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Primary Hyperaldosteronism without Suppressed Renin Due to Secondary Hypertensive Kidney Damage

Division of Endocrinology, Department of Medicine, Klinikum Benjamin Franklin, Freie Universität Berlin, 12200 Berlin, Germany

Address all correspondence and requests for reprints to: Prof. W. Oelkers, M.D., Klinikum Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail: oelkers{at}medizin.fu-berlin.de

	Abstract

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Primary hyperaldosteronism is characterized by high plasma and urinary aldosterone and suppressed PRA. Renin suppression is due to aldosterone-dependent sodium retention and mild extracellular volume expansion. We observed three patients with primary hyperaldosteronism, severe refractory hypertension, and normal to high normal PRA levels whose aldosterone/renin ratios were still elevated because of disproportionately high aldosterone levels. All available medical data on the patients as well as publications on the aldosterone/renin relationship in primary hyperaldosteronism were reviewed to explain the unusual findings.

In one patient, histologically proven renal arteriolosclerosis was the probable cause of the escape of PRA from suppression by an aldosterone-producing adenoma. In the other two patients, hypertensive kidney damage due to primary hyperaldosteronism was the most likely explanation for the inappropriately high PRA, as in patient 1. All patients had high normal or slightly elevated serum creatinine levels and responded to 200 mg spironolactone/day with increased serum creatinine and hyperkalemia. Hyperkalemia was probably due to a decreased filtered load of sodium and a spironolactone-induced decrease in mineralocorticoid function. Two patients were cured of hyperaldosteronism by unilateral adrenalectomy but still need some antihypertensive therapy, whereas one patient has probable bilateral adrenal disease, with normal blood pressure on a low dose of spironolactone.

In patients with severe hypertension due to primary hyperaldosteronism, PRA can escape suppression if hypertensive kidney damage supervenes. An increased aldosterone/PRA ratio is still useful in screening for primary hyperaldosteronism. These patients may respond to spironolactone therapy with a strong increase in serum creatinine and potassium. Early specific treatment of primary hyperaldosteronism is therefore indicated, and even a patient with advanced hypertension will profit from adrenalectomy or cautious spironolactone treatment.

	Introduction

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THE CLINICAL course of primary hyperaldosteronism can be extremely variable. A typical clinical constellation that raises suspicion of hyperaldosteronism is arterial hypertension plus hypokalemia. In early stages of the disease, serum potassium may still be in the normal range, and hypertension may be mild or very severe (1, 2, 3, 4). Even in normotensive patients, hypokalemia may be due to primary hyperaldosteronism (5). As renin via angiotensin II is the most important regulator of aldosterone secretion, increased or high normal plasma and urinary aldosterone and suppressed renin activity (PRA) or renin concentration are the typical hormonal findings that establish the diagnosis of primary hyperaldosteronism. As aldosterone is increased and renin suppressed, the aldosterone/renin ratio is increased. A plasma aldosterone (nanograms per dL) to PRA (nanograms per mL/h) ratio of more than 20 in conjunction with a plasma aldosterone level greater than 15 ng/dL (>0.42 nmol/L) makes the diagnosis of primary hyperaldosteronism very likely (2).

After establishing the diagnosis of primary hyperaldosteronism, it is important to determine whether the syndrome is caused by an adrenal adenoma (Conn’s syndrome), by idiopathic primary hyperaldosteronism without a tumor, or by some other very rare underlying adrenal disorders. Several recent reviews competently describe the differential diagnostic procedures (1, 2, 3, 4).

The present study presents three case histories to demonstrate that a normal or even a high normal PRA does not necessarily exclude the diagnosis of primary hyperaldosteronism. The findings indicate that severe arterial hypertension caused by primary hyperaldosteronism may lead to arteriolosclerotic kidney damage that counteracts renin suppression and accelerates the course of hypertension. Nevertheless, adequate treatment of primary hyperaldosteronism is still a very effective means for controlling hypertension in such patients.

	Case Histories

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Patient 1

In August 1974, a 46-yr-old male was referred to our endocrine/hypertension clinic because of severe refractory hypertension with blood pressure levels between 220/120 and 270/150 mm Hg. He had severe headaches, blurred vision, and palpitations and felt very weak. He had been treated with 0.4 mg reserpine, 40 mg furosemide, and analgesics before admission. His body mass index was 21.7 kg/m². The blood pressure was 270/150 mm Hg in both arms and was similar in the legs. No periumbilical or carotid bruit was heard. The cardiac apex beat was prominent; the heart rate was 60 beats/min and regular. The lungs were clear, and all peripheral pulses were palpable. Funduscopy showed bilateral retinopathia angiospastica without papilledema, and the electrocardiogram indicated severe left ventricular hypertrophy and horizontally depressed ST segments in the Wilson leads V3 to V6. The chest x-ray showed a slightly enlarged heart without pulmonary congestion.

Serum potassium was between 3.4–4.1 mmol/L, sodium was 139–144 mmol/L, and creatinine was 98–111 µmol/L. There was mild proteinuria without hematuria. After 6 days on a normal diet and 4 days on a standard diet containing 135 mmol sodium/day and 70 mmol potassium/day with no diuretic therapy, urinary aldosterone (18-glucuronide) excretion was elevated (78 nmol/day; normal, 8–44 nmol/day). Plasma aldosterone was not measured at that time. PRA was 2.2 ng/mL·h recumbent (normal, 0.5–4.0) and 5.5 ng/mL·h upright (normal, 1.0–6.0).

Urinary aldosterone excretion and PRA were hardly suppressed by a diet containing 300 mmol/day sodium plus 0.5 mg 9-fluorocortisol/day for 3 days (Fig. 1). Although renin was normal, the patient was considered to have primary hyperaldosteronism.

View larger version (65K): [in this window] [in a new window]   Figure 1. Patient 1. A, Unusually high PRA (recumbent and upright; arrows) compared to other patients with primary hyperaldosteronism on a normal (upper panel) or high (lower panel) sodium diet. Shaded zones, Normal ranges. AER, Aldosterone excretion rate. AER (µg/24 h) x 2.77 = nmol/24 h. B, Left adrenal venogram showing displaced intraadrenal veins surrounding the tumor (arrows). C, Adrenal adenoma of patient 1.

Postoperatively, urinary aldosterone excretion was low normal (11.9 nmol/day), and upright PRA ranged between 4–6 ng/mL·h. This result suggests that the tumor removed was an aldosteronoma and not an adrenal incidentaloma. Blood pressure control remained unsatisfactory until 1981, when minoxidil therapy (10 mg/day; plus pindolol and furosemide) was introduced. The blood pressure was then 130–150/70–85 mm Hg, serum potassium was 4.2–4.8 mmol/L, and serum creatinine was 133–150 µmol/L. However, the facial and leg edema that often accompanies treatment with minoxidil could not be fully controlled with diuretics. In 1993, minoxidil was replaced by 10 mg enalapril/day (plus 25 mg hydrochlorothiazide and 80 mg delayed action nifedipine). The now 61-yr-old patient feels well. His blood pressure is 130–150/70–90 mm Hg, with normal serum electrolytes and a serum creatinine level of 115 µmol/L. On this therapy, his PRA was 17.5 ng/mL·h and plasma aldosterone was 0.44 nmol/L (normal) in July 1999.

Patient 2

In May 1996, a 59-yr-old woman with severe refractory hypertension was referred to us from a community hospital, where she had been admitted because of orthopnea with a blood pressure of 280/170 mm Hg and a serum potassium of 2.9 mmol/L. She had previously been treated with a calcium channel blocker (amlodipine), delayed action metoprolol, dihydralazine, and 30 mg furosemide. Her hypertension was diagnosed in 1989, when her blood pressure was more than 200/120 mm Hg.

On admission, she had a body mass index of 31.6 kg/m² and a blood pressure of 200/100 mm Hg in both arms and legs. The cardiac apical beat was slightly displaced to the left; the lungs were clear, and no periumbilical or carotid bruit was heard. Funduscopy showed extremely narrow retinal arteries without hemorrhages or papilledema. Electrocardiogram and echocardiography indicated left ventricular hypertrophy with normal systolic function. Urinalysis revealed 2+ proteinuria, which almost disappeared after normalization of blood pressure.

At initial laboratory tests, serum potassium was 3.3 mmol/L, sodium was 140 mmol/L, and creatinine was 103 µmol/L. Ten days after withdrawing diuretic therapy and on a high sodium diet, urinary aldosterone excretion was 53 and 58 nmol/day on two occasions. In the postural stimulation test, performed while the patient was receiving doxazosin (2 mg twice daily) only, plasma aldosterone was elevated (1.49 and 1.44 nmol/L or 54 and 52 ng/dL recumbent and upright, respectively), and PRA was 1.6 and 1.8 ng/mL·h in the recumbent and upright positions. The plasma aldosterone/PRA ratio was elevated (Table 1). Normal ranges for plasma aldosterone in this laboratory are 0.1–0.7 nmol/L recumbent (0800 h) and 0.3–1.0 nmol/L upright (2200 h).

Eight weeks later, serum potassium was 4.6–5.5 mmol/L, creatinine was 123–132 µmol/L, and blood pressure was 120–130/85–95 mm Hg. An attempt to withdraw spironolactone completely from the treatment regimen led to markedly increased blood pressure and hypokalemia, events typical for patients with primary hyperaldosteronism.

At present, the patient feels completely well and is normotensive on a regimen of 25 mg spironolactone twice daily, 4 mg doxazosin, 25 mg atenolol, and 30 mg delayed action furosemide. Serum creatinine tended to decrease with time (last measurement, 115 µmol/L), and serum potassium is still high normal or elevated (4.9–5.5 mmol/L). In February 1999, the patient had a PRA of 2.3 ng/mL·h and a plasma aldosterone level of 1.44 nmol/L (52 ng/dL). Computed tomography in 1999 showed no change in the size of the adrenal nodules.

Patient 3

In July 1995, a 30-yr-old man was admitted to a department of general internal medicine because of headaches, nausea, and a blood pressure of 230/130 mm Hg. Hypertension had been diagnosed in 1993, but the patient took antihypertensive drugs only occasionally.

On admission in 1995, his serum potassium was 2.8 mmol/L, sodium was 142 mmol/L, and creatinine was 106 µmol/L. His body mass index was 26 kg/m². Apart from the hypertension, physical findings were normal. Funduscopy showed slightly narrowed retinal arteries without bleeding or papilledema. Hyperaldosteronism was suspected as the underlying disorder. After potassium chloride supplementation, urinary aldosterone excretion was slightly increased (47 nmol/day). In the postural stimulation test plasma aldosterone levels were 0.89 and 1.22 nmol/L (32 and 44 ng/dL), and PRA levels were 0.44 and 0.90 ng/mL·h in the supine and upright positions, respectively. The plasma aldosterone/PRA ratios were elevated (Table 1). Renal arteriography, urinary catecholamine excretion, and adrenal computed tomography yielded no pathological findings. Selective adrenal venous catheterization was technically unsuccessful. The patient was discharged with the recommendation to take spironolactone and antihypertensive drugs. In 1997 he suffered a stroke with right-sided brachiofacial paresis and motoric aphasia after having taken his recommended antihypertensive drugs (including spironolactone) only occasionally. He recovered completely and stopped taking the drugs in October 1998. In April 1999 he was admitted to this unit because of muscle weakness, dizziness, and sweating with a blood pressure of 230/160 mm Hg and a serum potassium of 2.2 mmol/L. His serum sodium was 144 mmol/L, and creatinine was 111 µmol/L. Urinary aldosterone excretion was markedly elevated at this time (291 nmol/day). Antihypertensive therapy with doxazosine and potassium supplementation reduced his blood pressure to 160–200/90–120 mm Hg. The postural stimulation test, adrenal computerized tomography, and adrenal venous catheterization were repeated because the very low serum potassium level indicated the presence of an adrenal adenoma (2, 7). The postural stimulation test yielded supine and upright values of plasma aldosterone of 3.33 and 2.86 nmol/L (120 and 103 ng/dL), and PRA levels of 2.5 and 4.2 ng/mL·h, and plasma aldosterone/renin ratios were elevated (Table 1).

This time, bilateral adrenal venous catheterization was successful, as shown in Table 2. The aldosterone/cortisol ratio was 9.8 peripherally, 48.5 in the left and 2.5 in the right adrenal vein, clearly indicating the source of increased plasma aldosterone in the left adrenal gland with suppression of contralateral aldosterone secretion (6). It is not clear why right adrenal aldosterone secretion remained suppressed in the presence of normal PRA. Computed tomography of the adrenal, however, showed no adenoma, and adrenal scintigraphy with [¹³¹I]iodomethyl-19-norcholesterol (NP-59) was negative. Therapy with 100 mg spironolactone twice daily, 5 mg minoxidil twice daily, 50 mg metoprolol twice daily, and 30 mg delayed action furosemide lowered the blood pressure to 130–160/80–110 mm Hg within 2 weeks. With this treatment, the patient was normokalemic (4.2–4.7 mmol/L), but serum creatinine increased to between 132–185 µmol/L. On May 5, 1999, the patient was adrenalectomized on the left side. Histology showed a yellow-colored adenoma with a maximal diameter of 18 mm, typical of an aldosteronoma.

Postoperatively, the patient was transiently hyperkalemic without spironolactone treatment. In July 1999 his blood pressure was 120–160/80–105 mm Hg during antihypertensive therapy. He also received 50 µg 9-fluorocortisol, because his aldosterone excretion rate was very low (2 nmol/day). Eight weeks postoperatively, his serum potassium was 4.8–5.3 mmol/L, creatinine was 141–176 µmol/L, plasma aldosterone was 0.24 nmol/L (8.7 ng/dL), and PRA was 2.0 ng/mL·h. The postoperative decrease in plasma aldosterone to less than 10% of the preoperative level proves that the tumor removed was an aldosteronoma.

	Discussion

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The patients described in this study differ in some respects from the majority of patients with primary hyperaldosteronism. First, their blood pressures at presentation were markedly higher than the average blood pressure found in our patients with primary hyperaldosteronism (7). Second, marked hypertensive retinopathy, although without papilledema, and serum creatinine levels at the upper normal limit or slightly higher were indicative of kidney damage. Third, although all patients undoubtedly had primary hyperaldosteronism, as indicated by an elevated aldosterone/renin ratio and/or the results of adrenalectomy, a normal or even high normal PRA was found at presentation in patients 1 and 2 and 4 yr thereafter in patient 3. Fourth, treatment with 200 mg spironolactone/day led to a markedly increased serum creatinine and hyperkalemia, events we have not observed in more than 50 other patients with primary hyperaldosteronism.

Primary hyperaldosteronism may coexist with renal artery stenosis (8, 9). As renal angiograms were normal in our patients, we assume they had renal arteriolosclerosis induced by arterial hypertension. In patient 1, renal arteriolosclerosis was histologically confirmed. The other two patients had no signs of a renoparenchymal disorder such as glomerulonephritis, and it can only be speculated that they also had renal arteriolosclerosis due to severe systemic hypertension. We assume that the escape of renin from suppression in these patients contributed to the severe hypertension. This view is in keeping with studies of the diminished suppressibility of renin in patients with essential hypertension and nephron heterogeneity and in hypertensive women taking oral contraceptives whose plasma angiotensinogen levels are very high (10, 11).

Another case of primary aldosteronism with elevated active renin concentration, markedly increased serum creatinine (336 µmol/L), and malignant hypertension was recently reported by Oka et al. (12). They cited several other case reports of primary hyperaldosteronism with malignant hypertension, in which renin concentration or activity remained suppressed. Even in patients with primary hyperaldosteronism and concomitant severe renal artery stenosis, PRA remained suppressed (8, 9). Bravo et al. (13) also reported normal PRA levels in patients with primary hyperaldosteronism 3–5 days after initiating a normal sodium diet, but did not describe special clinical characteristics of these patients. It should be noted that pretreatment with furosemide in our patients 1 and 2 could have contributed to the relatively high PRA levels. However, both patients were studied 10 days after they had stopped diuretic therapy and undergone sodium repletion. Furthermore, in patient 1, a high sodium diet plus administration of a mineralocorticoid did not significantly suppress PRA or its increase in the upright position.

In 1964 Conn et al. (14) concluded that hypertension in patients with primary hyperaldosteronism is relatively benign. This view was supported by an analysis of Laragh (15) in the early 1970s, who concluded that hypertensives with a low renin status are protected against vascular complications, whereas those with high renin hypertension are at high risk of developing such complications. These findings were contradicted by Beevers et al. (16) and, more recently, by Takeda et al. (17), who published results of the Research Committee on Disorders of Adrenal Hormones in Japan. They found no significant difference when comparing the incidence of vascular complications in 224 patients with aldosterone-producing adenomas to that in 224 sex- and age-matched patients with essential hypertension. Similar results were recently reported by Nishimura et al. (18). In both studies from Japan, proteinuria was found to be a marker for an increased risk of cardiovascular complications.

Thus, it is important to diagnose and specifically treat primary hyperaldosteronism at an early stage. Hypertension in patients with primary hyperaldosteronism is often unresponsive to the usual antihypertensive drugs, and diuretics tend to aggravate hypokalemia. Patients with hypokalemia as well as those with refractory hypertension should therefore be screened for primary hyperaldosteronism. Hiramatsu et al. (19) first suggested using the aldosterone/renin ratio as an aid in identifying patients with primary hyperaldosteronism. Although this ratio appears to be trivial at first glance, because it is increased by high aldosterone and low renin, it nevertheless seems to be useful in identifying patients with normokalemic primary hyperaldosteronism and those with aldosterone levels in the upper normal range for further differential diagnosis (2, 20, 21). The three cases described here show that the aldosterone/renin ratio can remain increased even if renin is no longer suppressed in primary hyperaldosteronism, due to supervening renovascular disease as a complication of severe hypertension.

Patient 1 in this report would probably have died from cardiovascular complications if the adrenal adenoma had not been removed in 1976. He is now normotensive and feels better than at any time in the past 25 yr while taking an angiotensin-converting enzyme inhibitor, a diuretic, and a calcium antagonist. Thus, his residual hypertension is partially renin dependent at present, probably due to renal arteriolar disease.

Patient 2, with probable bilateral adrenal disease, is normotensive on an unusually low dose of spironolactone plus furosemide and an -adrenergic receptor blocker. She may decide to undergo left adrenalectomy if her blood pressure can no longer be controlled or if the adrenal lesion(s) should grow.

In patient 3, we had the opportunity to observe the change from primary hyperaldosteronism with suppressed PRA in 1995 to a state of normal renin in 1999. As the patient had not taken antihypertensive drugs before he was restudied in 1999, this change was certainly not due to the administration of diuretics or spironolactone, a drug that may increase renin secretion and should never be given to patients with primary hyperaldosteronism before completing the diagnostic work-up (2, 3). Patient 3 also demonstrates that bilateral adrenal venous sampling is a very efficient tool for differentiating between unilateral and bilateral adrenal disease in patients with primary hyperaldosteronism with normal adrenal computed tomography or scintigram.

The increased serum creatinine and hyperkalemia in our three patients taking 200 mg spironolactone/day was probably due to lowered blood pressure after sodium loss, decreased filtered sodium load, and reduced mineralocorticoid function through aldosterone antagonism of the drug. Patient 3 had postoperative hypoaldosteronism, which often occurs in patients with aldosterone-producing adenomas (22). One could argue that the 200 mg/day spironolactone initially administered in our patients was too high a dose, although it did not cause any complications in many other patients with primary hyperaldosteronism. The recently published RALES study in patients with heart failure (23) indeed shows that much lower doses of spironolactone can be therapeutically effective. Thus, patients with primary hyperaldosteronism should also initially receive smaller doses of spironolactone, especially those with elevated or high normal serum creatinine levels.

In conclusion, advanced arterial hypertension in patients with primary hyperaldosteronism may lead to kidney damage and a reversal of renin suppression, a condition that may obscure diagnosis of the underlying disorder.

	Acknowledgments

 
This paper is dedicated to Prof. Michel B. Valloton, Head of Endocrinology at the Hopital Cantonal Universitaire (Geneva, Switzerland), and to Prof. Armin Distler, Head of Nephrology at Klinikum Benjamin Franklin, Freie Universitat Berlin (Berlin, Germany), on the occasion of their retirements from their academic positions.

Received December 29, 1999.

Revised March 13, 2000.

Revised May 15, 2000.

Accepted June 4, 2000.

	References

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