Bartter’s Syndrome, 1962

The process of hyperplasia of the juxtaglomerular apparatus appeared from fixed preparations to comprise four stages


Figure 8. Effects of angiotensin infused intravenously on systolic and diastolic blood pressure in normal subjects and in C. J. and M. W. Results shown represent increments above control pressure. Note that C. J. and M. W. showed less response at all dose levels.


Figure 9. Malpighian body of biopsy specimen of human kidney (C.J.) showing hyperplasia of juxtaglomerular collar of afferent arteriole. Regaud. Hematoxylin and eosin stain, original magnification ? 210.


Figure 10. Malpighian body (C.J.) showing enlargement of macula densa and hyperchromatism of portion of glomerular vessels (lower center). Regaud. Hematoxylin and cosin stain, original magnification ? 210.

(Fig. 11) . which may be reconstructed as follows; (1) hypertrophy of macula densa, (2) thickening of juxtaglomerular cells and hyperplasia of juxtaglomerular apparatus, (3) hyperchromatism of the vascular wall of part of the glomerulus, and (4) atrophy of the glomerulus.

Hypertrophy.

The macula densa was larger than normal, containing about 30 to 40 nuclei arranged in two or three rows. Studied in serial sections, the macula densa constituted the canopy (the vascular roof of the juxta-arteriolar section of the distal convoluted tubule (Fig. 10) . The cytoplasmic mass of the macula densa was free of granules, but rich in filamentous and globular mitochondria.

Thickening.

The muscular collar of the afferent arteriole was increased in thickness and length so that more of the muscular cells than normal appeared to have transformed into juxtaglomerular cells having large round nuclei in place of the original elongated nuclei typical of muscle fibers. Many of the juxtaglomerular apparatuses appeared to have two rows of juxtaglomerular (so-called glandibular) cells rather than one.

Hyperchromatism.

The basement membrane of a portion of the wall of the afferent arteriole was thicker than normal, and this thickened membrane appeared to have involved about one-third to one-half of the glomerular capillaries, whereas in uninvolved glomeruli of the same kidney the glomerular vessels appeared to have little or no basement membrane. The hyperchromatism of the glomerular capillaries, which appeared to form a syncytium, was apparently a result of this thickening of the basement membrane. The abnormal syncytium and the thickened basement membrane involved the entire glomerulus in some instances. That the hyperplasia of the perivascular collar of the afferent arteriole (JG cells) also involved the vessels of the glomerular tuft is evident by the presence of juxtaglomerular granules (demonstrable by Bowie’s strain) within the walls of the glomerular vessels.

Atrophy.

Approximately 40 per cent of the glomeruli showed marked evidence of atrophy. The small atrophic glomerulus was always associated with a greatly enlarged juxtaglomerular apparatus (Fig. 12) . Although it is possible that the atrophy of the glomerulus may have been a result of its failure to grow and mature in the first place, the gradual involvement of the glomerulus by the thickening basement membrane, and the alteration of the endothelial cells appear to show a relationship between dysfunction of the glomerulus on the one hand and the apparent atrophy on the other.

Patient M. W.

A percutaneous needle biopsy specimen of the right kidney was obtained. It was less than 1 mm. in width and 3 mm. in length, and contained 12 glomeruli. It was put in Zenker-formalin (Maximow’s 10 per cent). The sections were colored by the periodic acid-Schiff method and by Bowie’s strain for granules of the juxtaglomerular apparatus and by Altmann’s acid-fuchsin methyl green for batonets and general cytoplasmic preservation.

Most of the glomeruli were about twice the size of normal, and approximately half of the juxtaglomerular apparatuses were hyperplastic. (In some of the sections seven of twelve, and in others, five of ten were hyperplastic.) One juxtaglomerular apparatus involved the entire hilar portion of the glomerulus,


Figure 11. Freehand drawings of different types of hyperplastic juxtaglomerular apparatuses of the patient (C. J.) compared with the normal apparatus to show the possible stages of development of the lesion.


Figure 12. Partially atrophic Malpighian body (C. J.) with extremely hyperplastic juxtaglomerular apparatus which was larger than the glomerular body itself. Compare with Figure 22. The glomerulus appeared to be a remnant of an immature glomerulus. Another large glomerular body may be below. Regaud. Hematoxylin and eosin stain, original magnification ? 210.

and three involved about a third of the glomerulus. Four of the hyperplastic juxtaglomerular apparatuses contained granules. In one, the macula densa was about three times larger than normal; its multinucleated mass extended over the entire surface of the hyperplastic juxtaglomerular apparatus, forming a sheath of densely packed nuclei. There was a thin basement membrane between the macula densa and the hyperplastic juxtaglomerular apparatus. Two glomeruli were atrophic ( Fig. 13 and 14 ).

COMMENTS

There is one striking clinical difference between these two patients: one (C. J.) is clearly dwarfed, whereas the other (M. W.), although he grew slowly, is of normal stature. It may be that potassium depletion occurred earlier and was more severe in C. J., and that this in turn led to dwarfism, but such a sequence of events cannot be established from the available evidence. Despite this important difference, the mass of evidence suggests that both patients suffered from essentially the same syndrome.

The clinical abnormalities in patient M. W. closely resembled those in C. J. in four important aspects. Both had


Figure 13. Malpighian body (M. W.) showing hyperplastic juxtaglomerular apparatus. Bowie stain, original magnification ? 430.


Figure 14. Malpighian body (M. W.) showing hyperplasia and marked hypergranulation of juxtaglomerular apparatus and atrophy of glomerulus. Bowie stain, original magnification ? 430.


Figure 15. A, schema representing the physiologic role of the renin-angiotensin system. Arrows with solid heads represent stimulation, those with hollow heads, inhibition. Renin is shown liberating angiotensin I from an alpha 2 globulin; three functions are shown for angiotensin II, direct effect on blood pressure, retention of sodium by an effect on the tubule (or glomerulus) of the kidney and stimulation of aldosterone secretion. Aldosterone is shown stimulating blood pressure directly, and via retention of sodium. Some function of blood pressure, or pulse pressure, is shown inhibiting renin production and thus operating a “feedback.” B, schema to illustrate the defects in patients C. J. and M. W. A block in the ability of angiotensin II to elevate blood pressure results in decreased inhibition of renin production, increased production of renin, angiotensin I and angiotensin II, and in increase in aldosterone secretion. The blood levels of angiotensin II are elevated.

hypokalemic alkalosis, aldosteronism, normal blood pressure and a unique lesion of the juxtaglomerular apparatus. Both patients appeared to be mentally retarded. Whereas the results are equivocal in regards the effects of sodium deprivation, it appears likely ( vide infra) that the responses of the two patients to this procedure are not qualitatively different.

Both patients showed persistent hypokalemic alkalosis; one (C. J.) showed depletion of muscle potassium on direct analysis. In both patients the development of hypokalemic was associated with urinary loss of potassium in excess of intake. Urinary potassium loss ( vide infra) was decreased but not prevented by restriction of dietary sodium; in both patients it was prevented by infusion of human serum albumin (which lowered urinary sodium to zero) ( Fig 5 ), and by treatment with aldosterone antagonists. The excessive loss of potassium could thus be explained as accelerated distal tubular exchange of sodium for potassium under the influence of abnormally large amounts of aldosterone.

In both patients excretion of aldosterone was higher than that of normal subjects on comparable intakes of sodium; in C. J., it was shown to result not from tumor but from hyperplasia of the zona glomerulosa. The urinary aldosterone was not lowered by effective expansion of intravascular volume with human serum albumin; this is taken as evidence that the secretion of aldosterone in these patients is autonomous as regards hemodynamic factors [16] . (The rise in urinary aldosterone in C.J. with albumin may well be a result of the increase in body and serum potassium that it produced.)

In both patients the blood pressure was normal. It remained normal even when intravascular spaces were expanded with albumin, and thus the absence of hypertension cannot reasonably be attributed to hypovolemia. Hypertension might have been anticipated in these patients for two reasons. In the first place, they had aldosteronism: in the “classic” syndrome associated with adrenal cortical adenoma, hypertension is the rule, and is not prevented by potassium depletion comparable to that in our subjects. (Indeed, there is evidence other than that from this study to suggest that even in the “classic” syndrome the hypertension may not result from aldosterone alone. Aldosterone alone given to normal subjects even in large doses produces little or no hypertension [17] [18] , and patients with nephrosis and cirrhosis, secreting and excreting aldosterone in quantities larger than those reported for primary aldosteronism, generally have normal blood pressures.)

In the second place, both patients had hyperplasia and hypertrophy of the juxtaglomerular apparatus, histologic

lesions thus far unique. This suggests hypersecretion of renin, which should also lead to hypertension. In addition, both patients showed, on bioassay, elevated quantities of a pressor agent resembling angiotensin in the circulating blood. As will be discussed, the normal blood pressure suggests a pathophysiologic explanation for the syndrome.

There is little reason to suspect that aldosteronism or the resulting potassium depletion produced the renal lesion. Similar lesions have not been found in renal biopsy specimens from patients with primary or secondary aldosteronism [19] [20] or in the kidneys of potassium-depleted rats [21] . Administration of aldosterone or desoxycorticosterone to rats or cats receiving diets of average or high sodium content results in a decrease of prominence of the juxtaglomerular apparatus and ( vide infra) decrease of renin content of the kidney [22] [23] [24] [25] [26] .

It is possible that the aldosteronism and the lesion of the juxtaglomerular apparatus both resulted from an unidentified common cause. There is, however, much to suggest that the renal lesion may have led to the adrenal one.

Extracts of renal tissue have been shown to increase the size of the zona glomerulosa in rats [27] [28] . A considerable body of experimental evidence relates granulation of the juxtaglomerular apparatus, renal renin content and the action of sodium-retaining steroids. Thus, constriction of one renal artery leads to ipsilateral increase of juxtaglomerular granulation and renal renin content, and to contralateral decrease of both variables [26] [27] [28] [29] . The zona glomerulosa of the adrenal cortex shows hypertrophy [27] [28] [29] [30] . The decrease does not occur in the absence of the adrenals, but can be produced (even without constriction of the artery) by giving desoxycorticosterone and large quantities of sodium [23] [24] . These findings are consistent with the hypothesis that the renin released from the ischemic kidney stimulates the adrenal cortex to release aldosterone, which in turn lowers the renin content of the contralateral kidney. This is supported by the observations (1) that renin and angiotensin II are potent stimuli to aldosterone secretion in the hypophysectomized nephrectomized dog [31] [33] , and (2) that angiotensin II stimulates secretion of aldosterone by slices of beef adrenals [34] . Angiotensin II has also been shown to stimulate aldosterone excretion [35] and secretion [36] in normal human subjects.

Whereas the aldosteronism may thus result from the lesion of the juxtaglomerular apparatus, we have no explanation for the lesion itself. The presence of atrophic glomeruli in C.J., if they are not in fact secondary to the juxtaglomerular lesion, suggests a congenital etiology for the renal disease, and thus, perhaps, for the juxtaglomerular hyperplasia. Elaut [37] observed hyperplasia of the afibrillar cells (juxtaglomerular apparatus of Goormaghtigh) in dogs made hypertensive by section of baroceptor nerves, and Goormaghtigh [38] found the juxtaglomerular apparatus to be hypertrophied in dogs made hypertensive by the Goldblatt technic, and he and Kaufmann [39] described hypertrophy and hyperplasia of the afibrillar cells associated with hypertension in man. These lesions, all of which occurred in hypertensive subjects, showed no resemblance to those in these two patients (C.J. and M.W.).

C.J. could effectively lower urinary sodium until it was no higher than the sodium intake (Fig. 1) . Body weight was maintained. In M.W., however, urinary sodium continued to exceed sodium intake over a thirteen-day period (Fig. 2) of sodium deprivation. Despite these apparent differences, the results suggest that (1) the patients did not differ essentially as regards renal transport of sodium and (2) this was not normal in either patient. In C.J., sodium deprivation could not prevent the development of hypokalemia upon potassium restriction even when the urinary sodium had fallen to zero (Fig. 3) . Even with a potassium intake of 170 mEq. per day, serum potassium rose only slightly in this patient during twelve days of sodium deprivation. This is an abnormal response. In patients with primary aldosteronism, restoration of body potassium is readily accomplished when the dietary, and thus urinary sodium, is rigorously restricted [40] . The response suggests that a disproportionate amount of the filtered sodium is reabsorbed at distal sites in C. J., and that excretion of potassium and hydrogen ions by cation exchange is thereby facilitated. In M.W., the continued urinary loss of sodium with restriction of dietary sodium shown in Figure 2 was associated with a marked increase of dietary potassium, a procedure required for clinical reasons. In this study (Fig. 3) body weight did not continue to fall despite the continued loss of sodium, and serum sodium concentration actually rose during the last eight days of the study. The serum potassium rose by only 0.7 mEq. per L. despite a potassium intake of 200 mEq. for eight days. Accordingly, it is reasonable to attribute the continued urinary sodium loss to replacement of intracellular sodium with potassium. This is supported by the observation (Fig. 3) that urinary potassium remained substantially below the potassium intake throughout the studies. An “obligatory” renal sodium-losing lesion is ruled out by the finding that this patient could lower urinary sodium to zero (Fig. 5) .

Renin splits angiotensin I from a circulating alpha2 globulin, and this is further split by circulating converting enzyme to angiotensin II, which elevates the blood pressure. These relationships are shown diagrammatically in Figure 15 A. If the kidney in our patients were indeed producing excessive quantities of renin, as suggested from the histologic appearance of the juxtaglomerular apparatuses, there must be a block in the production or effectiveness of one or more of these agents to explain the absence of hypertension. Renin-containing extracts of human kidney were shown to induce hypertension in both patients. It was thus clear that there was not a complete block at any point in the sequence. The magnitude of the response, however (Fig. 8) , supported the proposition that a partial block did indeed exist. The response to angiotensin I again indicated the presence of converting enzyme in both subjects. Finally, hypertension developed in both patients with angiotensin II. However, the response in both patients was quantitatively clearly less than that of normal subjects. The initial response of systolic pressure was less than that obtained in the least responsive of the normal subject studied by Bock and associates [41] , and by ourselves [42] (see Fig. 8 ); moreover, with continued infusion the pressure fell in M.W. to much lower figures: a fall in pressure does not occur with continued infusions of comparable duration in normal subjects. Although the blood pressure response may indeed have been affected by potassium deficiency, which has been reported to lower the pressor response to angiotensin in rats [43] . This is unlikely, since the response in C. J. was no greater after serum potassium had been returned to normal.

It is not clear what controls the production of renin by the kidney, or whether it may be released except under extreme conditions involving renal ischemia. Some results suggest, however, that the renal arterial blood pressure or pulse pressure may serve to control renin secretion [44] . Whereas available evidence does not allow a definitive explanation for the syndrome in these patients, a hypothetical sequence of events may be suggested as a working hypothesis which fits best with the facts at hand. We suggest that these patients C. J. and M.W. may have, for reasons unknown, a primary impairment of the vascular response to angiotensin. This might lead by a lack of inhibitory (pressure or pulse pressure) impulses to activation of the juxtaglomerular apparatuses, with increased production of renin, leading in turn to overproduction of angiotensin I and angiotensin II. This is shown diagrammatically in Figure 15 B. Whereas the angiotensin II would be unable to induce hypertension because of the primary defect, it might still stimulate the adrenal cortex to overproduction of aldosterone. (Whereas angiotensin II stimulates secretion not only of aldosterone but also of hydrocortisone in the nephrectomized, hypophysectomized dog, a number of results suggest that it may stimulate secretion of aldosterone selectively in normal man [45] [46] ). In a patient with such a disease pattern, one should find overproduction of aldosterone, relatively independent of hemodynamic stimuli, and increased quantities of circulating angiotensin. Both were present in these patients.

SUMMARY

A new syndrome, characterized by hypertrophy and hyperplasia of the juxtaglomerular apparatus of the kidneys, aldosteronism resulting from adrenal cortical hyperplasia, and persistently normal blood pressure is described in two patients. Overproduction of aldosterone could not be prevented by sodium loading or by administration of albumin intravenously; it was associated with hypokalemic alkalosis and Pitressin-resistant impairment of urinary concentrating ability. In both subjects, increased amounts of circulating angiotensin were demonstrated; infusion of angiotensin II produced rises of blood pressure in both subjects considerably less than the rises induced by comparable doses in normal subjects.

The sequence of events, (1) primary resistance to the pressor action of angiotensin, (2) compensatory overproduction of renin and thus of angiotensin, and (3) stimulation of adrenal cortex by angiotensin is consistent with all the information available about the syndrome.

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