Plasma aldosterone regulation in anephric man

Transcription

1 Kidney International, Vol. 3 (1973), p. 1 5 EDITORIAL Plasma aldosterone regulation in anephric man The major role of the kidney in the regulation of aldosterone secretion is well-established [1 3]. The kidneys' dominance in controlling aldosterone output is mediated via the renin-angiotensin system which is remarkably responsive to changes in sodium intake as well as changes in body posture [4 9]. The majority of available evidence indicates that this pathway serves as the primary mechanism for the regulation of sodium balance in virtually all mammalian species [10]. Other factors stimulating aldosterone production include ACTH and changes in [Na] and [K] in the plasma [11 16]. Their role in the physiologic regulation of aldosterone secretion by the adrenal has been less well defined, due in large part to the predominance of the kidneys' role. This has required that these other factors be studied in nephrectomized animals during acute shortterm experiments following extensive surgery, including bilateral nephrectomy. The physiological significance of such studies must be accepted with some reservation. Despite this, some of these studies have raised the question as to whether significant regulatory mechanisms may exist that are independent of the kidney and the renin-angiotensin system [17, 18]. The anephric human maintained on hemodialysis has afforded the opportunity to examine some of these factors under more stable and physiologic conditions that assure absence of interference from an intact reninangiotensin system. It should, under such circumstances, be possible to look more carefully at the question of alternative means of aldosterone regulation exclusive of the renin-angiotensin system. Among the unsettled questions that may be examined in the context of an anephric subject are the following: 1) to what extent do other mechanisms merely modulate the activity of the renin-angiotensin system and to what extent do they independently influence aldosterone secretion? 2) if they exist as independent mechanisms, what are the initiating stimuli and what purposes do they serve? 3) are there unrecognized stimuli or mechanisms responsible for initiating and/or maintaining aldosterone production? 4) lastly, and perhaps most importantly from the standpoint of understanding the physiology of the anephric individual, is there a physiologic need for a!- dosterone; what useful purpose does it serve in the absence of the kidneys? Answers to most of these questions are either unavailable or can only be formulated in incomplete fashion from 1973, by the lnternational Society of Nephrology. currently available information. However, recent information from studies in anephric patients on hemodialysis makes it appropriate to review the present information bearing on these questions to see whether more complete answers may be obtained from further study of the anephric state. ACTH effects. Prior to the observations of Genest et al [19] and Laragh et al [20] that focused subsequent investigative efforts on the kidney as the seat of aldosterone regulation, it was established that ACTH administration stimulated aldosterone secretion [11, 12, 21]. Although much experimental work has established a role for ACTH in the regulation of aldosterone secretion, the precise mechanism whereby this effect is exerted remains unclear. Presently available evidence is most consistent with the concept that ACTH plays a supportive role (production of precursors for aldosterone) while the renin-angiotensin system provides the direct stimulation of aldosterone production [10]. Thus, the maximal aldosterone stimulating effect of the renin-angiotensin system appears to depend upon a concomitantly adequate output of ACTH [22]. In support of this view, aldosterone secretion following blood loss is known to be less in the hypophysectomized dog than in the normal dog [22, 23]. If the role of ACTH is only supportive, the anephric patient on hemodialysis should show no response in aldosterone production when ACTH is administered. The results of such studies have yielded conflicting results. Some investigators report little or no response to ACTH administration [18, 24, 251, while others describe a significant increase of production [26, 32]. Differences in the reported results are too large to be explained by methodologic variation. Further studies are clearly necessary. It has been suggested that volume depletion sensitizes the zona gbmerulosa to ACTH in the anephric state [26], but data showing an increase in plasma aldosterone in response to ACTH in anephric subjects in an expanded state have also been reported [32]. Additional study of this problem in which aldosterone responsiveness to ACTH is examined as a function of ECF or plasma volume, and circulating [K] and [Na] should provide clearer definition of the factors that modulate the response of aldosterone to ACTH infusion, thus clarifying the role of ACTH in aldosterone regulation in the absence of the renin-angiotensin system. The importance of carefully establishing the role of ACTH in anephric subjects is paramount since demonstration of 1

2 2 Walker! Cooke a direct role for ACTH in the absence of kidneys may offer a possible explanation for some of the discrepancies in the results of similarly designed studies in these individuals (see below). Non-renal sodium effects. The primary mechanism by which aldosterone responds to alterations in sodium is provided by the renin-angiotensin system. The primacy of this control mechanism has been clearly established in both normal and pathologic conditions. Whether the sodium has alternate stimulatory access to the adrenal gland by some mechanism that excludes the renin-angiotensin system is less certain. Some acute animal experiments suggest that the zona glomerulosa responds directly to lowered [Na] with increased aldosterone secretion [27] but such observations have usually been made in situations in which blood perfusing the adrenal gland had altered the concentrations of both sodium and potassium [13, 28], although some studies suggest that the lowered [Na] alone augments aldosterone output [15, 27]. It seems unlikely that this is an important mechanism in the human; in fact, marked suppression of aldosterone secretion in the syndrome of inappropriate secretion of antidiuretic hormone has been demonstrated even when the serum sodium concentration was as low as 115 meq/liter [29]. That these patients were capable of responding with an adequate aldosterone output was proven by demonstrating that they subsequently responded normally to sodium deprivation with an increased aldosterone output when the extra water was excreted and the plasma [Na] had returned to normal values [30]. These observations indicate that, in the human, volume expansion (even when induced by water administration or retention and leading to hypotonicity) is a much more potent suppressing stimulus than is hyponatremia a stimulus for increased aldosterone production. Thus, a primary sodium stimulating mechanism independent of the reninangiotensin system is either of little physiological significance or non-existent in the human. Studies from our laboratory in anephric individuals tend to support the view that no sodium-activated mechanism exists that is independent of the renin-angiotensin system [31]. When observations on plasma aldosterone were made in a group of anephric patients maintained in the supine position and studied on the first, third and fourth postdialysis days, plasma aldosterone was shown to rise more than tenfold from 1.1 to 13.3 ng/100 ml of plasma despite sodium retention during the interval as indicated by a mean weight gain of 1.05 kg. Similarly, no correlation between serum [Na] and plasma aldosterone could be demonstrated in these studies. We thus obtained no evidence that aldosterone was influenced by sodium in the anephric individual [31]. Results of other investigators have not always confirmed these findings. Several studies have reported similar findings [24, 25] but Mitra et al [32] could find no evidence for increased plasma aldosterone when anephric patients were volume depleted by peritoneal dialysis. These authors did record a decrease in plasma aldosterone concentration with subsequent volume expansion by means of an infusion of isotonic saline. However, the design of these latter experiments was such that alterations in metabolic clearance rate may have conspired to create the impression that this was a volume response. The patients had previously been standing and experienced difficulty with postural hypotension. The reduction in hepatic blood flow and metabolic clearance associated with hypotension could account, at least in part, for the observed increase in plasma aldosterone while the subjects were standing [33, 34]. Infusion of saline concomitantly with resumption of the supine position thus provides two stimuli that could influence the plasma aldosterone concentration; hence, clear interpretation of the results is not possible. Of more importance to the interpretation of their results is the possible role of ACTH in aldosterone production in the anephric state. No data are presently available on plasma ACTH levels in anephric subjects, so that it is only possible to make inferences from fluctuations in plasma cortisol levels [23]. In this context, it is of interest that they recorded a 50% increase in plasma cortisol concentration after two hours of quiet standing, with a subsequent reduction to the previous supine values when the subjects were returned to the supine position and infused with saline. In contrast, the changes which we observed were noted in the absence of significant changes in plasma corticoids [31]. The most plausible explanation for this difference is the differing activity in the two groups while standing. Their subjects stood quietly and experienced difficulty with postural hypotens ion; our patients ambulated slowly and were asymptomatic during the upright period. It is thus possible that postural hypotension could have resulted in ACTH release with a consequent increase in plasma corticoids and aldosterone. The uncertainties in interpretation of presently available data on anephric subjects further emphasize the necessity of a clearer definition of the role of ACTH in aldosterone regulation by anephric man. At present, changes in ACTH release and metabolic clearance rate would seem to provide plausible explanations for the disparate results of different investigators who have studied the response to volume changes in anephric subjects [26, 33, 44]. Weidman et al [25], Boyd and associates [18, 24], and ourselves [31] have all failed to find an inverse relation between changes in volume and changes in plasma aldosterone concentrations in anephric man, as contrasted with the results of Liddle, Duncan and Bartter [12]. Thus, there is not yet convincing evidence that changes in sodium balance effect a response in anephric man that is analogous to that reported in the anephric rat by Palmore, Marieb and Mulrow [35]. Posture. Studies of the effects of posture on plasma aldosterone have yielded conflicting data similar to those considered above. Several groups have failed to detect significant changes [24, 31, 33, 45], while others have reported variable results [25] or a regular increase with assumption of the upright posture [321. For reasons cited

3 Plasma aldosterone regulation in anephric man 3 above, the possibility that an observed increase in the upright posture is due to some combination of decreased metabolic clearance rate, ACTH release, and/or changes in plasma [K] cannot be excluded. Our observations in the early post-dialysis period showed very low values for plasma aldosterone with no change in the upright position after two hours of ambulation (supine , upright ng aldosterone per 100 ml plasma). On the third or fourth day post-dialysis, the mean values did not differ significantly between supine and upright positions (supine ; upright ng/l 00 ml), but several individual subjects showed large changes. In each instance these were associated with concordant changes in plasma [K]. Thus, the majority of the present evidence is consistent with the view that changes in the response to posture are not seen in the anephric individual except in the presence of coincidental stimuli such as changes in plasma [K], ACTH release or metabolic clearance rate. Further studies are necessary, however, to clearly define the role of these latter two influences in the anephric patient. Potassium. The role of potassium in the modulation of aldosterone secretion has been well established, although most early studies were done in intact subjects or experimental animals with a functioning renin-angiotensin system [37 39]. Laragh and Stoerk [40], however, suggested that plasma [K] stimulated the adrenal directly to produce aldosterone, and Denton, Goding and Wright [13] provided supporting evidence for this view from studies in an in vitro preparation. Numerous investigators [16, 27, 41] have confirmed this observation using different experimental approaches in several species. Baumber et al [42] have demonstrated that potassium administration, which serves to increase aldosterone output, also increases the [K] content of the adrenal gland. Burwell, Davis and Bartter [41], from in vitro studies suggested that K acts to facilitate conversion of deoxycorticosterone to corticosterone. These studies all identify an aldosterone-stimulating role for potassium that does not appear to involve the kidney. The predominant view to date, however, is that this is of little, if any physiologic significance in the intact animal [10], but there is no uniform agreement on this point [16]. Recent observations in anephric patients assign a prominent role to potassium in aldosterone production in the absence of kidneys. In contrast with the sodium effect on aldosterone production which vanishes with removal of kidneys, a highly significant correlation can be demonstrated between potassium and aldosterone concentrations in the plasma of anephric individuals [31]. Within a single individual these changes are even more closely correlated. In a series of studies examining the relation of posture, volume changes and changes in plasma composition to plasma aldosterone levels in anephric patients, it has only been possible to identify an association between changes in plasma [K] and changes in plasma aldosterone. Not only is an increase in [K] associated with an increase in aldosterone, but, conversely, in those individuals exhibiting a decrease in plasma [K] between serial observations, aldosterone also decreases as well. A report on the influence of changes in concentration of K in the dialysate upon plasma aldosterone concentration is consistent with these findings [25]. The precise mechanism whereby potassium exerts its influence upon aldosterone secretion cannot be inferred from these data. It is possible that changes in plasma [K] reflect changes in intracellular potassium and that intracellular K within the adrenal is the real determinant of plasma aldosterone levels in the anephric state. Studies cited [41, 42] would indicate that intracellular [K] is the more likely regulatory concentration. If so, then it may be expected that procedures that lower [K] by stimulating movement of potassium into cells would increase aldosterone output despite a decrease in plasma concentration. Adequate data are not available on this point, but several subjects have been observed in whom decreases in plasma [K] (unassociated with dialysis) must have represented movement of K into some cells within the body. In these subjects the lowered [K] was associated with a decreased plasma aldosterone. This could only be reconciled with the above view that intracellular K within the adrenal is of prime significance in the regulation of aldosterone secretion if such decreases in plasma [K] represents entrance of K selectively into other cells such as the liver, while K within the adrenal continues to decrease. This question requires further study and probably can be answered only by appropriately designed animal experiments. Otheè stimuli. Studies in anephric individuals have thus far provided useful information on the role of potassium in the regulation of plasma aldosterone, and the variable responses to ACTH suggest that further study of the anephric subject will permit a clearer definition of the role of ACTH in aldosterone regulation. Convincing evidence of a new and previously undefined regulatory mechanism has not yet been forthcoming. In fact, it may be premature to consider the question of additional regulatory mechanisms or stimuli before further defining the physiologic responses to known stimuli for aldosterone production in the anephric state, as well as the alterations in aldosterone metabolism that may arise therefrom. One serious shortcoming of the available studies is a lack of information about aldosterone secretory rates in the absence of the kidneys. A decreased capacity for conjugation or degradation resulting from loss of the kidneys and/or hepatic impairment secondary to uremia could lead to a progressive increase in plasma aldosterone in the absence of any increase in activity of the zona glomerulosa. The progressive increase in plasma aldosterone between dialyses in our studies, as well as those of others, could thus be explained in part in this fashion. It is also evident that such an explanation could well be provided by the significant correlation between changes of plasma [K] and aldosterone since plasma [K] also rises between dialyses. The strongest arguments against this as a satisfactory explanation for the observed correlation are the

4 4 Walker/Cooke results of the K depletion studies in which a rise of plasma aldosterone was prevented [311, and the association between a decreased plasma [K] and decreased plasma aldosterone in the absence of dialysis. Thus, while stimuli have been shown to alter plasma aldosterone in anephric humans, it is not possible to compare these responses with those seen in normal humans without further information on secretory rates and the metabolic clearance of aldosterone in the anephric patient. At this relatively early stage in the evolution of our knowledge of aldosterone physiology in the anephric state, it is hazardous to attribute unexpected responses to new or previously unrecognized stimuli. The question of whether changes in aldosterone have any physiologic significance in the absence of the kidney cannot be answered with certainty at present. The observations of Hayes, McLeod and Robinson [43] that fractional fecal K excretion increases in chronic renal failure, and that this represents a significant route of K excretion (up to 75 % of ingested K) in uremia, would suggest that the persistence of the potassium stimulus for aldosterone secretion in the anephric state may serve a useful physiologic purpose in these patients. The unexpected finding, in our studies, of marked fluctuations of plasma [K] in association with postural changes and ambulation in patients who have not been dialysed for several days and hence have a surfeit of potassium, further emphasizes the potential importance of such a mechanism in anephric patients [46]. W. Gordon Walker C. Robert Cooke Baltimore, Maryland Reprint requests to Dr. W. G. Walker, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. References 1. 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