Renin and the kidney.

Nephron 15: 279-305 (1975)

Renin and the Kidney1 A r n o l d M . C h o n k o , J ay H . S t e in a n d T homas F . F erris Department of Medicine, Ohio State University School of Medicine, Columbus, Ohio

Key Words. Renin-angiotensin system ■Catecholamines • Autoregulation • Congestive heart failure • Nephrotic syndrome • Cirrhosis • Bartter's syndrome Abstract. The factors involved in renin release have been extensively evaluated. The primary determinants are the transmural pressure at the afferent arteriole, sodium delivery to the macula densa, and the activity of the adrenergic nervous system. Other possible factors include circulating catecholamines, the serum and cerebrospinal fluid sodium con centration, serum potassium concentration, angiotensin II concentration, and antidiuretic hormone release. There is no convincing evidence that the renin-angiotensin system mediates renal autoregulation. Plasma renin activity is altered in a number of clinical settings. This parameter is elevated in most patients with cirrhosis and the nephrotic syn drome as well as in individuals with severe congestive heart failure. Despite inappropriately large weight gains, plasma renin suppresses normally with increased salt intake in edematous patients who have a normal glomerular filtration rate. The mechanisms of the alteration in the renin-angiotensin system in Bartter’s syndrome is still not clear.

Renin was the first hormone to be isolated from the kidney. In 1898, T igerand Bergmann [108] demonstrated that an extract of rabbit kidney raised arterial pressure when injected into another rabbit. However, there was little interest in the physiological role of renin until 1934, when G oldblatt et al. [38] demonstrated that renal artery occlusion could cause chronic hyper tension. This landmark experiment stimulated a research effort that has now identified the various components of the renin-angiotensin-aldosterone sys tem and partially clarified its role in regulating vascular volume and pressor responses. It is generally accepted that renin is a proteolytic enzyme with a 1 Supported by National Institutes of Health grants HL 13653-02, AM 13524-03 and HL05975-01, Clinical Research Center grant RR-34 from the National Institutes of Health, and grants from the Central Ohio Heart Association.

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molecular weight of 40,000 that has no vasoconstrictor properties of its own [96]. It interacts with renin substrate (angiotensinogen), an a-2-globulin syn thesized within the liver, to form angiotensin I. Angiotensin I is a very weak vasoconstrictor but is capable of stimulating aldosterone secretion by the adrenal cortex. As angiotensin I circulates through the lung and kidney, it is acted upon by converting enzyme which splits off two terminal amino acids to produce an octapeptide with very potent vasoconstrictor properties, angio tensin II. This peptide also is a potent stimulus to aldosterone secretion.

In 1939, G o o r m a g h t ig h [39] first used the term ‘juxtaglomerular appa ratus’ to describe that area of the nephron which consists of the juxtaglomeru lar cells and the macula densa. There are several lines of evidence that renal renin is secreted from this anatomic structure. First, there is a consistent correlation between the granule count of the juxtaglomerular cells and the renin content of the kidney. The granule count and the total renal renin con tent is increased in chronic renal artery constriction [106] and chronic sodium chloride depletion [80], and decreased in animals on a high salt diet with or without desoxycorticosterone acetate [80], Second, microdissection studies by B in g et al. [10,11], and C o o k and P ic k er in g [26] which utilized magnetic particles to isolate the glomeruli, localized the extractable renin to the vascular poles of the glomeruli. These findings have recently been confirmed by G ranger et al. [43], Third, there is specific staining of the juxtaglomerular cells of hog, dog, and rabbit after treatment with fluorescent antirenin anti bodies [45,46], Indeed, it has been demonstrated with this technique that there is specific staining of the juxtaglomerular cells with fluorescent antirenin anti bodies in patients with the Robertson-Kihara syndrome [25], Fourth, R obert son et al. [82,83] found in a cell culture obtained from human renal cortex that renin could be produced in the media only when cells with Bowie-positive granules were present. Although the general site of renin production is well established, the spe cific signal perceived by the kidney to regulate renin release continues to be the subject of great controversy. Some of the factors suggested to influence the renal release of renin are as follows: renal perfusion pressure; sodium delivery to the macula densa; adrenergic activity; circulating catecholamines; serum sodium concentration; cerebrospinal fluid sodium concentration; serum potassium concentration; angiotensin II, and antidiuretic hormone.


Renin Secretion

Renin and the Kidney

281

However, most of the experimental evidence suggests that three major mecha nisms dominate the control of renin release: alterations in the renal perfusion pressure (the baroreceptor hypothesis): the delivery of sodium to the distal tubule (the macula densa hypothesis), and alterations in adrenergic activity.

Initially it was suggested that renal ischemia accounted for the increased renin release in the G o ld bla tt model [38], HuiDOBROand B ra u n -M en en d ez [50], however, infused potassium cyanide into dogs and had their animals breathe increased concentrations of carbon monoxide, carbon dioxide (2-5%), and lower concentrations of oxygen (6-8%), without affecting renin release as long as hypotension was prevented. These findings subsequently were confirmed by S k in n er et al. [95], and most recently, by S pa th et at. [97]. S k in n er et al. also found that renal perfusion pressure could be reduced and renin release increased even when renal blood flow was unchanged. All of these points exclude renal ischemia as the mechanism of increased renin release when renal perfusion pressure is decreased. In 1940, K ohlsta ed t and P age [55], using an isolated kidney preparation, suggested that a decrease in arterial pulse pressure stimulated renin secretion. In contrast, K olff [56] showed that renin or a renin-like substance was released in response to renal artery constriction irrespective of pulsatile or nonpulsatile flow. In 1959, T obian et al. [107], first proposed that the juxtaglomerular cells might act as a stretch receptor that would respond to changes either in intravascular, afferent arteriolar pressure, alterations in the transmural pressure of the afferent arteriole at the site of the juxtaglomerular cells, or wall tension at this same site. In the model utilized by T obian [107], an isolated rat kidney was perfused at 85 mm Hg or at a pressure greater than 167 mm Hg and a comparison was made of the juxtaglomerular cell granulation in the perfused kidney and that of the opposite kidney. There was no difference in the juxta glomerular cell granulation index between the control and perfusion kidney at a pressure of 85 mm Hg, while a 42% decrease in granulation was found at the higher perfusion pressure. This suggested that an increase in renal per fusion pressure could suppress the production of renin from the juxtaglomeru lar cells. D avis et al. [12], studied a model of high output cardiac failure in duced in dogs with a large arteriovenous fistula. This model caused a reduc tion of mean renal arterial perfusion pressure despite the maintenance of a widened pulse pressure. Plasma renin activity was markedly increased. This


Baroreceptor Hypothesis


result again refuted the pulse pressure theory for renin release and further suggested that changes in renal perfusion pressure may regulate renin release. S k in n er et al. [95] utilized a model of renal artery constriction and found that juxtaglomerular cell granulation and release of renin into renal venous effluent increased simultaneously as renal perfusion pressure was gradually lowered. However, as will be discussed, these experimental maneuvers may decrease the delivery of sodium to the distal tubule, a factor which may also increase renin release [114]. To circumvent the problem of sodium delivery to the macula densa, D avis and colleagues [12,13,129] utilized a 'nonfiltering kidney’ model in the dog by cross-clamping the renal vascular hilus for 2 h in conjunction with permanent ipsilateral ureteral ligation and contralateral nephrectomy [12,13,129], The animals were maintained by peritoneal dialysis. In the first group of five studies in conscious dogs, a 20 ml/kg hemorrhage increased plasma renin activity from 6 to 22 ng angiotensin/min, with no significant change in substrate concentration. Reinfusion of the blood re turned arterial pressure to normal and renin secretion declined to the control level [12], Aortic constriction above the renal arteries also caused a similar increase in plasma renin activity [13]. These studies were repeated in animals that had been previously adrenalectomized and had undergone surgical and chemical denervation of the single remaining nonfiltering kidney. Renin secretion was again markedly elevated from 100 to 450 ng angiotensin/min with hemorrhage and aortic constriction. This increase in renin secretion could be abolished in denervated kidneys pretreated with papaverine hydro chloride, a smooth muscle paralytic agent that would presumably abolish sensitivity of the vascular baroreceptor [129]. Since the intrarenal administra tion of papaverine is also known to block renal autoregulation [110], the previous study suggests that the baroreceptor lies at the level of afferent arteriole within the juxtaglomerular apparatus. It was further demonstrated that the plasma renin activity was markedly increased in dogs with vena caval constriction with a nonfiltering kidney, and that this elevation could be re duced by intraarterial papaverine [130]. If the same experiment is repeated in an animal with a normal left kidney, the infusion of papaverine has no effect on the elevated plasma renin levels [130], This series of experiments clearly demonstrate that there is an intrarenal vascular receptor sensitive to pressure changes within the renal circulation and that renin secretion can be altered independently of sodium delivery to the macula densa. Most recently, K aloyanides et al. [53] described an experimental model in which the baro receptor could be shown to override the effects of the macula densa. In an isolated dog kidney preparation in which renal arterial pressure could be


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elevated above normal levels, ureteral obstruction increased renin secretion from 143 to 970 ng/min. When renal arterial pressure was increased from 103 to 164 mm Hg, the renin secretion returned to control levels, despite the persistence of elevated ureteral pressure. By reversing the order of the ex periment, renin secretion was suppressed below control levels with an in crease in renal artery pressure and returned to approximately the control level when ureteral obstruction was superimposed on the elevated perfusion pres sure. These data substantiate the overall importance of the baroreceptor in controlling renin release in their model.

In 1945, G o o r m a g h tig h [39] suggested that a functional relationship existed between the macula densa and the juxtaglomerular cells. This hypothe sis received its first experimental support in 1964 when V ander and M iller [114] found that the increased renin release induced by aortic constriction could be obviated with chlorothiazide, acetazolamide, or mannitol. Subse quent studies demonstrated that the increased renin release seen with elevated ureteral pressure [114], infusion of catecholamines at a constant renal per fusion pressure [29], and renal nerve stimulation [115] could be blocked with mannitol, sodium sulfate, chlorothiazide or acetazolamide. It was suggested that an inverse relationship existed between sodium delivery to the macula densa and renin release. Although tubular lumen at the area of the macula densa cannot be punctured, areas only slightly distal have been studied and data compatible with the V a nd er hypothesis have been obtained. D i B ona [30] superimposed ureteral obstruction on a mannitol diuresis and found a marked decrease in the fractional delivery of sodium in the early distal tubule as renal vein renin concentration rose from 20 to 34 ng/ml/24 h after ureteral obstruction. L a n d w e h r et al. [58] and G labman et al. [36] both found de creased sodium delivery to the distal tubule after a reduction in renal per fusion pressure. However, as further studies were carried out using the more potent diuretics, some apparent discrepancies were noted. Mercury bichlo ride, 2 mg/kg, given to dogs intramuscularly caused an elevation in plasma renin levels when urinary losses were not replaced but renin levels returned to control levels with volume expansion [117]. Furosemide given to rabbits increased plasma renin activity even while urinary losses were reinfused to prevent volume depletion [66], B r o w n et al. [18], found that chlorothiazide as well as mercurials increased renin release only when urinary losses were


Macula Densa Theory


not replaced, while V a n d er and C arlson [118] found that furosemide in creased renal venous renin in spite of correction of extracellular fluid loss. In another study, ethacrynic acid and chlorothiazide were given to dogs and urinary output was continuously reinfused [27], Ethacrynic acid markedly increased renal venous renin levels even when all urinary losses were corrected, while chlorothiazide had no significant effect in reinfusion studies. Also, when ureteral obstruction was induced at the time of ethacrynic acid administra tion, no further rise in renal vein renin occurred, but with release of the ureteral obstruction renin activity increased from 4,754 to 7,688 ng angio tensin II/100 ml plasma [27]. Therefore, renin release was increased at a time when there was markedly increased sodium delivery to the macula densa. Although this may be construed as being against the V a n d er hypothesis that increased sodium delivery to the macula densa inhibits renin release, another interpretation is possible. Since ethacrynic acid is an inhibitor of sodium transport across numerous epithelial structures, it might also inhibit sodium transport by the macula densa. Indeed, experiments by N ash et al. [72] suggest that the stimulus for renin release in related more to the sodium flux across the macula densa into the interstitium near the juxtaglomerular apparatus than to the amount of sodium delivery to the macula densa. Just how an increased sodium flux across the macula densa specifically regulates renin release is not clear. In contrast to these studies, T h u r a u et al. [111] proposed that an increased sodium concentration rather than decreased sodium load at the macula densa increased renin release. In studies in salt-depleted rats, retrograde distal tubular injections of hypertonic and isotonic sodium chloride and bromide produced proximal tubule collapse, while injections with mannitol or choline chloride had no effect. It was suggested that the increased sodium concen tration caused increased renin release which increased local release of angio tensin II, resulting in vasoconstriction and decreased glomerular filtration. This view seemed surprising since the preponderance of renal venous renin measurements indicate the opposite. In reconciling these differences, T hurau et al. [112] maintained that the local renal interstitial concentration of renin may not parallel changes in renal venous blood. A further discussion of this data will be given in the section on autoregulation. More evidence seemingly against the macula densa theory has recently been obtained by Y o u n g and R ostorfer [134]. Renal arterial osmolality was raised by infusing small volumes of hypertonic sodium chloride, dextrose, or urea into the renal ar teries of dogs. Renin release increased rapidly with each of these solutions at a time when both renal blood flow and glomerular filtration rate rose.


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285

Although no direct measurements were performed, it would seem likely that sodium delivery to the macula densa would also increase. These authors suggest that hyperosmolality decreased the cell volume of the juxtaglomerular apparatus which stimulated the release of renin. The relationship of this proposed osmotic effect on renin release to the overall regulation of renin is not presently clear.

Anatomic studies by Barajas [6] and W agermark et al. [124] have clearly demonstrated the presence of sympathetic nerve terminals in the proximity of the granulated cells of the juxtaglomerular arterioles. Just how these sym pathetic fibers influence renin release has been a matter of much speculation. Vander et al. [115] originally showed that placing a loop electrode around the renal artery and applying electrical stimuli resulted in increased renal venous renin activity. Others also found an increase in plasma renin activity following renal nerves stimulation [28,61,113]. Since the latter could alter renin release via a baroreceptor response, Vander et al. [115] performed further studies with intravenous infusions of epinephrine (5-6 ¡¿g/min) or nor epinephrine (12-16 (Jtg/min) while maintaining constant renal perfusion pres sure. However, both of these agents still caused an increase in plasma renin activity suggesting a direct adrenergic effect. Similar results were reported with intra-arterial infusions of norepinephrine [125]. Stimulation of sympa thetic vasomotor discharge by occlusion of the common carotid arteries caused release of renin despite maintenance of a constant renal perfusion pressure [21]. Renal artery infusions of norepinephrine or tyramine increased renin release in the presence of a constant renal perfusion pressure, while isoproterenol, angiotensin, vasopressin, serotonin and acetylcholine had no effect [21]. More conclusive data concerning the actual mechanism of increased renin release induced by sympathetic activity has been obtained from recent studies by J ohnson et al. [51] utilizing the nonfiltering kidney. Their data suggest that enhanced renal nerve stimulation and increased circulatory catecholamines have a direct effect on the renin secretory response of the juxtaglomerular cell independent of perfusion pressure or the delivery of sodium to the macula densa. The role of the central nervous system in the regulation of renin release has received attention in recent studies. Passo et al. [78] stimulated the medulla


Adrenergic System


oblongata near the obex in dogs and found increased plasma renin activity. Conversely, Z ehr and F eig l [135] found a 50% reduction in plasma renin activity following hypothalmic stimulation in conscious dogs. Both of these responses could be abolished by renal denervation. The latter authors suggest that a basal sympathetic discharge to juxtaglomerular cells was necessary for the maintenance of normal renin secretion. Data obtained by G o r d o n et al. [41], in a patient with severe autonomic insufficiency seem to corroborate this view. However, we have not been able to confirm these findings in other patients with autonomic insufficiency. The increase in renin secretion follow ing volume depletion appears to be mediated, at least in part, through renal sympathetic discharge. M o g il et al. [68], found that surgical renal denervation could prevent the increase in plasma renin activity seen with sodium depletion in normotensive and hypertensive dogs. B unag et al. [21] using ganglionic blockade and infiltrative anesthesia around the renal nerves blocked the usual response to hemorrhage, while H odg e et al. [49], used lidocaine blockade of the renal nerves to obtain a similar result. It has also been noted that sym pathetic stimulation can elicit increases in plasma renin at all levels of per fusion. However, the adrenergic effect predominates at a pressure above 100 mm Hg while alteration in pressure is the major determinant of renin release below 100 mm Hg [57], Conflicting data have been obtained regarding the role of adrenergic re ceptors in the release of renin. A ssaykeen et al. [2] and O tsuka et al. [77] found that the intravenous administration of epinephrine markedly increased renin release while norepinephrine and dopamine had little if any effect. Hypoglycemia induced rises in both plasma renin activity and epinephrine concentration and this response was blocked with adrenalectomy and propranol but not with intravenous phenoxybenzamine. It was concluded that the renin response seen with hypoglycemia was dependent upon adrenal epi nephrine release and that epinephrine stimulated renin secretion via a padrenergic mechanism. More recently, R eid et al. [81] found that the intra venous infusion of isoproterenol increased plasma renin activity and renin secretion rate even in the presence of renal denervation. In contrast, there was no change in renin release during direct intrarenal infusion of isoproterenol. The authors concluded that p-adrenergic stimulation of renin release is medi ated through extrarenal hemodynamic alterations. On the other, W in er et al. [127,128] found an increase in renin secretion with intrarenal infusions of norepinephrine and isoproterenol. Paradoxically, the increase in renin pro duction induced by norepinephrine, a predominantly a-receptor agonist, was suppressed by propranolol administration and the renin stimulating effect of


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Miscellaneous Factors Although it has been suggested that a decrease in plasma sodium concen tration per se stimulates renin release [17,79], these findings could readily be explained by other mechanisms which alter renin release. In addition, G ordon and P awsey [42] and N ewsome and Bartter [74] have found that hypotonic volume expansion in man decreased plasma renin activity despite significantly lowering the plasma sodium concentration. N ash et al. [72] however, found that hyponatremic volume expansion in dogs increased renin release, and this response could be blocked by a simultaneous intrarenal infusion of hypertonic sodium chloride. Since the increased renin release secondary to ureteral occlusion and aortic constriction above the renal arteries were also blunted by intrarenal hypertonic sodium chloride infusions, it was suggested that plasma sodium concentration did not directly alter renin release per se but did so through a tubular mechanism relating to decreased filtered sodium loads. Confirmation of this has been reported by S hade et al. [93] in the non filtering kidney model. With the demonstration by Bo n jo u r and M a lv in [15] that angiotensin increased circulating antidiuretic hormone levels, it seemed likely that the hyponatremia often noted in association with high plasma renin activity was more a result of the increased renin levels. More recently, B u n a g et al. [22] and T a g a w a et al. [103] have shown that infusions of vasopressin in physio logic doses can inhibit renin release. A similar inhibition of renin release was noted by W a th en et al. [125], and by V a n d er and G eelhoed [116] with the intrarenal administration of angiotensin II. S hade et al. [94] utilized the nonfiltering kidney model to clarify the mechanism by which these peptides sup pressed renin release. Their data suggested that both of these polypeptides acted directly on the juxtaglomerular cells and that a negative feedback loop may exist between renin release and the plasma level of angiotensin and anti


isoproterenol, a [3-receptor stimulator, was blocked by phentolamine adminis tration. In addition, infusion of cyclic adenosine monophosphate (cAMP) increased renin secretion and this response was abolished both by phentol amine and ¿/./-propranolol. This suggested that cAMP was an intracellular mediator of renin secretion and that the a- and ^-antagonists suppressed renin secretion at a step distal to cAMP production rather than by blockade of plasma membrane adrenergic receptors or by inhibition of adenyl cyclase. The reason for the apparent differences in these studies is not clear and further investigations are needed to clarify the exact role of the adrenergic receptors and cAMP in renin release mediated by the sympathetic nervous system.

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diuretic hormone. The data of Mouw et al. [70] supports this view. They found ventriculocisternal perfusion with low sodium solutions in conscious sheep caused increments in urine flow and plasma renin concentration and decreased sodium excretion without affecting plasma aldosterone levels or renal hemodynamics. They concluded that juxtaventricular tissue contains receptors sensitive to a decrease in sodium chloride concentration or osmo lality, activation of which causes antinatriuresis and renin secretion. Since a fall in osmolality is a potent inhibitor of antidiuretic hormone release, it was suggested that decreased circulating antidiuretic hormone resulted in both the rise in urine volume and plasma renin concentration. Attention was called to the possible relation between the plasma potassium level and renin release by V eyrat et al. [123] in studies in humans. They demonstrated that the administration of potassium chloride to salt-depleted normal subjects or patients with renovascular hypertension caused a fall in plasma renin activity [20,123]. A similar relationship was found in rats [92] and dogs [1], In the latter study it was found that potassium depletion in creased renin release in spite of the development of positive sodium balance [1], In addition, V a n d er [119] showed that the intrarenal infusion of potas sium chloride in dogs caused a fall in renin release in association with a natriuresis. S h a d e et al. [93] found that the infusion of potassium into the renal artery of a nonfiltering kidney had no effect on renin secretion, while in control animals a striking decrease in renin secretion in association with a marked natriuresis occurred. It was concluded that increased sodium delivery to the macula densa was responsible for the potassium-induced renin inhi bition. Indeed, KC1 infusions do increase sodium delivery to the early distal tubule [133].

T h u r a u et al. [111] first proposed an intrarenal feedback mechanism in which there was a direct relationship between sodium concentration at the macula densa and the release of renin at the individual nephron level. This initial view was based on studies in salt-depleted rats in which distal tubular microinjections of isotonic saline or bromide led to the collapse of the proximal tubule of the same nephron, while isomolar injections of mannitol had no effect [111], When these studies were repeated in sodium-loaded rats that were presumably renin depleted, there was no change in proximal tubular diameter. They proposed the following sequence: increased renin release, local angiotensin II formation, afferent arteriolar constriction, and a de


Autoregulation

289

creased glomerular filtration rate with resultant proximal tubule collapse. Other data that support this hypothesis include: the presence of myofibrils in the juxtaglomerular cells [47], the presence of renin substrate and coverting enzyme for angiotensin in the juxtaglomerular apparatus [44] and the presence of denovo angiotensin II in renal lymph [4], S c h n erm a n n [87], however, could not confirm the original observations of C ortney et al. [29], and found that the sodium concentration in the early distal tubule was not necessarily de pendent upon delivery rate. In fact, both S c h n erm a n n et al. [88] and M o r g a n and B erliner [69] noted that sodium concentration was high at very low delivery rates, then fell, but rose once again at perfusion rates greater than 20 nl/min in late proximal tubules. Subsequent studies [73,89,90] have further complicated the issue. In all these studies data has been presented which suggests that a feedback loop is operative in response to changes in distal delivery. Yet, the findings of the latter two studies are seemingly contra dictory. S c h n er m a n n et al. [90], found a nonlinear fall in the calculated glomerular pressure as perfusion rates out of the proximal tubule increased but demonstrated no effect at low flow rates or when delivery to the distal tubule was abolished. This latter finding confirms the work of B l a n t z et al. [14], Yet, N avar et al. [73] suggested from studies in the dog that abolishing delivery to the distal tubule increased nephron GFR in the proximal tubule at least when mean arterial pressure was high. This finding has not been con firmed in either the dog [54] or rat [64], As attractive as the glomerular feed back theory may be, it is apparent that firm experimental proof is lacking at the present time. In addition, the majority of whole kidney data concerning the relation of the renin-angiotensin system to the control of autoregulation are against a causal role. S c h m id [86] found that the autoregulation of blood flow and glomerular filtration could not be correlated with a change in renin release during either aortic constriction or renal venous occlusion. In the aortic con striction studies, autoregulation was abolished below 77 mm Hg but at this time renal resistance had markedly decreased despite a fourfold rise in renal venous renin activity [86], In similar studies, B ailie et al. [5] found that renal hilar lymph angiotensin II was also increased with a reduction in perfusion pressure and almost complete autoregulation. If the renin-angiotensin system had mediated autoregulation the opposite would have resulted. In addition, Belleau and E arley [9] found no difference in the degree of autoregulation in dogs on a normal sodium intake versus those given a high salt diet plus desoxycorticosterone acetate. Since the latter treatment would have dimin ished renal renin content, these studies further militate against renin having



290


an important role in autoregulation. Also, angiotensin infusion did not pre vent autoregulation through a wide range of pressure changes in these dogs. G agnon et al. [33] also found that intrarenal angiotensin infusion did not alter autoregulation, renal blood flow or glomerular filtration rate. It seems most likely that autoregulation of renal blood flow and glomerular filtration rate are due to alterations in intrinsic myogenic tone of the arterioles of the renal circulation rather than to alterations in the renin-angiotensin system.

The development of the radioimmunoassay technique has facilitated the ease and accuracy of plasma renin measurements and has led to extensive clinical investigation of this parameter. A clear understanding of the termi nology used in reporting this data is essential. In most instances plasma renin activity is reported rather than renin concentration. Plasma renin activity is determined indirectly by measuring the amount of angiotensin I generated by incubation of plasma containing renin substrate at a standard pH and in the presence of substances that inhibit degradation of the formed angiotensin I. Plasma renin activity is therefore dependent upon the endogenous amounts of both renin and substrate contained in a plasma sample. The actual plasma renin concentration can be determined only if during incubation, excess renin substrate is added. Then the only limitation to the amount of angiotensin generated will be the actual concentration of plasma renin. If excess renin is added to the incubation, a determination of renin substrate concentration is obtained. These facts are particularly relevant in studies of the effects of oral contraceptives upon the renin-angiotensin system. L aragh et al. [75] found that in nearly all patients using oral contraceptives, plasma renin substrate was markedly elevated. Plasma renin activity, however, was only elevated in about half of these patients since plasma renin concentration was reciprocally reduced. These data have been substantiated by Beckeroff et al. [8] and suggest that there may exist a negative feedback mechanism between elevated plasma angiotensin II levels and plasma renin concentration. Indeed, K aplan et al. [85] propose that the hypertension associated with the use of oral contra ceptives involves a diminished feedback suppression of renin concentration by elevated angiotensin II levels. Further studies are needed to clarify this proposal. Several extensive reviews have discussed the activity of the renin-angiotensin-aldosterone system in various clinical states [60,98,121]. In table I we


Clinical Significance o f Plasma Renin Measurements

291


Table I. Plasma renin activity and plasma aldosterone levels in various clinical states

Nonhypertensive states Salt loading Salt restriction Addison’s disease Fluid losses (diuretics, vomiting, diarrhea, hemorrhage, etc.) Salt-wasting nephritis Idiopathic autonomic insufficiency Propranolol Amino glutethimide Heparin Chronic lead poisoning Congestive heart failure Cirrhosis Nephrotic syndrome Cyclic edema

Plasma aldosterone concentration

N

N

t t t/N

t t t/N

t tt

t tt

1 Y

t/N

t t/N t t t t t/N t/N t/N

1

J Y

t/N t t t/N

t/N t/N t/N

I t t

t t t

t t

T

j/N

N

t t t/N t t/N t/N t/N

t/N t t t f/N t/N t/N N

1

t t 1

t 1

N

N

A

t


Hypertensive states Essential hypertension 80% 20% Malignant hypertension Renal artery stenosis Robertson-Kihara syndrome (J-G cell tumors) Preeclampsia/toxemia Conn’s syndrome (1° aldosteronism) Congenital adrenal hyperplasia 180H-DOC increases Cushing's syndrome Liddle’s syndrome Licorice ingestion Hyperthyroidism Hypothyroidism Acromegaly Isolated hypoaldosteronism Oral contraceptives Acute glomerulonephritis Acute renal failure Chronic renal failure

Plasma renin activity

292


have summarized the consensus of these findings as they relate to plasma renin activity and plasma aldosterone concentration. In the remainder of this discussion we will focus upon the activity of the renin-angiotensin system in two specific areas: edematous states and Bartter’s syndrome.

There is abundant evidence of enhanced activity of the renin-angiotensinaldosterone system in cirrhosis and the nephrotic syndrome. G enest and Veyrat [122] measured plasma renin activity in various edematous conditions and found that many patients with nephrotic syndrome or cirrhosis had levels greater than 3,000 ng AI/100 ml as opposed to control values of 20 ng Al/ml. Laragh et al. [59] demonstrated that aldosterone secretion rates were ex tremely elevated and did not suppress with salt loads in both groups of patients. Similarly, W olff et al. [131], found elevated plasma aldosterone levels in patients with cirrhosis or the nephrotic syndrome. There is evidence, how ever, that the situation in cirrhosis is much more complex. A yers [3] found that although plasma renin activity was elevated fourfold in these patients, there was a marked decrease in plasma renin-substrate. G abuzda et al. [91] studied 24 cirrhotics with ascites including seven with the hepatorenal syn drome. Plasma renin activity was elevated but renin substrate was decreased. Plasma renin concentration was elevated in all but to a greater extent in those patients with hepatorenal syndrome. It was noted that there was an inverse correlation between plasma renin concentration and glomerular filtration rate. While there are no adequate animal models of cirrhosis, several models have been used to simulate congestive heart failure. In most of these, there is evidence of enhanced renin release. G enest et al. [37] used a balloon to transiently obstruct venous return to the right atria of dogs and found a three fold increase in plasma renin activity. J ohnston et al. [52] found increased plasma renin levels in dogs with low cardiac output secondary to tricuspid insufficiency and pulmonic stenosis. In dogs with arteriovenous fistulas and high output cardiac failure, three of five animals showed increased plasma renin activity [52], In DOCA-treated dogs which developed a venous con gestive state after the creation of arteriovenous fistula, but did not have elevated right atrial pressures plasma renin activity remained low [52], D avis et al. [100] using larger arteriovenous fistulas in dogs demonstrated consistent rise in renin secretion from 600 to 2,000 ng A/min. D avis et al. [13] have also demonstrated that the mechanism of increased renin release with caval con


Edematous States

293

striction in dogs with nonfiltering kidneys is mediated by a baroreceptor mechanism. The clinical data obtained regarding the renin-angiotensin system in pa tients with congestive heart failure has been more variable. Increased plasma renin activity was reported by G enest et al. [37,122] in the majority of patients with untreated heart failure. Following treatment with diuretics and salt re striction, plasma renin activity decreased to low levels. M assani et al. [65] also reported increased plasma renin activity in untreated patients but found that natriuresis had no effect. Others, however, found normal plasma renin activity in untreated patients [19,48]. Following natriuresis, plasma renin activity gradually increased. Similar variability was found in aldosterone excretion rates in congestive heart failure. Some found increased aldosterone excretion rates [62,132] while others did not [71,84], L aragh [59] reported that in con trast to patients with cirrhosis and nephrotic syndrome, most patients with congestive heart failure had normal aldosterone secretion rates. More re cently, Vandongen and G ordon [120] found that plasma renin activity was low in patients with untreated cardiac failure and gradually increased with natriuresis. The reasons for such variability are not clear but may relate to changes in cardiac function with rest during hospitalization as well as to differences in the severity of cardiac disease in the different groups of patients studied. The cause of the edema in women with periodic or cyclic edema is un known but has been postulated to be due to one of three mechanisms: hypoproteinemia [35]; an increase in capillary permeability [105]; and excessive pooling of blood in the legs on standing [102], In all circumstances, plasma renin activity and aldosterone levels should be elevated, since each of these aberrations would result in either diminished plasma volume or arterial filling. Studies by S treeten et al. [101], and L uetscher [63] showed that these patients had elevated aldosterone secretion and excretion rates that did not suppress with increased salt intake. Recently, we studied eight women with this condition and obtained serial measurements of plasma renin activity and plasma aldosterone concentration while they were on low sodium (10 mEq) and high sodium (400 mEq) diets [31]. There was no significant difference in the suppressibility of the renin-angiotensin-aldostcrone axis in these women when compared with nine normal control females (fig. 1). During the 4 days of salt loading, the patients gained 5.5-6.0 kg, had a mean positive sodium balance of 938 mEq and were still in positive sodium balance at the end of the study. In contrast, control females gained only 1.2 kg. Both groups had normal plasma albumin levels and had normal creatinine clearances that were



294


not significantly altered during the study. Thus, sodium retention occurred with appropriate changes in GFR, and a fall in plasma renin activity and aldosterone concentration, demonstrating that other factors were operative in the production of edema in these patients. In conjunction with this investigation, patients with cirrhosis and ascites were similarly studied. With increased salt intake cirrhotics avidly retained sodium and gained 5.8 kg in 4 days. In contrast to the patients with cyclic edema, however, both plasma renin activity and plasma aldosterone levels failed to suppress (fig. 2). It should be noted that in these patients GFR was significantly reduced. Recently, we have studied several patients with cirrhosis and ascites who had normal glomerular filtration rates. Plasma renin activity suppressed normally with increased salt intake and remained suppressed during sodium retention [24]. In addition, in patients with congestive heart failure and the nephrotic syndrome with normal GFR, we have observed normal suppressibility of plasma renin activity with salt loads despite in appropriately large weight gains [24]. In a recent micropuncture study in rats in our laboratory, a comparison was made of the segmental analysis of sodium transport during volume expansion in normal rats, rats on a low salt diet, and rats on a low salt diet plus pretreatment with furosemide [99], In the first two groups, GFR and delivery of sodium to the early and late distal tubule was similar, yet sodium excretion was threefold greater in the control rats. In contrast, rats with low salt intake given furosemide had a marked decrease in both GFR and delivery of sodium to the early distal tubule. Thus, it might be construed that delivery to the early distal tubule and presumably the macula densa would not be altered during salt loading in models of moderate sodium retention if GFR remained constant. In contrast, when GFR was decreased early distal sodium delivery would fall. Thus, it may be that the ability to suppress renin in edematous patients with a normal GFR is a consequence of adequate sodium delivery to the macula densa over coming enhanced baroreceptor or adrenergic stimulation.

In 1962, B artter et al. [7] described a syndrome characterized by juxta glomerular hyperplasia, hyperaldosteronism, hypokalemia, metabolic alka losis, normal blood pressure and the absence of peripheral edema. Subsequent examples of the syndrome were described which had the following additional features: weakness, vomiting, salt craving and tetany in late infancy and early


Bartier's Syndrome


295

Day

Fig. 1. The suppressibility of plasma renin activity (PRA) in patients with cyclic edema versus normal women. There was no statistical difference in the rate of decline or final PRA in these groups. PRA was initially higher in patients with cyclic edema because of diuretic therapy given to render them edema-free at the outset of the study. — = Idiopathic edema; -----= controls.

2 3,000*g> 2,500 -

< 2,0 0 0 cl

1,500 50-

rt o

40 30-

E In in o

20

-

10

-

I------------1------------1----------- 1

3

4

Fig. 2. Persistently elevated plasma renin activity and plasma aldosterone concentration in six cirrhotic patients with ascites who gained 5.8 kg in 4 days while ingesting high sodium diets. Please note the markedly decreased glomerular filtration rates in these patients.


1 2 Day


childhood, mental and growth retardation, dwarfism, polyuria with impair ment of urinary concentrating ability, and increased renin activity [16,23,109]. Bartter’s syndrome has occurred in multiple siblings [109] and some authors suggest that it is a genetic disorder with an autosomal recessive pattern of inheritance [16]. Reports of its occurrence in adults with normal mental and physical development point to some patients having an acquired defect [104]. The pathophysiology of this disorder is unknown. B a rtter et al. [7] first suggested that the primary defect was vascular insensitivity to the pressor action of angiotensin. This would lead to a compensatory overproduction of renin, increased angiotensin generation, hyperaldosteronism, and hypokale mia. B r a ck ett et al. [16] reviewed the glomerular and vascular changes found on biopsy in patients with Bartter’s syndrome and suggested that an intrinsic congenital or acquired renal arteriolar or glomerular lesion resulted in de creased perfusion through afferent arterioles which set renin release at high levels. In support of this proposal, volume expansion with albumin failed to suppress plasma renin activity or to correct angiotensin insensitivity. Yet, it has been noted that a similar arteriolar lesion occurs in ‘familial chloride diarrhea’ a condition associated with chronic volume depletion and hyperreninemia. Thus, chronic hyperreninemia may cause the vascular lesion of the afferent arteriole. C a n n o n et al. [23] demonstrated mild but persistent renal sodium wasting in a single well-studied patient with the syndrome.They emphasized that insensitivity to angiotensin was not specific for Bartter’s syndrome but occurred whenever plasma renin activity was elevated, as in salt-depleted normal subjects, pregnant women, and patients with cirrhosis, nephrosis and malignant hypertension. They also demonstrated atypical atrophic changes within the macula densa cells and suggested that the syn drome was the result of a form of sodium-losing nephritis. Data in support of this proposal have been obtained by G oodman et al. [40] and W hite [126], In the former studies, plasma renin activity and plasma aldosterone secretion were both suppressed and sensitivity to angiotensin restored to normal with albumin infusions. In the study of W hite , rapid infusion of 3 liters saline resulted in correction of angiotensin insensitivity and suppression of plasma renin activity. In addition, the natriuretic response to saline loading was some what greater in these patients than in normal subjects. G ood m an et al. [40] also demonstrated that suppression of aldosterone secretion to normal levels by administration of albumin, aminoglutethimide or dexamethasone failed to correct the hypokalemia in these patients. These authors proposed that the initiating event in this syndrome was a mild impairment of proximal tubular


296


297

sodium reabsorption with increased distal sodium delivery and renal sodium wasting. Aldosterone-enhanced distal tubular sodium-potassium exchange would account for some but not all of the potassium-wasting state. In con trast, W h ite [126] felt the primary lesion was located distally since there was no other evidence of proximal tubular impairment. G a rd n er et al. [34] dem onstrated altered sodium transport in erythrocytes from six of eight patients with Banter’s syndrome further suggesting that the primary defect in Banter’s syndrome may be an inherited abnormality of sodium transport across mul tiple epithelial membranes. Although the salt-wasting theory is attractive there is little substantial evidence that these patients are truly volume-depleted. In fact, a recent study by N orby et al. [76] clearly demonstrated that this was not the case. M o d l in g e r et al. [67] using high doses of propanolol (360 mg/day) demon strated that plasma renin activity was decreased front 27.6 to 5.6 ng/ml/h and plasma aldosterone concentration fell from 26 to 14 ng/100 ml in a patient with Bartter’s syndrome. Concomitant with the decrease in plasma renin activity, blood volume tended to increase. This data suggests that the de creased blood volume was a result and not a cause of the hyperreninemia. In addition, propanolol and spironolactone administered simultaneously did not completely correct the hypokalemia. Previous studies have also shown that aminoglutethimide [40] and adrenalectomy [109] do not block potassiumwasting. N orby et al. [76] have studied a patient with this syndrome, and found no evidence of intravascular volume depletion, renal sodium-wasting, or a defect in diluting ability. Their patient demonstrated marked potassiumwasting despite spironolactone and decreased pressor responsiveness to both intravenous and intra-arterial infusions of angiotensin II and norepinephrine [32] primary renal tubular defect in potassium reabsorption could be a major factor in the pathogenesis of this condition. Further studies are needed to clarify this hypothesis.

References

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Human kidney pericytes produce renin.

The renin-angiotensin system and aging in the kidney.

Effect of human kidney lipids on human kidney renin activity.

Classical Renin-Angiotensin system in kidney physiology.

Storage form of renin in the dog kidney.

Evidence for the glycoprotein nature of kidney renin.

Distribution of renin in subcellular fractions from the rabbit kidney.

Renin-Angiotensin system blockers and cardiovascular death in kidney recipients.

Isolation of pure and stable renin from hog kidney.

Renin-Angiotensin system - considerations for hypertension and kidney.

Chronic pyelonephritis: the significance of renal renin and the vascular changes in the human kidney.

Interaction of the renin angiotensin and cox systems in the kidney.

The relationship between sodium excretion and renin secretion by the perfused kidney.

The purification and characterization of recombinant human renin expressed in the human kidney cell line 293.

Renin substrate in granules from rat kidney cortex.

[Immunocytochemical and morphometric studies on the development of renin-immunoreactive cells in the rat kidney].

Properties of renin granules isolated from rat kidney.

Studies on the isolation and properties of renin granules from the rat kidney cortex.

The renin-aldosterone axis in kidney transplant recipients and its association with allograft function and structure.

Renin, antidiuretic hormone and the kidney in water restriction and rehydration.

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System.

Effects of diabetes and insulin on expression of kallikrein and renin genes in the kidney.

A comparison of the properties of renin isolated from pig and rat kidney.

Regulation of renin release and intrarenal formation of angiotensin. Studies in the isolated perfused rat kidney.