ANNUAL REVIEWS
Further
Quick links to online content
Copyright 1975. All rights reserved
LOW RENIN HYPERTENSION
Annu. Rev. Med. 1975.26:259-275. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/27/15. For personal use only.
J.
Caulie Gunnells, Jr., MD. and William
L.
+7148
McGuffin, Jr., M.D. 1
Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710
Low or suppressed plasma renin activity was first described in association with primary aldosteronism in 1964 by Conn et al (1). They suggested that low plasma renin activity (PRA) was an essential component of the diagnostic criteria for primary aldosteronism and that renin measurements were useful in the evaluation of hypertensive patients in the search for the diagnosis of primary aldosteronism. Based on the finding of low or suppressed PRA in approximately 20 to 25% of their hypertensive patients, together with a previously reported high incidence of adrenal abnormalities in postmortem studies of patients with hypertension, they suggested that a normokalemic form of primary aldosteronism might comprise as many as 20% of patients otherwise classified as having benign essential hypertension (2). In the following year they described a patient with hypertension, suppressed PRA, normal serum potassium levels, and an elevated aldosterone excretion (3). In the several years following these initial reports, numerous other investigators measured PRA in large numbers of hypertensive patients, selected and unselected, finding low or suppressed levels ofPRA in 10-43%; however, in only a relatively small number of these patients was the diagnosis of primary aldosteronism actually established (4-22). These findings led several investigators to suggest that low plasma renin activity was a nonspecific finding which was unrelated to abnormalities of adrenal structure or function (4, 23). Between 1969 and 1971, three groups of investigators made preliminary observa tions suggesting that low renin hypertension was different from the usual variety of benign essential hypertension, and was related pathogenetically to the adrenal gland (16, 19, 22). In 1969, Woods et a1 (22) documented that aminoglutethimide, an inhibitor of adrenal steroidogenesis, produced a reduction of blood pressure in six of nine patients with suppressed renin activity and normal or low aldosterone levels. The second observation came from our own laboratories (16) in which four of six patients with low PRA and normal aldosterone excretion rates exhibited a reduction in blood pressure following subtotal adrenalectomy. Five of those patients had 'This work supported in part by Training Grant HL05848, Renal Division and CRU Grant MOIRR30. 259
Annu. Rev. Med. 1975.26:259-275. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/27/15. For personal use only.
260
GUNNELLS & MCGUFFIN
pathological abnormalities in the adrenal including one patient with a single adenoma. Moreover, postoperative studies in these patients demonstrated a return of renin responsiveness. The third set of observations came from Spark & Melby in 1971 (19), in which eight patients with low PRA and low aldosterone secretion rates responded to high dose (400 mg/day) spironolactone therapy with a normalization of blood pressure and significant weight loss. This was in contrast to 15 patients who had normal PRA who failed to show an appreciable change in blood pressure or weight reduction using similar doses of spironolactone over a five week period. It has become clear in the several years since these observations that hypertension associated with low PRA is a spectrum of disorders including primary aldostero nism with either adenoma or hyperplasia, various other forms of hypermineralocor ticoidism, low renin essential hypertension with no easily definable abnormality in mineralocorticoid production, but in which the hypertension seems clearly to be volume-dependent, and several other miscellaneous conditions. The observations cited above have led to considerable controversy regarding the criteria for establishing the low renin state, pathophysiologic mechanisms, as well as the indications aTJd modalities for treatment, and prognosis. The purpose of this paper is to review recent developments that have been the source of controversy in the syndrome of low renin hypertension. DEFINITION OF LOW RENIN HYPERTENSION
Low renin hypertension is characterized by the presence of hypertension in associa tion with a failure to demonstrate an appropriate rise in PRA in response to stimuli (posture, sodium restriction, and pharmacologic agents) that consistently stimulate a rise in PRA in other hypertensive patients or normal subjects (6, 8, 9, 11-14, 17-20, 24-28). Most investigators have recognized the difficulty of distinguishing low levels of renin activity from normal levels of renin activity in hypertensive patients on an ad lib sodium intake. The results of an investigation of renin responsiveness in 134 hypertensive patients from our own laboratory (Figure I and Table I) demonstrate a 26% incidence of suppressed PRA. In this study a five day period of sodium restriction (10 meq/day) plus diuretics on the fourth day was used to stimulate PRA. These results are comparable to those reported by others using a variety of maneuvers known to provoke an increase in PRA. The limitations of this somewhat lengthy approach to stimulate renin release have been replaced in part by the outpatient administration of "loop" diuretics such as furosemide either orally or intravenously, and the failure of patients to respond to such maneuvers with an appropriate increase in PRA has been judged to be evidence for the low renin state (29). In those studies in which the latter approach has been compared with previous protocols utilizing dietary sodium restriction, there has been generally good agreement and it is now accepted by most investigators that the use of furosemide to demonstrate the low renin state is a valid diagnostic maneuver. However, each group of investigators has used slightly differtnt protocols to elevate the PRA, making an evaluation of the litera ture difficult.
LOW RENIN HYPERTENSION
•
1600
0
26 1
Potients with Normal PRA Patients with Subnormal PRA
0
1400 � 0
a:
E 0
1200
Annu. Rev. Med. 1975.26:259-275. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/27/15. For personal use only.
Q
"I:j
S �
:�
1000
800
0
Further
Quick links to online content
Copyright 1975. All rights reserved
LOW RENIN HYPERTENSION
Annu. Rev. Med. 1975.26:259-275. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/27/15. For personal use only.
J.
Caulie Gunnells, Jr., MD. and William
L.
+7148
McGuffin, Jr., M.D. 1
Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710
Low or suppressed plasma renin activity was first described in association with primary aldosteronism in 1964 by Conn et al (1). They suggested that low plasma renin activity (PRA) was an essential component of the diagnostic criteria for primary aldosteronism and that renin measurements were useful in the evaluation of hypertensive patients in the search for the diagnosis of primary aldosteronism. Based on the finding of low or suppressed PRA in approximately 20 to 25% of their hypertensive patients, together with a previously reported high incidence of adrenal abnormalities in postmortem studies of patients with hypertension, they suggested that a normokalemic form of primary aldosteronism might comprise as many as 20% of patients otherwise classified as having benign essential hypertension (2). In the following year they described a patient with hypertension, suppressed PRA, normal serum potassium levels, and an elevated aldosterone excretion (3). In the several years following these initial reports, numerous other investigators measured PRA in large numbers of hypertensive patients, selected and unselected, finding low or suppressed levels ofPRA in 10-43%; however, in only a relatively small number of these patients was the diagnosis of primary aldosteronism actually established (4-22). These findings led several investigators to suggest that low plasma renin activity was a nonspecific finding which was unrelated to abnormalities of adrenal structure or function (4, 23). Between 1969 and 1971, three groups of investigators made preliminary observa tions suggesting that low renin hypertension was different from the usual variety of benign essential hypertension, and was related pathogenetically to the adrenal gland (16, 19, 22). In 1969, Woods et a1 (22) documented that aminoglutethimide, an inhibitor of adrenal steroidogenesis, produced a reduction of blood pressure in six of nine patients with suppressed renin activity and normal or low aldosterone levels. The second observation came from our own laboratories (16) in which four of six patients with low PRA and normal aldosterone excretion rates exhibited a reduction in blood pressure following subtotal adrenalectomy. Five of those patients had 'This work supported in part by Training Grant HL05848, Renal Division and CRU Grant MOIRR30. 259
Annu. Rev. Med. 1975.26:259-275. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/27/15. For personal use only.
260
GUNNELLS & MCGUFFIN
pathological abnormalities in the adrenal including one patient with a single adenoma. Moreover, postoperative studies in these patients demonstrated a return of renin responsiveness. The third set of observations came from Spark & Melby in 1971 (19), in which eight patients with low PRA and low aldosterone secretion rates responded to high dose (400 mg/day) spironolactone therapy with a normalization of blood pressure and significant weight loss. This was in contrast to 15 patients who had normal PRA who failed to show an appreciable change in blood pressure or weight reduction using similar doses of spironolactone over a five week period. It has become clear in the several years since these observations that hypertension associated with low PRA is a spectrum of disorders including primary aldostero nism with either adenoma or hyperplasia, various other forms of hypermineralocor ticoidism, low renin essential hypertension with no easily definable abnormality in mineralocorticoid production, but in which the hypertension seems clearly to be volume-dependent, and several other miscellaneous conditions. The observations cited above have led to considerable controversy regarding the criteria for establishing the low renin state, pathophysiologic mechanisms, as well as the indications aTJd modalities for treatment, and prognosis. The purpose of this paper is to review recent developments that have been the source of controversy in the syndrome of low renin hypertension. DEFINITION OF LOW RENIN HYPERTENSION
Low renin hypertension is characterized by the presence of hypertension in associa tion with a failure to demonstrate an appropriate rise in PRA in response to stimuli (posture, sodium restriction, and pharmacologic agents) that consistently stimulate a rise in PRA in other hypertensive patients or normal subjects (6, 8, 9, 11-14, 17-20, 24-28). Most investigators have recognized the difficulty of distinguishing low levels of renin activity from normal levels of renin activity in hypertensive patients on an ad lib sodium intake. The results of an investigation of renin responsiveness in 134 hypertensive patients from our own laboratory (Figure I and Table I) demonstrate a 26% incidence of suppressed PRA. In this study a five day period of sodium restriction (10 meq/day) plus diuretics on the fourth day was used to stimulate PRA. These results are comparable to those reported by others using a variety of maneuvers known to provoke an increase in PRA. The limitations of this somewhat lengthy approach to stimulate renin release have been replaced in part by the outpatient administration of "loop" diuretics such as furosemide either orally or intravenously, and the failure of patients to respond to such maneuvers with an appropriate increase in PRA has been judged to be evidence for the low renin state (29). In those studies in which the latter approach has been compared with previous protocols utilizing dietary sodium restriction, there has been generally good agreement and it is now accepted by most investigators that the use of furosemide to demonstrate the low renin state is a valid diagnostic maneuver. However, each group of investigators has used slightly differtnt protocols to elevate the PRA, making an evaluation of the litera ture difficult.
LOW RENIN HYPERTENSION
•
1600
0
26 1
Potients with Normal PRA Patients with Subnormal PRA
0
1400 � 0
a:
E 0
1200
Annu. Rev. Med. 1975.26:259-275. Downloaded from www.annualreviews.org Access provided by McMaster University on 01/27/15. For personal use only.
Q
"I:j
S �
:�
1000
800
0
