. Hence, subjects with primary aldosteronism have a disassociation between aldosterone (high)
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and renin (low) and thus, a high PA/PRA ratio (> 50); in secondary causes, however, both aldosterone and renin are high, resulting in a normal PA/PRA ratio (Fig. 1). In most cases of hypertension, this simple test helps to establish the secondary nature of hyperaldosteronism and directs the diagnostic evaluation toward renal artery disease. Although basal circulating PRA often is normal in RVH, administration of an ACE inhibitor to patients with RVH markedly increases PRA levels because of the enhanced release of renin from the ischemic kidney. For example, Imai and othersz9report a large increase in PRA 1 hour after administering 50 mg of captopril orally in patients with RVH. The increments in PRA after captopril are significantly less when administered to essential hypertensive subjects. This test is especially useful in subjects thought to have RVH but who show normal or reduced PRA levels, as may occur in patients taking antihypertensive agents (beta blockers) or in elderly hypertensive subjects. One study of hypertensive patients older than 40 years of age showed that increments in PRA of
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2.6 ng/mL/h or greater after treatment with captopril identified significant renal artery stenosis (sensitivity, loo%, specificity, 78%).28 This defect is reversible, as exemplified in a single patient studied by Ruby and colleagues53with severe hypertension and symptomatic hypokalemia. After surgical revascularization, reversal of the ischemia was followed by complete resolution of the hyperreninemic hyperaldosteronism as PRA, PA, and urinary and serum K normalized (Fig. 2). The two classic animal models of Goldblatt hypertension have provided an understanding of the temporal and adaptive responses in renin and aldosterone to stenosis. In the first model, one renal artery is clamped and the opposite kidney is removed to create one-kidney, one-
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Figure 2. Top panel, serum and urinary K, before and after revascularization of a unilateral renal artery stenosis. Lower panel, PRA and PA in same subject before and after surgery. Closed bars, pre-captopril, open bars, post-captopril. (From Ruby ST, Burch A, White WB: Unilateral renal artery stenosis seen initially as severe and symptomatic hypokalemia: pathophysiologic assessment and effects of surgical revascularization. Arch Surg 128:346, 1993; with permission.)
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clip RVH.41In this preparation, a transient elevation of PRA occurs for 6 to 10 days, then levels decline, but hypertension is sustained by volume expansion. In the other model, the two-kidney, one-clip (2-K, 1-C), model, an elevated PRA persists throughout the chronic maintenance phase of hyperten~ion.~~ A normal contralateral kidney in unilateral RVH should protect against hypertension as well as fluid and electrolyte imbalance, but that is not the case in this model. In the nonstenotic kidney, a rise in local AngII occurs, followed by arterial vasoconstriction, reduced GFR, and enhanced proximal Na retention. This paradoxic response of the normal kidney leads to a blunted pressure natriuresis curve and an increase in total exchangeable Na. From the stenotic kidney, the pressure distal to the lesion is never completely restored, thus it continues to provide a stimulus for renin release, whereas the contralateral kidney loses its ability to mount an adequate natriuretic response.49 It is not always possible to extrapolate some of the observations in experimental animals to clinical RVH in humans. Several studies report that the nonstenotic kidney often responds with an appropriate pressure natriuresis. Blanc and others7describe a case of malignant hypertension in a neonate who had hypovolemia secondary to severe renal Na losses, hypokalemia, and high PRA. An abdominal angiogram revealed nearly complete stenosis of the right renal artery but a normal left kidney. The clinical findings totally resolved with surgery, and because the involved kidney was completely occluded, the authors concluded that the normal kidney was responsible for the Na losses. McAreavy and coworkers44 studied 30 patients with unilateral renal artery stenosis and 5 with bilateral disease, measuring serum Na and K, exchangeable Na, plasma renin, AngII, and aldosterone. They identified six patients who were frankly hyponatremic and observed that they had higher blood pressure; lower plasma K levels; lower exchangeable Na; and higher PRA, AngII, and aldosterone. In these subjects, Na excretion was greater from the nonstenotic kidney and a positive correlation existed between the rate of Na excretion and arterial pressure. Hence, RVH patients with the highest rate of urinary Na loss seem to have the most severe hypertension and the lowest exchangeable Na (Fig. 3). Sato and associates60 studied changes in 22Naturnover and totalbody potassium during acute and chronic phases of hypertension in 2-K, 1-C rabbits. 22Nainjected intravenously was eliminated faster in hypertensive rabbits than in controls. Plasma aldosterone increased during the acute phase, and total-body potassium decreased significantly during the maintenance phase. A significant correlation was obtained between 22Naturnover and blood pressure. The authors concluded that volume overload was not a major factor in the acute or the chronic phase of hypertension in the RVH rabbit and that pressure natriuresis could explain the loss of Na. In rats with 2-K, 1-C RVH, Swales and colleague^^^ also found a significant correlation between arterial pressure and cumulative Na depletion. After removal of the contralateral kidney, natriuresis was reduced and exchangeable Na increased. In addition,
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Exchangeable Sodium (%)
Figure 3. Relation of the blood pressure to the exchangeable Na in patients with hyponatremia (A) and patients with normal serum Na (@). (From McAreavey D, Brown J, Cumming AMM, et al: Inverse relation of exchangeable sodium and blood pressure in hypertensive patients with renal artery stenosis. J Hypertension 1:297, 1983; with permission.)
AngII may directly participate in the Na response in renal artery stenosis by increasing pressure natriuresis and by exerting a natriuretic action on the Thus, in RVH, a variable secondary aldosteronism exists, and its effect on K loss or Na retention seems minimal. In fact, there is a greater and more consistent tendency toward Na loss from the contralateral, nonstenotic kidney that occurs independent of aldosterone and seems best related to blood pressure and the local effects of renal AngII. Malignant Hypertension
Malignant hypertension is accompanied by intense secondary aldosteronism, yet like in RVH, a tendency toward Na and volume depletion exists, which is more marked as the blood pressure increases. Many reports describe an inverse correlation between volume and blood pressure. With extracellular fluid volume being reduced by as much as 30%,
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these patients have renal sodium loss and volume depletion despite the increased levels of renin and ald~sterone.~ A vicious cycle is then set up where renal ischemia and volume depletion lead to further stimulation of renin release, AngII production, and aldosterone secretion. The shortloop feedback whereby AngII directly inhibits renin secretion is inoperative and is overriden by hyponatremia and hypovolemia, which act as intense stimuli for renin release. When faced with this state of severe hypertension with paradoxic increase in Na and water excretion, the therapy should address the systemic vasoconstriction and also should reestablish and maintain euvolemia. Stimulation of the renal juxtaglomerular cells to secrete large amounts of renin also is seen in patients with polyarteritis nodosa. These patients commonly have hypertension, high renin and aldosterone levels, and hyp~kalemia.~~ In 1948 Davson and others16 suggested that the hypertension in polyarteritis nodosa was secondary to renal ischemia as a result of the marked narrowing of the renal arterioles. In 1979 Stockigt and c o - ~ o r k e r soffered ~ ~ proof that the hypertension in polyarteritis nodosa was angiotensin dependent by eliciting a marked hypotensive response to blockade of the renin-angiotensin system with administration of the agent saralasin. Graham and LindopZ4confirmed the clinical hypothesis of renin dependency using immunocytochemical staining and by showing hyperplasia of renin-containing cells in the juxtaglomerular apparatus in focal ischemic areas of kidneys affected by classic polyarteritis nodosa.
Renin-producing Tumors
Renin-producing tumors, a rare form of hypertension usually occuring in young adults with severe hypertension and hypokalemia, are one of the best examples of secondary aldosteronism. The volume response to aldosterone seems more appropriate because the hypertension in renin-producing tumors is accompanied by normovolemia, rather than the hypovolemia of RVH and malignant hypertension. In this condition, sometimes termed primary reninism, the levels of PRA are among the highest recorded in hypertensive syndromes, often exceeding 50 ng/mL/h. Because these tumors can release immature forms of renin, the level of prorenin is elevated, and a high prorenin-to-renin ratio can distinguish this disorder from essential hypertension or RVH. Hypokalemia is the most constant routine laboratory finding, often being severe (Kc2.0 mmol/L), and is completely attributable to mineralocorticoidinduced renal K wasting. Several renin-producing tumors can cause this syndrome, and most of them are renal in origin. They include hemangioperi~ytomas~~ and renal cell carcin0mas,6~where endothelial cells are producing the renin and Wilms tumors. Some unusual extrarenal tumors also have been implicated, such as renin-producing Sertoli cell ovarian tumors34and pheochromocytomas, where the hyperreni-
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nemia is secondary to the excessive catecholamines, which then stimulate the juxtaglomerular cells to release renin.39 Pregnancy
Human gestation is characterized by a complex balance in the control of Na homeostasis and hemodynamic adjustments, following the need for Na by the expanding fetoplacental unit. A primary arterial vasodilation occurs selectively and early in pregnancy and leads to several consequences, including decreased systolic and diastolic blood pressure, enhanced cardiac output, a nonosmotic stimulation of thirst with increased vasopressin release, and stimulation of the renin-angiotensin system. Levels of sex steroid hormones such as estrogens and progesterone rise and contribute to the vasodilation. Normal pregnancy also has been associated with an early and marked refractoriness of blood pressure to AngII.20This loss of AngII pressor effect went unexplained for years, but evidence suggests a role for the endothelium and nitric animal models of pregnancy show increased plasma and urinary cyclic guanosine monophosphate, the second messenger for endothelium-derived relaxing factor." svstem occurs earlv The increase in activitv Gf the renin-an~iotensin " in pregnancy in association with the fall in systemic vascular resistance and occurs despite the increase in blood volume. In 1980 Wilson and colleagues78sequentially studied blood pressure, the renin-angiotensin system, and sex steroids throughout pregnancy and again 4 to 6 weeks after delivery. By 8 weeks of pregnancy, PRA was twice as high as baseline and doubled again by the 20th week to remain stable until term. By 8 weeks, mean PA had increased from 6.2 1.1 to 16.4 + 4.7 ng/dL. PA levels continued to rise during the next 2 months and then remained stable during the second trimester, but again rose to peak at mean levels of 59.4 + 13.9 ng/dL in the last trimester. These studies, which describe an early and sustained stimulation of the renin-angiotensin-aldosterone system, also have found a strong positive correlation between PA and PRA throughout pregnancy. Wilson and others77also observed a direct correlation bet-ween PA and progesterone, estradiol, and estriol. During pregnancy, plasma progesterone levels double by 8 weeks' gestation and continue to rise to reach a peak of 17-fold over baseline. To test the relation between sex steroids and aldosterone, Sealy and associates59measured PRA and aldosterone in eight patients undergoing ovarian stimulation in preparation for in vitro fertilization. They observed a marked increase in PRA and aldosterone, with ovarian stimulation that correlated with the rise in plasma progesterone and estradiol. Parallel results were seen in these same women when studied again during early pregnancy. In this study, PRA and aldosterone levels were high, yet hypokalemia was not observed. The maintenance of normokalemia throughout pregnancy is surprising because several factors such as high aldosterone, mild alkalosis, and increased vasopressin i
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are acting in force to promote urinary K loss. When electrolyte balance is studied during pregnancy, urinary Na and K excretion seems independent of the fluctuations in PRA and aldosterone (Fig. 4). Brown and others8 studied 14 healthy women on ad libitum diets, confirming that K excretion is held constant throughout pregnancy. The mechanisms responsible for K conservation in the face of high aldosterone remain unknown. An antikaliuretic role for progesterone, whose levels parallel aldosterone, has been proposed. Sharp and c o l l e a g ~ e sdemonstrated ~~ in
Gestation (weeks) Figure 4. Sequential relation throughout pregnancy of plasma aldosterone, urine aldosterone, urinary sodium, and potassium. (From Wilson M, Morganti AA, Zervoudakis I, et al: Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy. Am J Med 68:97, 1980; with permission.)
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vitro, an antimineralocorticoid effect of progesterone. Tamas and others70 sequentially measured urinary Na and K, TTKG, aldosterone, vasopressin, and endothelin-1 levels in 12 healthy pregnant women. TTKG was found to be low despite the high plasma and urinary aldosterone levels, suggesting resistance to aldosterone's action. Because urinary endothelin-1 excretion was increased, the authors postulated antialdosterone properties for the renal form of endothelin-1, which inhibits Na+,K+ATPase activity in the medullary collecting duct. During gestation, Na excretion does not correlate with aldo~terone,7~ yet the ability of the kidney to eliminate an acute Na load is not impaired, suggesting other factors in Na regulation. A relation of Na balance to atrial natriuretic peptide (ANP) has been reported in pregnancy.'j4 Earlier reports describe substantial increases in plasma ANP during pregnancy,15,72 and it was proposed that ANP was responsible for the peripheral vasodilation and the AngII resistance. Recent 35 using more sensitive assays, however, have observed reductions in ANP levels during pregnancy, most marked in the early phase and in the third trimester, when mechanisms to maintain volume expansion are most needed. Likewise, Thomsen and co-workers" found significantly lower levels of ANP in twin pregnancy, a state of even greater volume dependency compared with single gestation.35The usual inverse relation of ANP to aldosterone is preserved in pregnancy, considering that studies show high aldosterone/ANP ratios.18,66 These data indicate that ANP represents another mechanism contributing to the maintenance of blood volume, and, by responding to dietary intake and posture, ANP mav allow more flexibilitv than aldosterone in the modulation of sodium bafance. Overall, in pregnancy the evidence suggests a state of intense secondary aldosteronism, yet there are few manifestations of an excess of mineralocorticoid action. The major effect of aldosterone excess seems to be its contribution to the requisite volume expansion of gestation, yet its potential detrimental effects (high blood pressure and K loss) seem to be offset by other hormonal and hernodynamic changes in normal pregnancy. Chronic Renal Failure
Subjects with chronic renal failure display some features of aldosteronism, such as a low Na/K ratio in the ~ a l i v aand ~ ~ in , ~the ~ In addition, other studies have shown elevated plasma aldosterone in endstage renal disease,1275 but evidence for secondary aldosteronism often is not apparent because the characteristic findings are masked by other uremic complication^.^^, 67 Despite the absence of renal K excretion in hemodialysis patients, only a few develop hyperkalemia in the interdialytic period. This indicates that in uremia, nonrenal K disposal mechanisms assume a critical role in the defense against hyperkalemia. Normally two mechanisms
account for K homeostasis, both involving aldosterone. The first maintains K balance by matching K excretion to dietary intake, with the kidney excreting 90% to 95% of total ingested K and the gut, 5% to Panese and others50 found a 2.5-fold increase in active rectal K secretion in patients with chronic renal failure. Likewise, Hayes and colleagues27showed that about 30% of dietary K is excreted via the intestinal route in chronic renal failure compared with 12% in controls, and in patients with successful kidney transplants, the recovery of renal function is accompanied by a reduction in fecal K excretion. Uremic patients placed on a low-K diet decrease their intestinal K excretion, raising the question of whether this adaptation represents a decreased gut absorption of K or a true active secretion. Martin and using the dialysis bag technique, found increased rectal K excretion and negative potential difference across the intestinal lumen in patients with chronic renal failure. In this study, plasma aldosterone levels were higher in patients than in controls; however, the scatter of data on aldosterone precluded an assessment of its role. Sandle and ass0ciates,5~using the same techniques, found higher rectal K excretion in 10 individuals on chronic ambulatory dialysis and 7 on intermittent hemodialysis, but no difference in aldosterone between patients and controls. Recently the same studied the effect of a 70% nephrectomy on K transport in rats fed a regular diet. In isolated preparations of the distal colon, they found no changes in the Na and K conductance. In contrast, in animals fed a diet enriched in K, nephrectomy resulted in a large amiloride-sensitive elevation in transepithelial voltage, and studies in the distal colonic epithelium revealed a twofold increase in basolateral Na+,K+ pump activity. In essence, all of the above studies support a role for aldosterone in the K adaptation in uremia. The second mechanism for K disposal shifts K from extracellular to intracellular compartment^.^ This process, referred to as extrarenal K disposal, is rapid, taking place within a few minutes. It is known that acute and chronic administration of K increases aldosterone secretion in animals79and humans,17,l9 but its participation in mediating cellular K shifts is less certain. Although insulin and beta-adrenergic stimulation are established mediators of extrarenal K disposal, data favor a role for aldosterone. Alexander and Levinsky3 showed that normal rats maintained chronically on a high-K diet have enhanced tolerance to an acute K load. This protective effect of chronic high-K intake against acute K changes in serum is present even in nephrectomized rats, suggesting a shift away from the kidneys toward extrarenal K pathways.68This process is abolished by adrenalectomy and restored by administration of desoxycorticosterone, suggesting a mineralocorticoid effect. This role for mineralocorticoids has been confirmed by Tuck and who reported that the peak incremental response of aldosterone to potassium chloride infusion was higher in dogs that underwent nephrectomy than in controls (Fig. 5). These findings also indicate an enhanced adrenal sensitivity to K in uremia. Sugerman and assessing the effect of mineralocorticoids on K disposal in anephric individuals, measured
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serum K, aldosterone, and salivary and fecal electrolytes in response to K loading over 48 hours, followed by an acute oral K load. They found that the volume of distribution of the acute K load was greater with deoxycorticosterone (DOCA) than with spironolactone administration and concluded that a mineralocorticoid effect was required in extrarenal K disposal. A moderately convincing case for secondary aldosteronism can be made in chronic renal failure; however, its profile is unique. The driving force for aldosterone release is not the renin-angiotensin system but the potassium ion. The site of action of aldosterone is not on the kidney but is shifted to other targets. The excess aldosterone is not detrimental, but in fact is mostly beneficial for K homeostasis and needs to be preserved. Because aldosterone seems to be as vital as insulin21 in preventing hyperkalemia in renal failure, it is critical to use caution with therapies that interfere with its effect, such as ACE inhibitors or beta blockers. Iatrogenic Secondary Hyperaldosteronism Intestinal Diversion
Intestinal diversion offers another example of secondary aldosteronism. The management of bladder extrophy, carcinoma of the bladder, or urine incontinence may require insertion of the ureter into the intestine. Sometimes creation of an intestinal or gastric pouch to replace or augment the bladder is needed. The metabolic complications of these tech-
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niques are multiple and are related to the absorptive and secretory properties of the gastrointestinal segment incorporated in the urinary tract. When gastric tissue is used for urinary reconstruction, severe secondary hyperaldosteronism with subsequent hypochloremic, hypokalemic metabolic alkalosis can occur.32Gosalbez and associatesz3report the case of two children in whom severe hypochloremic, hypokalemic metabolic alkalosis developed after volume depletion secondary to gastrointestinal losses. One patient, who had mild elevations of plasma gastrin levels, responded to Hz blockers. The second was found to have marked hypergastrinemia and high PA and PRA levels, and failed to respond to Hz blockers and the H-K pump blocker, omiprazole. In this setting the metabolic alkalosis was thought to be related to an excessive excretion of hydrochloric acid by the gastric pouch. Volume depletion often triggers this acid-base imbalance, but it also has been reported with normal body fluid. Intense secondary hyperaldosteronism also can complicate small bowel resection.25 This is related primarily to loss of colon function. Patients with an ileostomy have high stomal Na output leading to Na depletion, low urinary Na, and high aldosterone. Ladefoged and 01gaar~ ~~ compared plasma volume, PA, PRA, and urine Na and K excretion in 16 patients with small bowel resection: 8 had ileostomy and 8 had at least half of the colon in place. Patients with at least half of the colon intact were only slightly volume contracted and had normal aldosterone and PRA. In contrast, patients with no colonic function displayed high aldosterone levels, which were positively correlated to renal Na excretion and plasma volume. An infusion of aldosterone further decreased their urinary Na excretion but did not affect stomal Na losses. In ureteral diversion and bowel resection, the secondary aldosteronism, although appropriate, often fails to reestablish normal volume and electrolyte homeostasis, requiring either reversal of the procedure or other temporizing measures, such as saline Infusion or administration of Hz blockers to counteract its complications. Cyclosporin-induced Hypertension
Cyclosporine is an 11-amino acid fungal peptide widely used as an immunosuppressive agent to prevent allograft rejection. It is also used in the treatment of various autoimmune diseases. This agent is known to have significant side effects. The most important side effect is a doserelated nephrotoxicity, manifested by a rise in serum creatinine with a simultaneous decrease in GFR.33The compound was found to reduce renal blood flow, GFR, and sodium excretion whereas it produces vasoconstriction of the glomerular afferent arteriole with increased renal vascular resistance and hypertension. The cyclosporine induced hypertension is associated with a marked increase in sympathetic nervous but the renin-angiotensin-
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aldosterone system also has been implicated in the pathogenesis. Julien and others30 found that supine and upright PRA levels were increased with a low-Na diet in 33 hypertensive transplant patients. In the liver allograft recipients, plasma aldosterone in the upright position also was significantly elevated. Ciresi and associate^'^ showed that chronic administration of cyclosporine to dogs reduces the Na excretion associated with activation of the renin-angiotensin system. Cugini and others13 found high PRA and aldosterone levels in 18 cyclosporine-treated transplant patients. In a subsequent study of 13 cardiac transplant patients, the same authors14 confirmed the existence of hyperreninemic hyperaldosteronism associated with elevated ANP levels. Although cyclosporine seems to cause a state of hyperaldosteronism accompanied by high renin, controversies have originated from the fact that its administration can be complicated by hyperkalemia. In fact, some investigators have found hyporeninism and hypoaldosteronism in hyperkalemic, cyclosporine-treated patients,' whereas others describe normal PRA and ddosterone or higher peak aldosterone levels in response to an acute potassium load. Aguilera and others2 measured PRA, PA, and TTKG in five cvclosvorine-treated subiects with idiovathic uveitis and in five who I were not on the agent. ~idosteroneand ?TKG were positively correlated in both groups, suggesting an incomplete form of tubular acidosis rather than tubular resistance to aldosterone. Kame1 and others31 related the hyperkalemia to an increased permeability of the tubule to chloride in the presence of cyclosporine. This newer understanding of the pathophysiologic mechanisms also implies that treatment of cyclosporineinduced hyperkalemia with loop diuretic agents is more effective than the use of mineralocorticoid agents. i
SUMMARY
Conditions of secondary aldosteronism are common in clinical medicine, occurring in normotensive and hypertensive settings. In some conditions such as edema disorders, this represents a partially beneficial response to restore volume and Na at the expense of hypokalemia. In RVH and malignant hypertension, the aldosteronism may be beneficial, but most evidence shows a detrimental impact. In both situations, aldosterone does not compensate fully for Na degredation and facilitates K loss. In pregnancy, aldosterone's effect is more successful for volume conservation, and the action on K is almost completely overridden by other K-sparing factors. Chronic renal failure seems to best benefit from hyperaldosteronism, but the response is limited because aldosterone must act on extrarenal targets. In iatrogenic causes of secondary aldosteronism, the effects of aldosterone are mostly detrimental. The overall conclusion supports the hypothesis that aldosterone functions best in physiologic situations, but in pathophysiologic settings it does not perfectly compensate for the basic defect. This implies that in these complex
conditions, successful therapy should address the disorder in aldosterone and also the other underlying pathophysiologic mechanisms.
References 1. Adu D, Michael J, Turney J, et al: Hyperkalaemia in cyclosporin-treated renal allograft recipients. Lancet 1:371, 1983 2. Aguilera S, Derey G, Desjobert H, et al: Effects of cyclosporine on tubular acidification function in patients with idiopathic uveitis. Am J Nephrol 12425, 1992 3. Alexander EA, Levinsky NG: An extrarenal mechanism of potassium adaptation. J Clin Invest 47740, 1968 4. Bantle JP, Nath KA, Sutherland ER, et al: Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients. Arch Intern Med 145:505, 1985 5. Barraclough MA: Sodium and water depletion with acute malignant hypertension. Am J Med 40:265, 1966 6. Bast1 C, Hayslett JP, Binder HJ: Increased large intestinal secretion of potassium in renal insufficiency. Kidney Int 12:9, 1977 7. Blanc F, Bensman A, Baudon JJ: Renovascular hypertension: A rare cause of neonatal salt loss. Pediatr Nephrol 10:304, 1991 8. Brown MA, Sinosich MJ, Saunders DM, et al: Potassium regulation and progesteronealdosterone interrelationships in human pregnancy: A prospective study. Am J Obstet Gynecol 155:349, 1986 9. Bunchman TE, Sinaiko AR: Renovascular hypertension presenting with hypokalemic metabolic alkalosis. Pediatr Nephrol 4:169, 1990 10. Ciresi DL, Lloyd MA, Sandberg SM, et al: The sodium retaining effects of cyclosporine. Kidney Int 41:1599, 1992 11. Conred KP, Vernier KA: Plasma level, urinary excretion and metabolic production of cGMP during gestation in rats. Am J Physiol 257:R847, 1989 12. Cope CL, Pearson J: Aldosterone secretion in severe renal failure. Clin Sci 25:331,1963 13. Cugini P, Battisti P, DiPalma L, et al: Secondary aldosteronism documented by plasma renin and aldosterone circadian rhythm in subjects with kidney or heart transplantation. Ren Fail 14:69, 1992 14. Cugini P, Lucia P, Scibilia G, et al: Twenty-four-hour pattern of atrial natriuretic peptide in heart transplantation: Evidence for lack of circadian rhythm. Int J Cardiol 42:7, 1993 15. Cusson JR, Gutkowska J, Rey E, et al: Plasma concentration of atrial natriuretic factor in normal pregnancy. N Engl J Med 313:1230, 1985 16. Davson J, Ball J, Platt R: The kidney in periarteritis nodosa. Q J Med 17175, 1948 17. Dluhy RG, Axelrod L, Underwood RH, et al: Studies of the control of plasma aldosterone concentration in normal man: 11. Effect of dietary potassium and acute potassium infusion. J Clin Invest 51:1950, 1972 18. Finn WL, Tunny TJ, Klemm A, et al: Sodium and volume dysregulation after apparently normal pregnancy is suggested by abnormal levels of atrial natriuretic peptide, renin and aldosterone. Clin Exp Pharm Physiol 18:269, 1991 19. Gann DS, Delea CS, Gill JR, et al: Control of aldosterone secretion by change of body potassium in normal man. Am J Physiol207104, 1964 20. Gant NF, Daley GL, Chand S, et al: A study of angiotensin I1 pressor response throughout primagravid pregnancy. J Clin Invest 52:2682,1973 21. Gifford JD, Rutsky EA, Kirk KA, et al: Control of serum potassium during fasting in patients with end-stage renal disease. Kidney Int 35:90, 1989 22. Go11 RD, Mookerjee BK: Correlation of biochemical parameters in serum and saliva of chronic azotemic patients and patients on chronic hemodialysis. J Dialysis 2399, 1978 23. Gosalbez R, Woodard JR, Broecker BH, et al: Metabolic complications of the use of stomach for urinary reconstruction. J Urol 150:710, 1993
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24. Graham PC, Lindop GBM: The renin-secreting cell in polyarteritis: An immunocytochemical study. Histopathology 16:339, 1990 25. Grischkan D, Steiger E, Fazio V: Maintenance of home hyperalimentation in patients with lugh output jejunostomies. Arch Surg 114:838, 1979 26. Harris PJ, Navar LG: Tubular transport responses to angiotensin. Am J Physiol 248:F261, 1985 27. Hayes CP, McCleod MI, Robinson R: An extrarenal mechanism for the maintenance of potassium in severe chronic renal failure. Assoc Am Physicians 80:207, 1967 28. Idrissi A, Fournier H, Renaud B, et al: The captopril challenge test as a screening test for renovascular hypertension. Kidney Int 34:S138, 1988 29. Imai Y, Abe K, Gtsuka Y, et al: Exaggerated response of renin secretion to captopril (SQ 14225) in renovascular hypertension. Jpn Heart J 21:793, 1980 30. Julien J, Farge D, Kreft-Jais C, et al: Cyclosporine-induced stimulation of the renin angiotensin system after liver and heart transplantation. Transplantation 56:885, 1993 31. Kame1 J, Ethier J, Levin A, et al: Post-transplant hyperkalemia in patients on cyclosporine. Clin Invest Med 12:B70, 1989 32. Kinahan TJ, Khoury AE, McLorie G, et al: Omeprazol in post-gastrocystoplasty metabolic alkalosis and aciduria. J Urol 147:435, 1992 33. Klintmalm CBG, Iwatsuki S, Starzl TE: Nephrotoxicity of cyclosporin A in liver and kidney transplant patients. Lancet 1:470, 1981 34. Korzet A, Nouriel H, Steiner Z, et al: Resistant hypertension associated with a reninproducing ovarian sertoli cell tumor. Am J Clin Pathol 85:242, 1986 35. Kvist JK, Fogh-Anderson N, Jaszczak P: Atrial natriuretic peptide, blood volume, aldosterone and sodium excretion during twin pregnancy. Acta Obstet Gynecol Scand 73:14, 1994 36. Ladefoged K, Olgaard K: Sodium homeostasis after small bowel resection. Scand J Gastroenterol 208:361, 1985 37. Lang F, Rehwald W: Potassium channels in renal epithelial transport regulation. Physiol Rev 72:1, 1992 38. Lauler DP, Hickler RB, Thorn GB: The salivary sodium-potassium ratio. N Engl J Med 267:1136, 1962 39. Lene T, Thiede HM, Atlas SA, et al: Hyperreninemia and secondary hyperaldosteronism in a patient with pheochromocytoma and von Hippel-Lindau disease. Nephron 62:345, 1992 40. Lewin A, Blaufox MD, Castle H, et al: Apparent prevalence of curable hypertension in the Hypertension Detection and Follow-up Program. Arch Intern Med 145:424, 1985 41. Liard JF, Cowley AW, McCaa RE, et al: Renin, aldosterone, body fluid volumes and the baroreceptor reflex i n the development and reversal of Goldblatt hypertension in conscious dogs. Circ Res 34:549, 1974 42. Martin RS, Panese S, Virginillo M, et al: Increased secretion of potassium in the rectum of humans with chronic renal failure. Am J Kidney Dis 2:105, 1986 43. Maxwell MH: Cooperative Study of Renovascular Hypertension: current status. Kidney Int 8:S153, 1975 sodium 44. McAreavev , D, Brown 1, Cummine " AMM, et al: Inverse relation of exchaneable " and blood pressure in hypertensive patients with renal artery stenosis. J Hypertens 1:297, 1983 45. McKenna TJ, Sequeira SJ, Hefferman A, et al: Diagnosis under random conditions of all disorders of the renin-angiotensin-aldosterone axis, including primary hyperaldosteronism. J Clin Endocrinol Metab 73:952, 1991 46. Morton JJ, Wallace ECH: The importance of the renin-angiotensin system in the development and maintenance of hypertension in the two-kidney, one-clip hypertensive rat. Clin Sci 64:359, 1983 47. Molnar M, Herenlendy F: Nw-nitro-L-arginine, an inhibitor of nitric oxide synthesis, increases blood pressure in rats and reverses the pregnancy-induced refractoriness to vasopressor agents. Am J Obstet Gynecol 166:1560, 1992 48. Mujais SK, Chekal MA, Jones WJ, et al: Modulation of renal sodium-potassiumadenosine triphosphate by aldosterone. J Clin Invest 76:70, 1985 , A
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49. Navar LG: Renovascular hypertension: Pathophysiology. In Izzo JI, Black HR (eds): Hypertension Primer. Dallas, American Heart Association, 1993, p 99 50. Panese S, Martin RS, Virginillo M, et al: Mechanism of enhanced transcellular potassium secretion in man with chronic renal failure. Kidney Int 31:1377, 1987 51. Pedrinelli R, Graziadei L, Taddei S, et al: A renin-secreting tumor. Nephron 46:380, 1987 52. Quinn SJ, Williams GH: Regulation of aldosterone secretion. Annu Rev Physiol 50:409, 1988 53. Ruby ST, Burch A, White WB: Unilateral renal artery stenosis seen initially as severe and symptomatic hypokalemia: pathophysiologic assessment and effects of surgical revascularization. Arch Surg 128:346, 1993 54. Sandle GI, Gaiger E, Tapster S, et al: Evidence for large intestinal control of potassium homoeostasis in uraemic patients undergoing long-term dialysis. Clin Sci 73:247, 1987 55. Sandle GI, McGlone F, Davies RJ: Electrophysiology of rat distal colon after partial nephrectomy: Implications for K transport. Pflugers Arch 412172, 1988 56. Savin H, Jutrin I, Ravid H: Persistent hypokalemia due to bilateral fibromuscular dysplasia of the renal arteries. Clin Nephrol 25:199, 1986 57. Scherrer V, Vissing SF, Morgan BJ, et al: Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. N Engl J Med 328:693, 1990 58. Schon DA, Silva P, Hayslett JP: Mechanism of potassium excretion in renal insufficiency. Am J Physiol 227:1323, 1974 59. Sealy JE, Itskovitz-Eldor J, Rubattu S, et al: Estradiol- and progesterone-related increases in the renin-aldosterone system: Studies during ovarian stimulation and early pregnancy. J Clin Endocrinol Metab 79:258, 1994 60. Sato S, Kaku T, Kurimochi M, et al: Changes in sodium-22 turnover and total body potassium in two-kidney, one-clip renovascular hypertension. Jpn Circ J 55:524, 1991 61. Sharp GW, Komack CL, Leaf A: Studies on the binding of aldosterone in the toad bladder. J Clin Invest 45:450, 1966 62. Stanton B, Pan L, Deetjen H, et al: Independent effects of aldosterone and potassium on induction of potassium adaptation in rat kidney. J Clin Invest 79:198, 1987 63. Steffens J, Bock R, Braedel HU, et al: Renin-producing renal cell carcinoma. Eur Urol 18:56, 1990 64. Steegers EAP, Benraad TJ, Jongsma HW, et al: Effects of dietary sodium restriction and posture on plasma levels of atrial natriuretic peptide, aldosterone and free aldosterone in normal human pregnancy. J Endocrinol 124507, 1990 65. Stockigt JR, Topliss DJ, Heweth MF: High renin hypertension in necrotizing vasculitis [letter]: N Engl J Med 300:1218, 1979 66. Stratta P, Canavese C, Gurioli L, et al: Ratio between aldosterone and atrial natriuretic peptide in pregnancy. Kidney Int 36:908,1989 67. Sugarman A, Brown RS: The role of aldosterone in potassium tolerance: Studies in anephric humans. Kidney Int 34:397,1988 68. Sugarman A, Khan T: Parathyroid hormone impairs extrarenal potassium tolerance in the rat. Am J Physiol254:F385, 1998 69. Swales JD, Thurston H, Queiroz PP, et al: Sodium balance during the development of experimental hypertension. J Lab Clin Med 83539, 1972 70. Tamas P, Worgall S, Sulyok E, et al: Renal electrolyte and water handling in normal pregnancy: Possible role of endothelin-1. Eur J Obstet Gynecol Reprod Biol55:89,1994 71. The1 MC, Mannon RB, Allen NB: Hyperrenin-hyperaldosterone dependent malignant hypertension in polyarteritis nodosa. South Med J 86:1400, 1993 72. Thomsen , TK., Storm TL, Thamsborg G, et al: Increased concentration of circulating atrial natriuretic peptidd during noymal pregnancy. Eur J Obstet Gynecol Reprod ~ i z 27:197, 1988 73. Thomsen Fogh-Anderson N, Jaszczak P, et al: Atrial natriuretic peptide (ANP) decreases during normal pregnancy as related to hemodynamic changes and volume regulation. Acta Obstet Gynecol Scand 72103, 1993 74. Tuck ML, Davidson MB, Asp N, et al: Augmented aldosterone and insulin responses to potassium infusion in dogs with renal failure. Kidney Int 30:883, 1986
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75. Weidmann P, Maxwell MH, DeLima J, et al: Control of aldosterone responsiveness in terminal renal failure. Kidney Int 7:351, 1975 76. West ML, Bendz 0, Chen CB, et al: Development of a test to evaluate the transtubular potassium concentration gradient in the cortical collecting duct in vivo. Miner Electrolyte Metab 12:226, 1986 77. Wilson DR, Ing TS, Metcalf-Gibson A, et al: The chemical composition of faeces in uremia, as revealed in vivo by faecal dialysis. Clin Sci 35:197, 1968 78. Wilson M, Morganti AA, Zervoudakis I, et al: Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy. Am J Med 68:97, 1980 79. Young DB, McCaa RE, Pan YJ, et al: Effectiveness of the aldosterone-sodium- and potassium-feedback control system. Am J Physiol 231:945, 1976
Address reprint requests to Michael Tuck, MD Ill-E VA Medical Center 16111 Plurnmer Street Sepulveda, CA 91343
0889-8529/95 $0.00
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SECONDARY ALDOSTERONISM Dalila B. Corry, MD and Michael L. Tuck, MD
Secondary hyperaldosteronism occurs in states of low effective arterial blood volume, which activates the renin-angiotensin-aldosterone axis. The resultant increase in plasma aldosterone (PA) concentration stimulates the distal reabsorption of sodium (Na) by the kidney to restore blood volume. This Na-retaining effect occurs in association with an increase in potassium (K) excretion. As a rule, a loss of K is a consequence of all states of hyperaldosteronism, providing that the kidney is normal. This condition is seen even when the serum K is lower than normal and if the organism is K depleted. The serum K level, however, is not always predictable, because in complex pathophysiologic situations or physiologic conditions such as pregnancy, an array of hormonal and nonhormonal factors can alter aldosterone's effect on blood pressure and electrolytes. Likewise, in certain conditions, paradoxic renal salt losses occur despite secondary aldosteronism. This review analyzes the responses of blood pressure, body fluid, Na, and K to an excess of aldosterone in various clinical conditions. NORMAL ALDOSTERONE FUNCTION
The renin-angiotensin-aldosterone system responds to several factors, including intravascular volume changes, Na, and K.52The primary stimulus is through fluid volume because hypovolemia and hyponatremia increase renin release, which in turn acts as a proteolytic enzyme on angiotensinogen to produce angiotensin I. Angiotensin I, in concert
From the Department of Medicine, Olive View Medical Center, Sylmar; the Veteran's Administration Medical Center, Sepulveda; and the School of Medicine, Department of Medicine, University of California, :>os Angeles, Los Angeles, California
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 24. NUMBER 3 . SEPTEMBER 1995
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with the endothelial form of angiotensin-converting enzyme (ACE), is converted to angiotensin IS (AngII). This octapeptide then exerts its action on the adrenal gland to release aldosterone; this response to AngII is greatly increased by a decrease in Na intake. K is the other major regulator of aldosterone, and the adrenal gland responds to K by stimulating aldosterone release independent of body Na, volume status, or the activity of the renin-angiotensin system. Several new aspects to the renin-angiotensin system cascade of peptide production may be important in the interpretation of states of secondary aldosteronism. In addition to AngII, studies show that the decapeptide angiotensin I also is a substrate for the production of the proposed vasodilator heptapeptide, angiotensin 1-7 (AngIII), mediated by tissue endopeptidases. Administration of AngII receptor blockers favors increased production of AngIII, suggesting that the pathway comes into action to protect against rising levels of AngII. Angiotensin 3-8 is another biologically active product of this system whose action is uncertain. The effect of a given circulating level of aldosterone on overall Na handling by the distal tubule depends on several factors, such as the volume of the filtrate reaching the cortical collecting duct and the composition of the luminal and intracellular fluid. In contrast, in K handling, aldosterone operates in a less complex fashion. Aldosterone acts on renal electrolyte transport in two sequential steps. Early it activates the apical Na conductive pathway and thereby the entry of Na into the principal cells of the cortical collecting duct. An increase in the cytosolic Na concentration increases this cation reabsorption via the basolateral Na+,K+ pumps. Later, continued exposure to aldosterone results in the insertion of additional Na+,K+ pump units into the cortical collecting In a healthy kidney, this increase in Na reabsorption is followed by extracellular volume expansion resulting after a few days of continued aldosterone exposure to an augmentation of glomerular filtration rate (GFR), together with an inability for the proximal tubule to further increase its Na reabsorption. Larger loads of Na then are delivered to the cortical collecting duct, which, despite the constant stimulation of aldosterone, allows more Na to stay in the lumen, therefore an escape phenomenon limits the effects of hyperaldosteronism on retention of Na. Aldosterone excess continues, however, to activate K excretion mechanisms, providing a steady stimulus to K depletion. Patients with high levels of mineralocorticoids have a relatively faster reabsorption of Na in the cortical collecting duct. This electrogenic reabsorption of the cation Na in excess of anions generates a negative lumen charge with increases in the transepithelial potential difference, which favors the movement of K into the tubular lumen. The second process is the movement of K via the conducting channels in the apical membrane of the principal cells of the cortical collecting ducts. The conducting properties of these channels are increased by aldosterone, and this effect is enhanced in the presence of active v a s ~ p r e s s i nMore.~~ over, aldosterone increases the density of these K conductive pathways.62
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Consequently, K secretion and excretion stay high throughout the duration of aldosterone exposure. Thus, regardless of the factors triggering and sustaining the state of secondary hyperaldosteronism, the force for K loss is continuous, threatening K homeostasis, whereas the force for Na reabsorption is transient and balanced by other factors, leaving only mild Na retention and volume excess. In cases of complex electrolyte disorders, calculation of the transtubular K gradient (TTKG) permits a semiquantitative evaluation of the K secretory process and represents an index of aldosterone bioactivity. By reflecting the ratio of the concentration of K in the tubular fluid and the plasma, it allows a rapid analysis of a given disorder in K homeo~tasis.~~ ISCHEMIC HYPERTENSIVE CONDITIONS Renovascular Hypertension
Renovascular hypertension (RVH) is the most common cause of secondary hypertension, with a prevalence rate of 0.2% to 5% of the general p o p ~ l a t i o nThe . ~ ~ blood pressure elevation is secondary to renal ischemia, resulting from a variety of extrinsic or intrinsic lesions of one or both renal arteries or their segmental branches. Although the primary lesion is anatomic, this condition is considered to be an endocrine form of hypertension because the altered renal hemodynamics provide a strong stimulus for the renin-angiotensin-aldosterone system. Clinical features in the classic descriptions of RVH include abdominal bruits, accelerated hypertension (often resistant to antihypertensive agents), renal insufficiency, and hypokalemia. In 1975 reported a 16% incidence rate of hypokalemia (K < 3.5 mmol/L) in RVH based on data from the Cooperative Study for Renovascular Hypertension. Other reports have confirmed the association of hypokalemia with RVH, observing an incidence rate between 10% and 20%.9,56 Despite activation of the renin-angiotensin system in RVH, only moderate secondary hyperaldosteronism occurs. Therefore the findings of hypokalemic alkalosis in a hypertensive patient often direct the diagnostic evaluation toward adrenal causes of mineralocorticoid excess (primary aldosteronism) and away from a diagnostic approach seeking renal parenchymal or renal artery disease. In differentiating between states of primary and secondary aldosteronism, basal measures of renin and aldosterone often are not accurate because of their normal physiologic variability. PA and plasma renin activity (PRA) measured in the basal state have improved in diagnostic accuracy, and expressing them as the PA/PRA ratio to screen primary from secondary hyperaldosteronism has been advocated. McKenna and associates45found that when measured under random conditions, the relation between PA and PRA expressed as a ratio differentiates between primary and secondary hyperaldosteronism. Hence, subjects with primary aldosteronism have a disassociation between aldosterone (high)
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and renin (low) and thus, a high PA/PRA ratio (> 50); in secondary causes, however, both aldosterone and renin are high, resulting in a normal PA/PRA ratio (Fig. 1). In most cases of hypertension, this simple test helps to establish the secondary nature of hyperaldosteronism and directs the diagnostic evaluation toward renal artery disease. Although basal circulating PRA often is normal in RVH, administration of an ACE inhibitor to patients with RVH markedly increases PRA levels because of the enhanced release of renin from the ischemic kidney. For example, Imai and othersz9report a large increase in PRA 1 hour after administering 50 mg of captopril orally in patients with RVH. The increments in PRA after captopril are significantly less when administered to essential hypertensive subjects. This test is especially useful in subjects thought to have RVH but who show normal or reduced PRA levels, as may occur in patients taking antihypertensive agents (beta blockers) or in elderly hypertensive subjects. One study of hypertensive patients older than 40 years of age showed that increments in PRA of
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2.6 ng/mL/h or greater after treatment with captopril identified significant renal artery stenosis (sensitivity, loo%, specificity, 78%).28 This defect is reversible, as exemplified in a single patient studied by Ruby and colleagues53with severe hypertension and symptomatic hypokalemia. After surgical revascularization, reversal of the ischemia was followed by complete resolution of the hyperreninemic hyperaldosteronism as PRA, PA, and urinary and serum K normalized (Fig. 2). The two classic animal models of Goldblatt hypertension have provided an understanding of the temporal and adaptive responses in renin and aldosterone to stenosis. In the first model, one renal artery is clamped and the opposite kidney is removed to create one-kidney, one-
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Figure 2. Top panel, serum and urinary K, before and after revascularization of a unilateral renal artery stenosis. Lower panel, PRA and PA in same subject before and after surgery. Closed bars, pre-captopril, open bars, post-captopril. (From Ruby ST, Burch A, White WB: Unilateral renal artery stenosis seen initially as severe and symptomatic hypokalemia: pathophysiologic assessment and effects of surgical revascularization. Arch Surg 128:346, 1993; with permission.)
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clip RVH.41In this preparation, a transient elevation of PRA occurs for 6 to 10 days, then levels decline, but hypertension is sustained by volume expansion. In the other model, the two-kidney, one-clip (2-K, 1-C), model, an elevated PRA persists throughout the chronic maintenance phase of hyperten~ion.~~ A normal contralateral kidney in unilateral RVH should protect against hypertension as well as fluid and electrolyte imbalance, but that is not the case in this model. In the nonstenotic kidney, a rise in local AngII occurs, followed by arterial vasoconstriction, reduced GFR, and enhanced proximal Na retention. This paradoxic response of the normal kidney leads to a blunted pressure natriuresis curve and an increase in total exchangeable Na. From the stenotic kidney, the pressure distal to the lesion is never completely restored, thus it continues to provide a stimulus for renin release, whereas the contralateral kidney loses its ability to mount an adequate natriuretic response.49 It is not always possible to extrapolate some of the observations in experimental animals to clinical RVH in humans. Several studies report that the nonstenotic kidney often responds with an appropriate pressure natriuresis. Blanc and others7describe a case of malignant hypertension in a neonate who had hypovolemia secondary to severe renal Na losses, hypokalemia, and high PRA. An abdominal angiogram revealed nearly complete stenosis of the right renal artery but a normal left kidney. The clinical findings totally resolved with surgery, and because the involved kidney was completely occluded, the authors concluded that the normal kidney was responsible for the Na losses. McAreavy and coworkers44 studied 30 patients with unilateral renal artery stenosis and 5 with bilateral disease, measuring serum Na and K, exchangeable Na, plasma renin, AngII, and aldosterone. They identified six patients who were frankly hyponatremic and observed that they had higher blood pressure; lower plasma K levels; lower exchangeable Na; and higher PRA, AngII, and aldosterone. In these subjects, Na excretion was greater from the nonstenotic kidney and a positive correlation existed between the rate of Na excretion and arterial pressure. Hence, RVH patients with the highest rate of urinary Na loss seem to have the most severe hypertension and the lowest exchangeable Na (Fig. 3). Sato and associates60 studied changes in 22Naturnover and totalbody potassium during acute and chronic phases of hypertension in 2-K, 1-C rabbits. 22Nainjected intravenously was eliminated faster in hypertensive rabbits than in controls. Plasma aldosterone increased during the acute phase, and total-body potassium decreased significantly during the maintenance phase. A significant correlation was obtained between 22Naturnover and blood pressure. The authors concluded that volume overload was not a major factor in the acute or the chronic phase of hypertension in the RVH rabbit and that pressure natriuresis could explain the loss of Na. In rats with 2-K, 1-C RVH, Swales and colleague^^^ also found a significant correlation between arterial pressure and cumulative Na depletion. After removal of the contralateral kidney, natriuresis was reduced and exchangeable Na increased. In addition,
SECONDARY ALDOSTERONISM
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Exchangeable Sodium (%)
Figure 3. Relation of the blood pressure to the exchangeable Na in patients with hyponatremia (A) and patients with normal serum Na (@). (From McAreavey D, Brown J, Cumming AMM, et al: Inverse relation of exchangeable sodium and blood pressure in hypertensive patients with renal artery stenosis. J Hypertension 1:297, 1983; with permission.)
AngII may directly participate in the Na response in renal artery stenosis by increasing pressure natriuresis and by exerting a natriuretic action on the Thus, in RVH, a variable secondary aldosteronism exists, and its effect on K loss or Na retention seems minimal. In fact, there is a greater and more consistent tendency toward Na loss from the contralateral, nonstenotic kidney that occurs independent of aldosterone and seems best related to blood pressure and the local effects of renal AngII. Malignant Hypertension
Malignant hypertension is accompanied by intense secondary aldosteronism, yet like in RVH, a tendency toward Na and volume depletion exists, which is more marked as the blood pressure increases. Many reports describe an inverse correlation between volume and blood pressure. With extracellular fluid volume being reduced by as much as 30%,
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these patients have renal sodium loss and volume depletion despite the increased levels of renin and ald~sterone.~ A vicious cycle is then set up where renal ischemia and volume depletion lead to further stimulation of renin release, AngII production, and aldosterone secretion. The shortloop feedback whereby AngII directly inhibits renin secretion is inoperative and is overriden by hyponatremia and hypovolemia, which act as intense stimuli for renin release. When faced with this state of severe hypertension with paradoxic increase in Na and water excretion, the therapy should address the systemic vasoconstriction and also should reestablish and maintain euvolemia. Stimulation of the renal juxtaglomerular cells to secrete large amounts of renin also is seen in patients with polyarteritis nodosa. These patients commonly have hypertension, high renin and aldosterone levels, and hyp~kalemia.~~ In 1948 Davson and others16 suggested that the hypertension in polyarteritis nodosa was secondary to renal ischemia as a result of the marked narrowing of the renal arterioles. In 1979 Stockigt and c o - ~ o r k e r soffered ~ ~ proof that the hypertension in polyarteritis nodosa was angiotensin dependent by eliciting a marked hypotensive response to blockade of the renin-angiotensin system with administration of the agent saralasin. Graham and LindopZ4confirmed the clinical hypothesis of renin dependency using immunocytochemical staining and by showing hyperplasia of renin-containing cells in the juxtaglomerular apparatus in focal ischemic areas of kidneys affected by classic polyarteritis nodosa.
Renin-producing Tumors
Renin-producing tumors, a rare form of hypertension usually occuring in young adults with severe hypertension and hypokalemia, are one of the best examples of secondary aldosteronism. The volume response to aldosterone seems more appropriate because the hypertension in renin-producing tumors is accompanied by normovolemia, rather than the hypovolemia of RVH and malignant hypertension. In this condition, sometimes termed primary reninism, the levels of PRA are among the highest recorded in hypertensive syndromes, often exceeding 50 ng/mL/h. Because these tumors can release immature forms of renin, the level of prorenin is elevated, and a high prorenin-to-renin ratio can distinguish this disorder from essential hypertension or RVH. Hypokalemia is the most constant routine laboratory finding, often being severe (Kc2.0 mmol/L), and is completely attributable to mineralocorticoidinduced renal K wasting. Several renin-producing tumors can cause this syndrome, and most of them are renal in origin. They include hemangioperi~ytomas~~ and renal cell carcin0mas,6~where endothelial cells are producing the renin and Wilms tumors. Some unusual extrarenal tumors also have been implicated, such as renin-producing Sertoli cell ovarian tumors34and pheochromocytomas, where the hyperreni-
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nemia is secondary to the excessive catecholamines, which then stimulate the juxtaglomerular cells to release renin.39 Pregnancy
Human gestation is characterized by a complex balance in the control of Na homeostasis and hemodynamic adjustments, following the need for Na by the expanding fetoplacental unit. A primary arterial vasodilation occurs selectively and early in pregnancy and leads to several consequences, including decreased systolic and diastolic blood pressure, enhanced cardiac output, a nonosmotic stimulation of thirst with increased vasopressin release, and stimulation of the renin-angiotensin system. Levels of sex steroid hormones such as estrogens and progesterone rise and contribute to the vasodilation. Normal pregnancy also has been associated with an early and marked refractoriness of blood pressure to AngII.20This loss of AngII pressor effect went unexplained for years, but evidence suggests a role for the endothelium and nitric animal models of pregnancy show increased plasma and urinary cyclic guanosine monophosphate, the second messenger for endothelium-derived relaxing factor." svstem occurs earlv The increase in activitv Gf the renin-an~iotensin " in pregnancy in association with the fall in systemic vascular resistance and occurs despite the increase in blood volume. In 1980 Wilson and colleagues78sequentially studied blood pressure, the renin-angiotensin system, and sex steroids throughout pregnancy and again 4 to 6 weeks after delivery. By 8 weeks of pregnancy, PRA was twice as high as baseline and doubled again by the 20th week to remain stable until term. By 8 weeks, mean PA had increased from 6.2 1.1 to 16.4 + 4.7 ng/dL. PA levels continued to rise during the next 2 months and then remained stable during the second trimester, but again rose to peak at mean levels of 59.4 + 13.9 ng/dL in the last trimester. These studies, which describe an early and sustained stimulation of the renin-angiotensin-aldosterone system, also have found a strong positive correlation between PA and PRA throughout pregnancy. Wilson and others77also observed a direct correlation bet-ween PA and progesterone, estradiol, and estriol. During pregnancy, plasma progesterone levels double by 8 weeks' gestation and continue to rise to reach a peak of 17-fold over baseline. To test the relation between sex steroids and aldosterone, Sealy and associates59measured PRA and aldosterone in eight patients undergoing ovarian stimulation in preparation for in vitro fertilization. They observed a marked increase in PRA and aldosterone, with ovarian stimulation that correlated with the rise in plasma progesterone and estradiol. Parallel results were seen in these same women when studied again during early pregnancy. In this study, PRA and aldosterone levels were high, yet hypokalemia was not observed. The maintenance of normokalemia throughout pregnancy is surprising because several factors such as high aldosterone, mild alkalosis, and increased vasopressin i
+
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are acting in force to promote urinary K loss. When electrolyte balance is studied during pregnancy, urinary Na and K excretion seems independent of the fluctuations in PRA and aldosterone (Fig. 4). Brown and others8 studied 14 healthy women on ad libitum diets, confirming that K excretion is held constant throughout pregnancy. The mechanisms responsible for K conservation in the face of high aldosterone remain unknown. An antikaliuretic role for progesterone, whose levels parallel aldosterone, has been proposed. Sharp and c o l l e a g ~ e sdemonstrated ~~ in
Gestation (weeks) Figure 4. Sequential relation throughout pregnancy of plasma aldosterone, urine aldosterone, urinary sodium, and potassium. (From Wilson M, Morganti AA, Zervoudakis I, et al: Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy. Am J Med 68:97, 1980; with permission.)
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vitro, an antimineralocorticoid effect of progesterone. Tamas and others70 sequentially measured urinary Na and K, TTKG, aldosterone, vasopressin, and endothelin-1 levels in 12 healthy pregnant women. TTKG was found to be low despite the high plasma and urinary aldosterone levels, suggesting resistance to aldosterone's action. Because urinary endothelin-1 excretion was increased, the authors postulated antialdosterone properties for the renal form of endothelin-1, which inhibits Na+,K+ATPase activity in the medullary collecting duct. During gestation, Na excretion does not correlate with aldo~terone,7~ yet the ability of the kidney to eliminate an acute Na load is not impaired, suggesting other factors in Na regulation. A relation of Na balance to atrial natriuretic peptide (ANP) has been reported in pregnancy.'j4 Earlier reports describe substantial increases in plasma ANP during pregnancy,15,72 and it was proposed that ANP was responsible for the peripheral vasodilation and the AngII resistance. Recent 35 using more sensitive assays, however, have observed reductions in ANP levels during pregnancy, most marked in the early phase and in the third trimester, when mechanisms to maintain volume expansion are most needed. Likewise, Thomsen and co-workers" found significantly lower levels of ANP in twin pregnancy, a state of even greater volume dependency compared with single gestation.35The usual inverse relation of ANP to aldosterone is preserved in pregnancy, considering that studies show high aldosterone/ANP ratios.18,66 These data indicate that ANP represents another mechanism contributing to the maintenance of blood volume, and, by responding to dietary intake and posture, ANP mav allow more flexibilitv than aldosterone in the modulation of sodium bafance. Overall, in pregnancy the evidence suggests a state of intense secondary aldosteronism, yet there are few manifestations of an excess of mineralocorticoid action. The major effect of aldosterone excess seems to be its contribution to the requisite volume expansion of gestation, yet its potential detrimental effects (high blood pressure and K loss) seem to be offset by other hormonal and hernodynamic changes in normal pregnancy. Chronic Renal Failure
Subjects with chronic renal failure display some features of aldosteronism, such as a low Na/K ratio in the ~ a l i v aand ~ ~ in , ~the ~ In addition, other studies have shown elevated plasma aldosterone in endstage renal disease,1275 but evidence for secondary aldosteronism often is not apparent because the characteristic findings are masked by other uremic complication^.^^, 67 Despite the absence of renal K excretion in hemodialysis patients, only a few develop hyperkalemia in the interdialytic period. This indicates that in uremia, nonrenal K disposal mechanisms assume a critical role in the defense against hyperkalemia. Normally two mechanisms
account for K homeostasis, both involving aldosterone. The first maintains K balance by matching K excretion to dietary intake, with the kidney excreting 90% to 95% of total ingested K and the gut, 5% to Panese and others50 found a 2.5-fold increase in active rectal K secretion in patients with chronic renal failure. Likewise, Hayes and colleagues27showed that about 30% of dietary K is excreted via the intestinal route in chronic renal failure compared with 12% in controls, and in patients with successful kidney transplants, the recovery of renal function is accompanied by a reduction in fecal K excretion. Uremic patients placed on a low-K diet decrease their intestinal K excretion, raising the question of whether this adaptation represents a decreased gut absorption of K or a true active secretion. Martin and using the dialysis bag technique, found increased rectal K excretion and negative potential difference across the intestinal lumen in patients with chronic renal failure. In this study, plasma aldosterone levels were higher in patients than in controls; however, the scatter of data on aldosterone precluded an assessment of its role. Sandle and ass0ciates,5~using the same techniques, found higher rectal K excretion in 10 individuals on chronic ambulatory dialysis and 7 on intermittent hemodialysis, but no difference in aldosterone between patients and controls. Recently the same studied the effect of a 70% nephrectomy on K transport in rats fed a regular diet. In isolated preparations of the distal colon, they found no changes in the Na and K conductance. In contrast, in animals fed a diet enriched in K, nephrectomy resulted in a large amiloride-sensitive elevation in transepithelial voltage, and studies in the distal colonic epithelium revealed a twofold increase in basolateral Na+,K+ pump activity. In essence, all of the above studies support a role for aldosterone in the K adaptation in uremia. The second mechanism for K disposal shifts K from extracellular to intracellular compartment^.^ This process, referred to as extrarenal K disposal, is rapid, taking place within a few minutes. It is known that acute and chronic administration of K increases aldosterone secretion in animals79and humans,17,l9 but its participation in mediating cellular K shifts is less certain. Although insulin and beta-adrenergic stimulation are established mediators of extrarenal K disposal, data favor a role for aldosterone. Alexander and Levinsky3 showed that normal rats maintained chronically on a high-K diet have enhanced tolerance to an acute K load. This protective effect of chronic high-K intake against acute K changes in serum is present even in nephrectomized rats, suggesting a shift away from the kidneys toward extrarenal K pathways.68This process is abolished by adrenalectomy and restored by administration of desoxycorticosterone, suggesting a mineralocorticoid effect. This role for mineralocorticoids has been confirmed by Tuck and who reported that the peak incremental response of aldosterone to potassium chloride infusion was higher in dogs that underwent nephrectomy than in controls (Fig. 5). These findings also indicate an enhanced adrenal sensitivity to K in uremia. Sugerman and assessing the effect of mineralocorticoids on K disposal in anephric individuals, measured
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Figure 5. Incremental changes in plasma aldosterone in response to KCL infusion in control and renal failure dogs maintained on 60 mEq (A) or 200 mEq (B) potassium diet. (From Tuck ML, Davidson MB, Asp N, et al: Augmented aldosterone and insulin responses to potassiuim infusion in dogs with renal failure. Kidney Int 30:883, 1986; used with permission from Kidney International.)
serum K, aldosterone, and salivary and fecal electrolytes in response to K loading over 48 hours, followed by an acute oral K load. They found that the volume of distribution of the acute K load was greater with deoxycorticosterone (DOCA) than with spironolactone administration and concluded that a mineralocorticoid effect was required in extrarenal K disposal. A moderately convincing case for secondary aldosteronism can be made in chronic renal failure; however, its profile is unique. The driving force for aldosterone release is not the renin-angiotensin system but the potassium ion. The site of action of aldosterone is not on the kidney but is shifted to other targets. The excess aldosterone is not detrimental, but in fact is mostly beneficial for K homeostasis and needs to be preserved. Because aldosterone seems to be as vital as insulin21 in preventing hyperkalemia in renal failure, it is critical to use caution with therapies that interfere with its effect, such as ACE inhibitors or beta blockers. Iatrogenic Secondary Hyperaldosteronism Intestinal Diversion
Intestinal diversion offers another example of secondary aldosteronism. The management of bladder extrophy, carcinoma of the bladder, or urine incontinence may require insertion of the ureter into the intestine. Sometimes creation of an intestinal or gastric pouch to replace or augment the bladder is needed. The metabolic complications of these tech-
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niques are multiple and are related to the absorptive and secretory properties of the gastrointestinal segment incorporated in the urinary tract. When gastric tissue is used for urinary reconstruction, severe secondary hyperaldosteronism with subsequent hypochloremic, hypokalemic metabolic alkalosis can occur.32Gosalbez and associatesz3report the case of two children in whom severe hypochloremic, hypokalemic metabolic alkalosis developed after volume depletion secondary to gastrointestinal losses. One patient, who had mild elevations of plasma gastrin levels, responded to Hz blockers. The second was found to have marked hypergastrinemia and high PA and PRA levels, and failed to respond to Hz blockers and the H-K pump blocker, omiprazole. In this setting the metabolic alkalosis was thought to be related to an excessive excretion of hydrochloric acid by the gastric pouch. Volume depletion often triggers this acid-base imbalance, but it also has been reported with normal body fluid. Intense secondary hyperaldosteronism also can complicate small bowel resection.25 This is related primarily to loss of colon function. Patients with an ileostomy have high stomal Na output leading to Na depletion, low urinary Na, and high aldosterone. Ladefoged and 01gaar~ ~~ compared plasma volume, PA, PRA, and urine Na and K excretion in 16 patients with small bowel resection: 8 had ileostomy and 8 had at least half of the colon in place. Patients with at least half of the colon intact were only slightly volume contracted and had normal aldosterone and PRA. In contrast, patients with no colonic function displayed high aldosterone levels, which were positively correlated to renal Na excretion and plasma volume. An infusion of aldosterone further decreased their urinary Na excretion but did not affect stomal Na losses. In ureteral diversion and bowel resection, the secondary aldosteronism, although appropriate, often fails to reestablish normal volume and electrolyte homeostasis, requiring either reversal of the procedure or other temporizing measures, such as saline Infusion or administration of Hz blockers to counteract its complications. Cyclosporin-induced Hypertension
Cyclosporine is an 11-amino acid fungal peptide widely used as an immunosuppressive agent to prevent allograft rejection. It is also used in the treatment of various autoimmune diseases. This agent is known to have significant side effects. The most important side effect is a doserelated nephrotoxicity, manifested by a rise in serum creatinine with a simultaneous decrease in GFR.33The compound was found to reduce renal blood flow, GFR, and sodium excretion whereas it produces vasoconstriction of the glomerular afferent arteriole with increased renal vascular resistance and hypertension. The cyclosporine induced hypertension is associated with a marked increase in sympathetic nervous but the renin-angiotensin-
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aldosterone system also has been implicated in the pathogenesis. Julien and others30 found that supine and upright PRA levels were increased with a low-Na diet in 33 hypertensive transplant patients. In the liver allograft recipients, plasma aldosterone in the upright position also was significantly elevated. Ciresi and associate^'^ showed that chronic administration of cyclosporine to dogs reduces the Na excretion associated with activation of the renin-angiotensin system. Cugini and others13 found high PRA and aldosterone levels in 18 cyclosporine-treated transplant patients. In a subsequent study of 13 cardiac transplant patients, the same authors14 confirmed the existence of hyperreninemic hyperaldosteronism associated with elevated ANP levels. Although cyclosporine seems to cause a state of hyperaldosteronism accompanied by high renin, controversies have originated from the fact that its administration can be complicated by hyperkalemia. In fact, some investigators have found hyporeninism and hypoaldosteronism in hyperkalemic, cyclosporine-treated patients,' whereas others describe normal PRA and ddosterone or higher peak aldosterone levels in response to an acute potassium load. Aguilera and others2 measured PRA, PA, and TTKG in five cvclosvorine-treated subiects with idiovathic uveitis and in five who I were not on the agent. ~idosteroneand ?TKG were positively correlated in both groups, suggesting an incomplete form of tubular acidosis rather than tubular resistance to aldosterone. Kame1 and others31 related the hyperkalemia to an increased permeability of the tubule to chloride in the presence of cyclosporine. This newer understanding of the pathophysiologic mechanisms also implies that treatment of cyclosporineinduced hyperkalemia with loop diuretic agents is more effective than the use of mineralocorticoid agents. i
SUMMARY
Conditions of secondary aldosteronism are common in clinical medicine, occurring in normotensive and hypertensive settings. In some conditions such as edema disorders, this represents a partially beneficial response to restore volume and Na at the expense of hypokalemia. In RVH and malignant hypertension, the aldosteronism may be beneficial, but most evidence shows a detrimental impact. In both situations, aldosterone does not compensate fully for Na degredation and facilitates K loss. In pregnancy, aldosterone's effect is more successful for volume conservation, and the action on K is almost completely overridden by other K-sparing factors. Chronic renal failure seems to best benefit from hyperaldosteronism, but the response is limited because aldosterone must act on extrarenal targets. In iatrogenic causes of secondary aldosteronism, the effects of aldosterone are mostly detrimental. The overall conclusion supports the hypothesis that aldosterone functions best in physiologic situations, but in pathophysiologic settings it does not perfectly compensate for the basic defect. This implies that in these complex
conditions, successful therapy should address the disorder in aldosterone and also the other underlying pathophysiologic mechanisms.
References 1. Adu D, Michael J, Turney J, et al: Hyperkalaemia in cyclosporin-treated renal allograft recipients. Lancet 1:371, 1983 2. Aguilera S, Derey G, Desjobert H, et al: Effects of cyclosporine on tubular acidification function in patients with idiopathic uveitis. Am J Nephrol 12425, 1992 3. Alexander EA, Levinsky NG: An extrarenal mechanism of potassium adaptation. J Clin Invest 47740, 1968 4. Bantle JP, Nath KA, Sutherland ER, et al: Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients. Arch Intern Med 145:505, 1985 5. Barraclough MA: Sodium and water depletion with acute malignant hypertension. Am J Med 40:265, 1966 6. Bast1 C, Hayslett JP, Binder HJ: Increased large intestinal secretion of potassium in renal insufficiency. Kidney Int 12:9, 1977 7. Blanc F, Bensman A, Baudon JJ: Renovascular hypertension: A rare cause of neonatal salt loss. Pediatr Nephrol 10:304, 1991 8. Brown MA, Sinosich MJ, Saunders DM, et al: Potassium regulation and progesteronealdosterone interrelationships in human pregnancy: A prospective study. Am J Obstet Gynecol 155:349, 1986 9. Bunchman TE, Sinaiko AR: Renovascular hypertension presenting with hypokalemic metabolic alkalosis. Pediatr Nephrol 4:169, 1990 10. Ciresi DL, Lloyd MA, Sandberg SM, et al: The sodium retaining effects of cyclosporine. Kidney Int 41:1599, 1992 11. Conred KP, Vernier KA: Plasma level, urinary excretion and metabolic production of cGMP during gestation in rats. Am J Physiol 257:R847, 1989 12. Cope CL, Pearson J: Aldosterone secretion in severe renal failure. Clin Sci 25:331,1963 13. Cugini P, Battisti P, DiPalma L, et al: Secondary aldosteronism documented by plasma renin and aldosterone circadian rhythm in subjects with kidney or heart transplantation. Ren Fail 14:69, 1992 14. Cugini P, Lucia P, Scibilia G, et al: Twenty-four-hour pattern of atrial natriuretic peptide in heart transplantation: Evidence for lack of circadian rhythm. Int J Cardiol 42:7, 1993 15. Cusson JR, Gutkowska J, Rey E, et al: Plasma concentration of atrial natriuretic factor in normal pregnancy. N Engl J Med 313:1230, 1985 16. Davson J, Ball J, Platt R: The kidney in periarteritis nodosa. Q J Med 17175, 1948 17. Dluhy RG, Axelrod L, Underwood RH, et al: Studies of the control of plasma aldosterone concentration in normal man: 11. Effect of dietary potassium and acute potassium infusion. J Clin Invest 51:1950, 1972 18. Finn WL, Tunny TJ, Klemm A, et al: Sodium and volume dysregulation after apparently normal pregnancy is suggested by abnormal levels of atrial natriuretic peptide, renin and aldosterone. Clin Exp Pharm Physiol 18:269, 1991 19. Gann DS, Delea CS, Gill JR, et al: Control of aldosterone secretion by change of body potassium in normal man. Am J Physiol207104, 1964 20. Gant NF, Daley GL, Chand S, et al: A study of angiotensin I1 pressor response throughout primagravid pregnancy. J Clin Invest 52:2682,1973 21. Gifford JD, Rutsky EA, Kirk KA, et al: Control of serum potassium during fasting in patients with end-stage renal disease. Kidney Int 35:90, 1989 22. Go11 RD, Mookerjee BK: Correlation of biochemical parameters in serum and saliva of chronic azotemic patients and patients on chronic hemodialysis. J Dialysis 2399, 1978 23. Gosalbez R, Woodard JR, Broecker BH, et al: Metabolic complications of the use of stomach for urinary reconstruction. J Urol 150:710, 1993
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49. Navar LG: Renovascular hypertension: Pathophysiology. In Izzo JI, Black HR (eds): Hypertension Primer. Dallas, American Heart Association, 1993, p 99 50. Panese S, Martin RS, Virginillo M, et al: Mechanism of enhanced transcellular potassium secretion in man with chronic renal failure. Kidney Int 31:1377, 1987 51. Pedrinelli R, Graziadei L, Taddei S, et al: A renin-secreting tumor. Nephron 46:380, 1987 52. Quinn SJ, Williams GH: Regulation of aldosterone secretion. Annu Rev Physiol 50:409, 1988 53. Ruby ST, Burch A, White WB: Unilateral renal artery stenosis seen initially as severe and symptomatic hypokalemia: pathophysiologic assessment and effects of surgical revascularization. Arch Surg 128:346, 1993 54. Sandle GI, Gaiger E, Tapster S, et al: Evidence for large intestinal control of potassium homoeostasis in uraemic patients undergoing long-term dialysis. Clin Sci 73:247, 1987 55. Sandle GI, McGlone F, Davies RJ: Electrophysiology of rat distal colon after partial nephrectomy: Implications for K transport. Pflugers Arch 412172, 1988 56. Savin H, Jutrin I, Ravid H: Persistent hypokalemia due to bilateral fibromuscular dysplasia of the renal arteries. Clin Nephrol 25:199, 1986 57. Scherrer V, Vissing SF, Morgan BJ, et al: Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. N Engl J Med 328:693, 1990 58. Schon DA, Silva P, Hayslett JP: Mechanism of potassium excretion in renal insufficiency. Am J Physiol 227:1323, 1974 59. Sealy JE, Itskovitz-Eldor J, Rubattu S, et al: Estradiol- and progesterone-related increases in the renin-aldosterone system: Studies during ovarian stimulation and early pregnancy. J Clin Endocrinol Metab 79:258, 1994 60. Sato S, Kaku T, Kurimochi M, et al: Changes in sodium-22 turnover and total body potassium in two-kidney, one-clip renovascular hypertension. Jpn Circ J 55:524, 1991 61. Sharp GW, Komack CL, Leaf A: Studies on the binding of aldosterone in the toad bladder. J Clin Invest 45:450, 1966 62. Stanton B, Pan L, Deetjen H, et al: Independent effects of aldosterone and potassium on induction of potassium adaptation in rat kidney. J Clin Invest 79:198, 1987 63. Steffens J, Bock R, Braedel HU, et al: Renin-producing renal cell carcinoma. Eur Urol 18:56, 1990 64. Steegers EAP, Benraad TJ, Jongsma HW, et al: Effects of dietary sodium restriction and posture on plasma levels of atrial natriuretic peptide, aldosterone and free aldosterone in normal human pregnancy. J Endocrinol 124507, 1990 65. Stockigt JR, Topliss DJ, Heweth MF: High renin hypertension in necrotizing vasculitis [letter]: N Engl J Med 300:1218, 1979 66. Stratta P, Canavese C, Gurioli L, et al: Ratio between aldosterone and atrial natriuretic peptide in pregnancy. Kidney Int 36:908,1989 67. Sugarman A, Brown RS: The role of aldosterone in potassium tolerance: Studies in anephric humans. Kidney Int 34:397,1988 68. Sugarman A, Khan T: Parathyroid hormone impairs extrarenal potassium tolerance in the rat. Am J Physiol254:F385, 1998 69. Swales JD, Thurston H, Queiroz PP, et al: Sodium balance during the development of experimental hypertension. J Lab Clin Med 83539, 1972 70. Tamas P, Worgall S, Sulyok E, et al: Renal electrolyte and water handling in normal pregnancy: Possible role of endothelin-1. Eur J Obstet Gynecol Reprod Biol55:89,1994 71. The1 MC, Mannon RB, Allen NB: Hyperrenin-hyperaldosterone dependent malignant hypertension in polyarteritis nodosa. South Med J 86:1400, 1993 72. Thomsen , TK., Storm TL, Thamsborg G, et al: Increased concentration of circulating atrial natriuretic peptidd during noymal pregnancy. Eur J Obstet Gynecol Reprod ~ i z 27:197, 1988 73. Thomsen Fogh-Anderson N, Jaszczak P, et al: Atrial natriuretic peptide (ANP) decreases during normal pregnancy as related to hemodynamic changes and volume regulation. Acta Obstet Gynecol Scand 72103, 1993 74. Tuck ML, Davidson MB, Asp N, et al: Augmented aldosterone and insulin responses to potassium infusion in dogs with renal failure. Kidney Int 30:883, 1986
w,
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75. Weidmann P, Maxwell MH, DeLima J, et al: Control of aldosterone responsiveness in terminal renal failure. Kidney Int 7:351, 1975 76. West ML, Bendz 0, Chen CB, et al: Development of a test to evaluate the transtubular potassium concentration gradient in the cortical collecting duct in vivo. Miner Electrolyte Metab 12:226, 1986 77. Wilson DR, Ing TS, Metcalf-Gibson A, et al: The chemical composition of faeces in uremia, as revealed in vivo by faecal dialysis. Clin Sci 35:197, 1968 78. Wilson M, Morganti AA, Zervoudakis I, et al: Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy. Am J Med 68:97, 1980 79. Young DB, McCaa RE, Pan YJ, et al: Effectiveness of the aldosterone-sodium- and potassium-feedback control system. Am J Physiol 231:945, 1976
Address reprint requests to Michael Tuck, MD Ill-E VA Medical Center 16111 Plurnmer Street Sepulveda, CA 91343