Hypertension in chronic renal failure

Hypertension in Chronic Renal Failure An Abnormal Relation Between Sodium and the Renin-Angiotensin System

M. A. SCHALEKAMP, D.G.

BEEVERS.

J. D. BRIGGS,

M.D.*

M.B., M.R.C.P.

M.B., M.R.C.P.

J. J. BROWN, B.Sc., M.0.. D. L. DAVIES,

M.R.C.P.

M.D., M.R.C.P.

R. FRASER, M.Sc., Ph.D. M. LEBEL. M.D.? A. F. LEVER, B.Sc.. M.B., M.R.C.P. A. MEDINA,

M.D.

J. J. MORTON,

&SC., Ph.D.

J. I. S. ROBERTSON, M. TREE, BSc..

B.Sc., Ph.D.

Ph.D.

Glasgow, Scotland

From the MRC Blood Pressure Unit, Western Infirmary, Glasgow. G-11 6NT, Scotland. Requests for reprints should be addressed to Dr. A. F. Lever, MRC Blood Pressure Unit, Western Infirmary, Glasgow, G-l 1 6NT, Scbtland. *Present address: Department of Internal Medicine, Zuiderziekenhuis, Rotterdam, The Netherlands. j’Present address: L’HBtel-Dieu de Qubec, 11 C6te du Palais, Quebec, Canada. tPresent address: Apart0 Postal 15.101, en Las Delicas, Maracaibd, Venezuela.

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 anglotensin II are abnormally high in relation to exchangeable sodium. The abnormality may well contribiite to the hypertension in this syndrome. In a minority of cases blood pressure cannot be controlled by dialysis. In these, r&in levels are particularly high and rise even further in response to therapeutic sodium depletiori. 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 relatioh to exchangeable sodium is abnormal. It is suggested that the rise in arterial pressbre 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 weli as thiz basis for its cure. Sodium and renin have often been ihvoked in the pathogenesis of hypertension. Although excess sodium can undoubtedly raise blood ljressure in certain ciicumstances [I-S], the effect is not invariable, and a consistent relationship between blood pressure and the level of exchangeable or plasma sodium is not commonly found in hyperterisive patients [S]. Renin also has an undoubted pressor effect [7], and circulating levels of renin and its active product, angiotensin I I, seem within the pressor range [8,9]. Yet, in most forms of hypertension in man, there is no corlsistent or close relationship between blood pressure and the plasma concentration of renin and angiotensin [6]. The failure to find a relationship between blood pressure and sodium, and blood pressurk and renin, may to some extent be attributable to the inverse relationship between sodium and renin. Thus, sodium excess may raise blood pressure but it also reduces renin. Part of the difficulty of interpretation may arise, therefore, because two pressor systems (sodium and renin) are inversely related, and overactivity of one leads to underactivity of the other. For example, in Conn’s syndrome sodiuti retention is probdbly responsible for the inverse correlation between sodium and blood pressure, and for the positive correlation between renin and blood pressure [6]. Consideration of a role for sodium in hypertension in isolation from a role for renin may be profitless for these reasons.

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A different approach to the problem derives from the suggestion that plasma renin concentration in certain forms of hypertension is inappropriately raised in relation to sodium status [lo131; levels of renin within the range found in normotensive subjects may then become abnormal in the presence of sodium retention and raise blood pressure. As will be discussed there is now evidence for such a derangement in patients whose hypertension is associated with chronic renal failure [14]. The plan of this review, therefore, is to discuss the clinical and biochemical manifestations of hypertension with chronic renal failure, the evidence for an abnormal relation between sodium and renin in this and other forms of hypertension, and the pathogenic mechanism which may be involved in such a relationship. HYPERTENSION IN CHRONIC RENAL FAILURE Blood pressure commonly rises as chronic renal failure advances to the point where regular dialysis treatment is needed to maintain life [5,15-201. The mechanism of this form of hypertension is more intensively studied and perhaps better understood than most. One reason for this may be that it is now possible to influence sodium and renin independently in man, the former by dialysis, the latter by bilateral nephrectomy. Also of great interest to the investigator is the possibility that hypertension with chronic renal failure may take two forms: one common and more clearly related to sodium excess, the other rare and possibly attributed to renin excess. The manifestation and management of these two syndromes will be considered first. Sodium-Dependent Hypertension Controlled by Regular Dialysis. Most hypertensive patients with chronic renal failure have evidence of sodium or water excess. Exchangeable sodium, plasma volume and extracellular fluid volume are increased [3,21-231, significant positive correlations exist between blood pressure and exchangeable sodium or extracellular fluid volume before dialysis begins [14,24], and sodium and water depletion by dialysis can reduce blood pressure [3,5,13-19,251. Generally, circulating levels of renin, renin activity, angiotensin I and angiotensin II in these patients are normal or slightly increased [19,23,25291. Intractable Renin-Dependent Hypertension. Much less commonly, hypertension with chronic renal failure fails to respond to regular dialysis treatment, and in some patients blood pressure *may actually rise as therapeutic sodium and water depletion leads to marked loss of body weight

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[16,19,26-28,30-321. Before dialysis, patients in this category have higher renin levels than patients whose blood pressure is readily controlled by dialysis [32], and there is no doubt that during the unsuccessful attempt to control blood pressure by dialysis, plasma renin and angiotensin concentrations are usually far higher than in patients who respond to treatment [17,19,26-28,31-331. Bilateral nephrectomy is often undertaken in the intractable case, and it may be life-saving. Blood pressure, total peripheral resistance and plasma levels of renin, angiotensin I and angiotensin II decrease after the operation [16, 17,19,20,26-371, and the subsequent reduction of plasma renin concentration is related to the fall in blood pressure [20,29]. Plasma aldosterone is also increased before operation and, like renin and angiotensin, it decreases after bilateral nephrectomy [19,27,28]. It is of incidental interest that reduction of aldosterone in the dog after nephrectomy was one of the earliest clues that the renin-angiotensin system influences aldosterone secretion [38]. Other reviews in this series deal more fully with the relation of renin and aldostelone in hypertension [39] and with the primary oversecretion of aldosterone [40]. Basis for Distinction of Controllable and IntractaBecause some patients beble Hypertension. come normotensive after regular dialysis and others do not, it does not follow that two distinct syndromes exist. It is equally possible that there is a spectrum of responsiveness, most patients responding partially, some completely and a few not at all. Another possibility is that a different response may be a consequence of different treatment: sodium and water depletion is standard therapy and in most patients it succeeds, but it is possible that overenthusiastic fluid withdrawal by dialysis may aggravate the situation. Dialysis technics vary, and it is noteworthy that in some centers [17,18,26] intractable hypertension is encountered more often than in others [41,42]. It is also probably true that centers vary in the extent to which they depend upon sodium depletion alone as a means of controlling blood pressure. In a high proportion of patients blood pressure may be controlled by a combination of regular dialysis treatment and hypotensive drugs. A further possibility, discussed in the final section of this review, is that the different blood pressure response to dialysis is attributable to a different renin response to sodium depletion. Whatever the mechanism of the difference, it is of practical importance that most hypertensive patients with chronic renal failure will respond to regular dialysis (with or without hypotensive drugs), and when

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blood pressure remains high, a difficult situation develops which may be controlled only by bilateral nephrectomy Cardiac Output and Peripheral Resistance in Hypertension with Chronic Renal Failure. Cardiac output is often increased in hypertensive patients with chronic renal failure [33,43-451. Peripheral resistance is also usually increased, and a significant correlation has been noted between peripheral resistance and concurrent plasma renin activity [33]. After operation, renin and peripheral resistance decrease [33]. As is discussed subsequently, the observations on cardiac output are of interest in relation to recent ideas about the role of the heart in the pathogenesis of hypertension. However, anemia is commonly found in chronic renal failure, and it could at least partly account for the raised cardiac output [43]. Kim et al. [44] have recently shown that, when allowance is made for anemia, cardiac index may be no higher in hypertensive than in normotensive patients with chronic renal failure, the former having the higher resistance. Autoregulation in the Pathogenesis of HypertenLedingham and Cohen [46,47] have sugsion. gested that renal hypertension may pass through an early phase in which cardiac output only is increased, and subsequently, as a result of “autoregulation of tissue perfusion,” cardiac output falls and hypertension is sustained by increased total peripheral resistance. The mechanism of the rise of pressure is not established, but myogenic vasoconstriction [46,47] and swelling of the blood vessel wall with reduction of its lumen [12,48,49] are two possibilities. There is certainly good evidence that increased cardiac output can precede a raised resistance in the early stages of some hypertensive disorders [50-531, and although this may occur in hypertension with chronic renal failure, the evidence for it is not as good [44] and more serial measurements of cardiac output are needed to settle the point. Hypertension After Bilateral Nephrectomy. It has been known for some time that blood pressure can rise in animals after bilateral nephrectomy and that retention of sodium and water are at least partly responsible for such renoprival hypertension [54]. The development of regular dialysis enabled prolonged observations to be made in man and, as in the animal studies, sodium and water retention seem important when blood pressure rises [55], there being a correlation between blood pressure and exchangeable sodium [5]. Coleman and his colleagues [52] have made the interesting observation that, although cardiac output rises initially as sodium is retained, peripheral resistance subsequently increases and blood September

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pressure remains elevated whereas cardiac output falls. This lends further support to the autoregulation theory. Plasma Levels of Renin and Angiotensin After NeAlthough renin, renin activity, angiophrectomy. tensin I and angiotensin II decrease after bilateral nephrectomy, they usually do not disappear entirely from plasma [19,20,27-29,56-591. The residual activity is unlikely to represent a false-positive reaction as the technics used are based on wholly different principles, and values obtained for angiotensin I and angiotensin II by radioimmunoassay are those expected from renin levels measured by bioassay [29]. Renin can be detected in plasma for at least 1 year after the operation [20,29]. Its source is not established, but there are several possibilities since renin-like enzymes have been extracted from a variety of organs other than the kidney [60-631. Thirst and Angiotensin. Infusion of large quantities of angiotensin II provokes drinking in rats [64]. The nervous centers responsible seem to be located in the anterior diencephalon [65]. Possibly relevant to these observations is the occasional complaint of excruciating and insatiable thirst in hypertensive patients whose chronic renal failure is associated with high circulating levels of renin [27,28]. In each of the patients described, bilateral nephrectomy reduced renin and abolished thirst. However, in our experience, thirst is not an invariable complaint in patients with high circulating renin or angiotensin I I. INTERACTION OF SODIUM AND THE RENIN-ANGIOTENSIN SYSTEM IN HYPERTENSION

Patients with Chronic Renal Failure and Malignant-phase Hypertension. As already described, plasma levels of renin and angiotensin II are sometimes normal and at other times increased in patients with hypertension and chronic renal failure. Exchangeable sodium may also be normal or increased. From these and other observations the idea developed that the interrelation of renin and sodium was abnormal in the sense that the amount of renin circulating was too high for the prevailing level of exchangeable sodium [8,1013,191. This was recently tested in a study [ 141 in which the relationship between exchangeable sodium and the renin-angiotensin system was first established in subjects with normal blood presthose with cardiac failure or sure, excluding edema. An inverse relationship between sodium and the renin-angiotensin system was found (Figure 1) as would be expected if some aspect of sodium status, possibly related to plasma volume or extracellular fluid volume, was a stimulus to 1973

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PI-

Plasma Renin Concentration units/I

At+teain

0 Concentration Pg/ml

1ooc

‘1

100

l

1OC

lc

1 Plasma Angiotensinfl pg/ml

l60

a0

100 120 140 Tdc~lExchange& Sodium%

ll

between exchangeable sodiFigure 2. Relationship um and plasma angiotensin II concentration. Mean f 2 SD as in Figure 1. Open circles indicate patients with normal blood pressure and chronic renal failure; solid circles, patients with hypertension with chronic renal failure; solid squares, patients with malignant phase hypertension. None of the patients was receiving drug therapy. From Davies et al. Lancet 1: 683, 1973

[741.

a0

120

160

Exchangeable Sodium%

Figure 1. Relationship between exchangeable sodium and the plasma concentrations of renin (top) and angiotensin II (bottom) in subjects with normal blood pressure. Mean f 2 SD are shown. See Davies et al. [14] for details of cases included and for expression of exchangeable sodium. Data from patients with and without renal failure are shown as open circles and open squares, respectively. From Davies et al. Lancet 1: 683, 1973 [ 141.

renin release [66]. As compared with these results, the angiotensin levels for hypertensive patients are often abnormally high in relation to exchangeable sodium (Figure 2). Although abnormalities of this kind were not invariable, they were considerably more common than isolated abnormalities of sodium, renin and angiotensin II (Figure 3). About one third of the patients whose renin, angiotensin II and exchangeable sodium values were all within the normotensive range had

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disordered relations between sodium and the renin-angiotensin system. When blood pressure was not raised in patients with chronic renal failure, the relationship between exchangeable sodium and renin was normal (Figures 1 and 2). Furthermore, when blood pressure was reduced by regular dialysis or by bilateral nephrectomy in hypertensive patients, a previously abnormal relationship between exchangeable sodium and angiotensin became normal (Figure 4). When blood pressure could not be reduced by these means, the sodium:renin and sodium:angiotensin relationship usually remained abnormal (Figure 3). A similar situation was found in two of three patients with malignant-phase hypertension but without severe renal failure (Figure 2). This is in accordance with the results obtained by Laragh [39] in an analysis of urinary sodium excretion and plasma renin activity. Relation Between Sodium and the Renin-Angiotensin System in Essential Hypertension and in Hypertension with Evidence of Mineralocorticoid

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Figure 3. Relative frequency of abnormalities of exchangeable sodium (NaE), plasma renin concentration (PRC), plasma angiotensin II concentration, and of the relations of NaE:renin and NaE:angiotensin in patients with hypertension, chronic renal failure and malignant-phase hypertension. Horizontal lines indicate the range found in normotensive subjects. The scale for NafPRC and for NaE:PAC is in standard deviations of the mean for normotensive subjects (as in Figure 1). “U” represents data from untreated patients and “T” data from treated but still hypertensive patients. Solid triangles indicate measurements in patients with intractable hypertension. Plasma Angmtensin Cmcentrotion w/ml

!j

EXCHANGEABLE

SOOIUM X

Figure 4. Relationship between plasma angiotensin II concentration and exchangeable sodium (left) in hypertensive patients with chronic renal failure responding to dialysis treatment alone (0 before, and 0 after treatment) or to bilateral nephrectomy (A before and A after). Changes in normotensive patients with dialysis (0) and bilateral nephrectomy (A) are also shown (right). From Davies et al. Lancet 1: 683, 1973 [74].

HYPERTENSION

PlasmaRmin

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Cauentmtion

(U/l)

Figure 5. Relationship between plasma renin concentrations and exchangeable sodium in untreated patients with primary hyperaldosteronism, low renin hypertension (low renin ht), excess plasma levels of desoxycorticosterone (DOC excess) and essential hypertension (essential ht).

A Untreated A Spiro l Rntsurgary

Figure 6. Response of NaE:plasma renin relationship to treatment with spironolactone in Conn’s syndrome. Dose of spironolactone was sufficient to reduce blood pressure and to correct electrolyte abnormalities.

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Excess. Observations described in the previous section raise the possibility that the relationship between sodium and the renin-angiotensin system might be abnormal in other forms of hypertension. Illustrated in Figures 5 and 6 are data from untreated patients with essential hypertension, primary hyperaldosteronism and other forms of suspected mineralocorticoid excess. In each of these the relationship between exchangeable sodium and renin, and exchangeable sodium and angiotensin, was within the normotensive range. Treatment with spironolactone or by surgery in primary hyperaldosteronism produced the expected increase of renin or decrease of exchangeable sodium and, here again, the sodium:renin and sodium:angiotensin relationships remained within the normotensive range (Figure 6). Thus, evidence presented so far is compatible with the idea that the rise in blood pressure in chronic renal failure (but not in essential hypertension or primary hyperaldosteronism) results partly or wholly from circulating levels of renin and angiotensin which are too high for the prevailing exchangeable sodium. Angiotensin may then raise blood pressure by its vasoconstrictor effect, possibly enhanced by sodium retention [8]. Studies in man suggest that the vasoactivity of angiotensin is indeed closely related to the state of sodium balance [67]. Retention of sodium and water per se may also play some part as after bilateral nephrectomy. These processes are considered in more detail in the sections which follow. POSSIBLE

MECHANISMS

CAUSING

HYPERTENSION

Renin Inappropriate to Sodium. We have previously proposed that two different mechanisms might raise blood pressure in the various hypertensive syndromes [12]. One, renin inappropriate to sodium, has been discussed in previous sections and is illustrated schematically in Figure 7. The suggested primary lesion (event 1 of Figure 7) is that plasma renin concentration is too high for prevailing exchangeable sodium. The sequence of events in a patient with intractable hypertension, for example, is that therapeutic sodium loss would tend to reduce blood pressure (by reducing mechanism 7 of Figure 7), its effect would be outweighed by the rise in renin and angiotensin I I (mechanisms 1, 2 and 3). A similar sequence might occur in unilateral renal artery stenosis without renal failure in which the unaffected normal kidney might promote sodium loss and secondary hyperaldosteronism [6870]. By virtue of the stenosis, however, renin release would remain excessively high and would rise further with sodium depletion. Moreover,

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Renin

:lfl

Sodium

\

Loss

1

b

<

B p

1

i\ngiotensin

Aldosterone

representation of pathologic Figure 7. Schematic events in patients with intractable hypertension. See text for explanation.

renin appears to play a role in the maintenance of. hypertension in the salt-depleted animal with only one clipped kidney in situ (one kidney model) as shown by the reversal of the blood pressure elevation by an infusion of a specific inhibitor of angiotensin II [71]. The response of renin to other stimuli might also be enhanced. It may be relevant that Kaneko and his colleagues [72] have shown that renin release is abnormally increased when blood pressure is acutely reduced in hypertensive patients with renal artery stenosis. Resetting of Pressure:Natriuresis Mechanism. The second lesion postulated [12] is that the mechanism by which an increase of pressure promotes sodium loss [73] is reset at a higher level of pressure [74,75]. As a result of the abnormality, sodium will be retained and blood pressure will

[ Sodium

Renin \ Angiot :ensin

Aldosterone

representation of pathologic Figure 8. Schematic events in patients with Corm’s syndrome. See text for explanation.

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PlosmoRenin concentration

Plasma Angiotensin culcentrotiar

U/L l

BP Normal

A

BP 4 A BP )

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100

1t

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1

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I

I

100

140

1

160 I

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NoE%

Figure 9.

Changes in the NaE:renin (left) and NaE:angiotensin with controllable hypertension and chronic renal failure.

rise to the point at which ,sodium balance can be restored (Figure 8). In the earlier review [I 21 several forms of hypertension were considered to have this as their basic fault; it was suggested that in Conn’s syndrome excess aldosterone (effect b) inight, by pronioting sodium retention, raise the level of blood piessure dt which sodium balance could be maint&%d: D&a illustrated in Figurd 5 are compatible with this insofar as the relaiion between sodium and the renin-anbiotensin system (eifects 1 and 2 of Figure 7) arit normal. The possibility that a similar disorder might be preseni in essential hypertension was also discussed [12]. Again, the evidence (Figure 6) is in Accord inasmuch as the relaiion of renin and sodium is hithin the normotensive range. The Primary Lesion in Controllable Hypertension with Chronic Renal Fai!ure. It was also suggested [12] that the controllable form of hypertension with chronic renal failure might result from the second lesion-resetting of the pressure:natriuresis mechanism (Figure 8a). However, unless another abnormality is to be invoked to explain the high blood pressure in these patients, it would be expected that their sodium:renin relationship is normal. Clearly this is not the case, since renin

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II (right) relationships

in patients

and angiotensin II are usually abnormally high in relation to exchangeable Sodium when such patients are untieated (Figures 2 and 3). On the other hand, from the small number of observtitiohs available (Figures 4 and 9) the relationship does become normal during successful control of blood pressure by dialysis, and this raises an inteiesting possibility which could account both for the tendency of hypertension to develop in the first place and for its response to dialysis. It is suggested that in patients with chronic renal failure and the controllable form of hypertension, the .regression of renin on exchangeable sodium has a shallower slope than ndrmal, as illustrated .schematicaily in Figure 10. This could arise because renin release is unresponsive to changes in sodium balance. The hypothetical events which would follow are that relatively minor dietary sodium excess would lead to sodium retention, that renin would not decrease normally and that an abnormal sodium excess:renin relationship would develop, and that blood pressure would rise. It is known that the blood pressure of such patients is sensitive to relatively minor changes in sodium intake [3,5,17,25], and Warren and Ferriss [76] have shown that plasma renin activity fails to sup-

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press normally with sodium excess and with DOCA administration. They also suggest that this could be important in raising blood pressure. The renin levels in these patients also seem unresponsive to sodium depletion (at least in the range in which blood pressure is raised). This we suggest is responsible for the fall in blood pressure during sodium depletion. Ledingham [13] has made the same proposal, and again there is some supporting evidence. The rise of renin activity in patients of this type is relatively small during deprivation of dietary sodium or during sodiumand water-depleting regular dialysis treatment [20,25,27,32,76-791, and a decrease in plasma renin concentration may sometimes occur in these circumstances after salt- and water-depleting hemodialysis [17,27,79]. In Figure 9 are plotted renin, angiotensin II and exchangeable sodium data from patients with the controllable form of hypertension. These indicate a more horizontal than normal relation between exchangeable sodium and the renin-angiotensin system in that the reduction of exchangeable sodium by dialysis did

PLASMARENIN CONCENTRATION

\

I

IN CHRONIC

NaE Figure 10. Schematic representation of directions in which the NaE:renin relation might change in patients with controllable and intractable hypertension. In the former the relation is more horizontal than that in normotensive subjects, whereas in the latter the relatibn is parallel but displaced to the right of that in normotensive subjecti. It is not implied that the NaE:renin reiation is necessarily the same initially in the two groups of hypertensive patients.

PlasmaRenin calc&mtion

A

U

l

I

i

I

>12

I

12

I a

, I

I

4

B&m RegulatDidysis During Regular Diifysis

I

? >12

Sk&k

12

Months

Months of plasma renin concentrations in patients Figure 11. Serial measurements sion (left) and controllable hypertension (right) with chronic renal failure.

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not lead to the expected increase in renin and angiotensin II concentration. The observation is therefore compatible with the proposal that an unresponsive sodium:renin mechanism is the cause of the controllable hypertension in chronic renal failure and the basis of its cure. The nature of this unresponsive state is not established. One possibility is that excess sodium is contained in a space inaccessible to the renin release mechanism. Removal of sodium from this space by dialysis would then fail to provoke renin. Another possibility is that the underlying renal disease has deranged the renin release mechanism to the point where renin is inappropriate to sodium status. Different Abnormalities in the Controllable and Intractable Form of Hypertension. The existence of a relatively inflexible renin mechanism in catients with controllable hypertension suggests a simple difference from intractable hypertension. In the latter, renin release may be abnormally raised in relation to sodium status but it remains so at all levels of exchangeable sodium. Renin release increases further after sodium loss therefore. As illustrated schematically in Figure 10 an attempt to reduce blood pressure by sodium depletion would be thwarted by an increase in renin. Again there is some evidence to support the idea; marked increases in renin and angiotensin have been noted in patients with intractable hypertension during the unsuccessful attempt to control blood pressure [19,20,27,28,79], and Figure 11 summarizes our previous experience with the addition of more recent data. As can be seen, plasma renin concentration tends to increase during the dialysis regimen in patients with intractable hypertension and to remain relatively unchanged over the same period in patients whose blood pressure is subsequently well controlled. Although this difference may to some extent reflect the more vigorous sodium depletion attempted in the intractable cases,

the fact that renin rises and blood pressure does not fall until the kidneys are removed agrees with the idea. This different response of renin may be the basis for a distinction between controllable and intractable hypertension, and it would be a relatively simple matter to predict the outcome of dialysis by measuring the response of renin to sodium and fluid depletion and sodium loading. Brown and his colleagues [12,27,28] and Ledingham [13] have made the point that renin may rise most during sodium and fluid depletion in the intractable form of hypertension. Furthermore, there is evidence in these patients that renin levels at comparable sodium and fluid states are already higher before dialysis is undertaken [80]. CONCLUSIONS It is suggested that blood pressure rises in chronic renal failure because circulating levels of renin and angiotensin II are inappropriately high in relation to sodium status. This may arise in two ways: in the larger group of patients responding to dialysis, hypertension develops because renin fails to suppress normally with sodium retention. Renin levels are then inappropriately high in relation to sodium whereas blood pressure is raised. However, when sodium is removed by dialysis, blood pressure falls because renin fails to rise. The relatively horizontal relation between renin and exchangeable sodium is, therefore, the cause of the disorder and the basis of its cure. Hypertension of this type is sodium-dependent [32] in the sense that excess sodium, relative to renin, is its cause. Renin is also inappropriately high in relation to sodium in the smaller number of patients with intractable hypertension, but here renin rises even further in response to therapeutic sodium depletion. It is suggested that this may perpetuate the hypertension.

REFERENCES 1.

2.

3.

4. 5.

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Koletsky S, Goodsitt, AM: Natural history and pathogenesis of renal ablation hypertension. Arch Path 69: 654,196O. Douglas BH, Guyton AC, Langston JB, Bishop VS: Hypertension caused by salt loading. II. Fluid volume and tissue pressure changes. Amer J Physiol 207: 669,1964. Blumberg, A, Nelp WB, Hegstrom RM, Scribner BH: Extracellular volume in patients with chronic renal disease treated for hypertension by sodium restriction. Lancet 2: 69, 1967. Dahl LK, Knudsen KD, Heine MA, Leitl GJ: Effects of chronic excess salt ingestion. Circ Res 22: 11, 1968. Wilkinson R, Scott DF, Uldall PR, Kerr DNS, Swinney J: Plasma renin and exchangeable sodium in the hypertension of chronic renal failure. Quart J Med 39: 377, 1970.

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Davies DL, Beevers DG, Brown JJ, Fraser R, Ferriss JB, Lever AF, Medina A, Morton JJ, Robertson JIS: Sodium and the renin-angiotensin system in patients with hypertension. Proceedings of the IVth International Congress of Endocrinology, 1973. Pickering GW, Prinzmetal M: Some observations on renin, a pressor substance contained in normal kidney, together with a method for its biological assay. Clin Sci 3: 211, 1938. Bianchi G, Brown JJ, Lever AF, Robertson JIS, Roth N: Changes of plasma renin concentration during pressor infusions of renin in the conscious dog: the influence of dietary sodium intake. Clin Sci 34: 303, 1968. Chinn RH, Dusterdieck G: The response of blood pressure to infusion of angiotensin II. Relation to plasma concentrations of renin and angiotensin II. Clin Sci 42: 489, 1972.

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10.

11.

12.

13. 14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

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