J.J. Brown

Hypertension in chronic renal failure: An abnormal relation between sodium and the renin-angiotensin system

Abstract Hypertensive patients with chronic renal failure show evidence of an abnormal relationship between sodium and the reninangiotensin system in that circulating levels of renin and angiotensin II are abnormally high in relation to exchangeable sodium. The abnormality may well contribute to the hypertension in this syndrome. In a minority of cases blood pressure cannot be controlled by dialysis. In these, renin levels are particularly high and rise even further in response to therapeutic sodium depletion. It is suggested that this may perpetuate the hypertension. In most patients, however, blood pressure can be controlled by dialysis and, in these, renin and angiotensin II levels are lower, but, again, their relation to exchangeable sodium is abnormal. It is suggested that the rise in arterial pressure in this group results from a failure of renin to suppress normally with sodium retention. This would also explain the fall in blood pressure with sodium depletion at hemodialysis. The inflexibility of the renin-angiotensin system in its relation to sodium may be the cause of hypertension as well as the basis for its cure.

PLASMA RENIN, RENIN SUBSTRATE, ANGIOTENSIN II, AND ALDOSTERONE IN HYPERTENSIVE DISEASE OF PREGNANCY

Abstract Plasma concentrations of renin, renin substrate, angiotensin II, and aldosterone were measured in the peripheral venous blood of women with hypertension and proteinuria in late pregnancy and in a control group of normal pregnant women matched for age, parity, time of gestation, and posture. All four substances were found to be significantly lower in the hypertensive group as compared with normal pregnancy. Therefore, raised circulating levels of renin, renin substrate, angiotensin II, and aldosterone cannot be invoked in the pathogenesis of pregnancy hypertension. This suppression of the renin-angiotensin-aldosterone system in hypertensive disease of pregnancy could represent an adjustment to an increase in the circulating level of some unidentified pressor agent or mineralocorticoid.

Renin relationships in congestive cardiac failure, treated and untreated

Abstract Renin concentration was measured in 155 plasma samples from 79 patients with congestive cardiac failure, 23 samples being obtained from 21 patients before the start of treatment. Before treatment, renin was variously subnormal, high, and within the normal range. Initially normal renin levels might become high with diuretic therapy; conversely, in other patients high pretreatment values subsided to normal with therapy. In yet other instances renin remained within the normal range throughout. In both untreated and treated patients, plasma renin concentration was closely related inversely to plasma sodium and directly to plasma urea concentration. Before treatment, plasma renin was found to be closely related inversely to plasma tCO 2 , and directly, but rather less closely, to plasma potassium. Neither of these relationships remained significant when treated patients were considered. Renin-mediated intrarenal vasoconstriction is considered as the possible cause of the typically reduced renal blood flow, with a relatively high filtration fraction, of cardiac failure. In particular, a hypothesis is put forward in which a renin-mediated selective reduction of renal inner-medullary blood flow in cardiac failure might be responsible for the disproportion between the high urinary osmolality in relation to that of plasma, and for oliguria, uremia, and hyponatremia. It is proposed that the retarded renal inner-medullary blood flow enhances countercurrent exchange, and thus also limits the extent of urea retention, while simultaneously tending to build up osmolality in the inner medulla and so inhibit water excretion. Renin is further considered as a possible contributor to diuretic resistance.

ABNORMAL RELATION BETWEEN EXCHANGEABLE SODIUM AND THE RENIN-ANGIOTENSIN SYSTEM IN MALIGNANT HYPERTENSION AND IN HYPERTENSION WITH CHRONIC RENAL FAILURE

Abstract Exchangeable sodium and plasma levels of renin and angiotensin II were measured in patients with normal blood-pressure and in patients with hypertension, either in the malignant phase or associated with chronic renal failure. In normotensive subjects exchangeable sodium correlated inversely with plasma-renin concentration and with plasma-angiotensin-II. Abnormally high levels of renin and angiotensin II, relative to exchangeable sodium, were found in the hypertensive patients. This accords with the suggestion that renin release, inappropriately high in relation to sodium balance, may raise blood-pressure in certain types of hypertension.

IS LOW-RENIN HYPERTENSION A STAGE IN THE DEVELOPMENT OF ESSENTIAL HYPERTENSION OR A DIAGNOSTIC ENTITY ?

A study of the frequency distribution of plasma-renin concentration in 81 patients with essential hypertension produced no evidence of a distinct sub-population with low renin levels. An arbitrary dividing line was used, therefore, to define low-renin hypertension (36% of patinets). Patients in this group were older than those with normal renin levels, and there was a significant negative correlation between renin and age among all patients. Low-renin hypertension was not characterized by increased exchangeable sodium, but exchaneable postassium was significantly lower than in patients with normal plasma-renin. This difference became insignificant when five patients in the low-renin group with persistent hypokalaemia were excluded. It is concluded that low-renin hypertension does not represent a separate diagnostic entity but that plasma-renin falls with age in essential hypertension.

HYPERTENSION AND SECONDARY HYPERALDOSTERONISM ASSOCIATED WITH A RENIN-SECRETING RENAL JUXTAGLOMERULAR-CELL TUMOUR

Abstract A case of renin-secreting renal juxtaglomerular-cell tumour is described in an 8-year-old child. Severe hypertension associated with hypokalaemia was accompanied by raised plasma concentrations of renin, angiotensin II, and aldosterone in peripheral blood. The secondary hyperaldosteronism was shown not to be due to the malignant phase or to renal-artery stenosis. The tumour was lateralised by the demonstration of higher concentrations of renin and angiotensin II in left than in right renal venous plasma, and visualised on selective renal arteriography. The patient showed much greater elevation of blood-pressure and plasmaaldosterone than normal subjects infused with angiotensin to produce comparable plasma-angiotensin-II levels. Before operation, both head-up tilting and dietary sodium restriction caused a further striking increase of peripheral renin and angiotensin II. The hypertension and biochemical abnormalities were all relieved by removal of the affected kidney. The tumour had a very high content of renin. Extreme care is necessary in interpreting minor differences in renin level in renal veins if false-positive or falsenegative diagnoses are to be avoided.

Sodium and the renin-angiotensin system in essential hypertension and mineralocorticoid excess.

Abstract Exchangeable sodium (NaE) was increased in untreated primary hyperaldosteronism but normal in treated primary hyperaldosteronism and in untreated essential hypertension, low-renin hypertension, and hypertension with excess 11-deoxycorticosterone ( D OC). The relation between NaE and plasma-renin was normal in essential hypertension and primary hyperaldosteronism but subnormal in low-renin hypertension and DOC excess. Depression of renin in low-renin hypertension cannot therefore be attributed to abnormal sodium retention.

RENAL ABNORMALITY OF ESSENTIAL HYPERTENSION

Abstract Although homœostatic mechanisms relate sodium balance, renin, and arterial pressure, the reduction of renin sometimes seen in essential hypertension cannot be attributed to abnormal sodium retention. It is proposed instead that renin decreases and sodium status remains normal because the pressure-natriuretic mechanism within the kidney is reset by increased filtration fraction. Neurogenic factors may raise blood-pressure and cause resetting by some other means at an early (labile) stage of essential hypertension, but, once filtration fraction is raised and remains elevated on withdrawal of the neurogenic component, essential hypertension will have a renal cause. A similar mechanism may account for the failure of secondary hypertension to fall when its cause is removed.

The treatment of low-renin (“primary”) hyperaldosteronism

Abstract Sixty-four patients with low-renin (“primary”) hyperaldosteronism underwent adrenal surgery. A unilateral adrenocortical adenoma was found in 48; no tumor was identified in 14, the adrenal glands then usually showing hyperplasia of the zona glomerulosa. The adrenal lesion in two further patients was difficult to classify. There was a significant fall in systolic and diastolic blood pressure after operation in both the adenoma and hyperplasia groups, although the fall in diastolic pressure was significantly greater in the adenoma group. Blood pressure fell to an arbitrary normal level in 56 per cent of patients with adenoma and in 15 per cent of patients in the hyperplasia group. Ninety-five patients with primary hyperaldosteronism received spironolactone for a minimum period of four weeks. There was a significant fall in mean systolic and diastolic pressure during treatment in both the adenoma and hyperplasia groups. However, the fall in diastolic pressure was again significantly greater in the adenoma group. There was a significant positive correlation between the fall in blood pressure during spironolactone and following adrenal surgery. Eighteen patients also received amiloride preoperatively and again there was a significant fall in systolic and diastolic blood pressure, although levels were slightly higher than during spironolactone or after subsequent adrenal surgery. Nineteen patients received a two week course of dexamethasone, without effect on blood pressure or the electrolyte abnormalities. It is suggested that removal of the tumor-bearing gland is usually the treatment of choice for patients with an aldosterone producing adenoma, provided preoperative spironolactone has reduced blood pressure to normal or near normal. However, long-term spironolactone is an acceptable alternative. For patients in the hyperplasia group, long-term spironolactone is usually the treatment of choice. If this drug is not tolerated, amiloride may be substituted. If preoperative spironolactone does not produce a satisfactory hypotensive response, adrenal surgery is unlikely to do so and hypertension should be controlled with other conventional hypotensive drugs. All patients with primary hyperaldosteronism in whom an adrenocortical adenoma is not identified preoperatively should be screened for the rare glucocorticoid-remediable variant. Dexamethasone 1 to 2 mg. daily for two to four weeks will reverse the biochemical abnormalities and reduce blood pressure. When an adrenocortical carcinoma is suspected, prompt surgical excision is required.

Low Blood Pressure in Down's Syndrome A Link With Alzheimer's Disease?

Low blood pressure is reported in Downs syndrome (DS). To assess this and determine whether low pressure results from the disease or from long-term residence in hospital, we measured blood pressure with a random-zero sphygmomanometer in three groups of patients: 52 DS inpatients, 62 DS outpatients, and 60 outpatients with other forms of mental handicap. Relative to normal reference populations, blood pressure was low in both DS inpatients (systolic, score -33 mm Hg, P < .0001) and DS outpatients (-25 mm Hg, P < .0001). It was normal in non-DS outpatients (-4.0 mm Hg, P = .3). Blood pressure rose normally with age in the non-DS group but not in the DS group. We conclude that blood pressure is low in DS and that this is a feature of the disease rather than of the protected environment in which patients live. A mechanism related to trisomy 21 is likely, and there may be a link with Alzheimers disease (AD) because blood pressure is also low in Alzheimers and a high proportion of Ds patients develop this disease. If, as is likely, blood pressure is lowered in Alzheimers by the neuropathy, the same neuropathy developing early in DS may also reduce blood pressure.