Bartter’s Syndrome, 1962

REFERENCES

1. Pronove, P., MacCardle, R. C. and Bartter, F. C. Aldosteronism, hypokalemia, and a unique renal lesion in a five year old boy. Acta Endocrinologica. supp. 51, p. 167, July 1960.

2. Pechet, M. M., Bowers, B. and Bartter, F. C. Metabolic studies with a new series of 1,4-diene steroids. I. Effects in Addisonian subjects of prednisone, prednisolone, and the 1, 2 dehydroanalogues of corticosterone, desoxycorticosterone, 17 hydroxy-11 desoxycorticosterone and 9 alpha fluorocortisol. J. Clin. Invest., 38: 681, 1959.

3. Kliman, B. and Peterson, R. E. Double isotope derivative assay of aldosterone in biological extracts. J. Biol. Chem., 235: 1639, 1960.

4. Dawson, J., Dempsey, E., Bartter, F. C., Leaf, A. and Albright, F. Evidence for the presence of an amphotheric electrolyte in the urine of patients with renal tubular acidosis. Metabolism, 2: 225, 1953.

5. Conway, E. J. Microdiffusion analysis and volumetric error, 3rd rev., p. 87. Crosby Lockwood and Sons, Ltd. London, 1950.

6. Zimmermann, W. Colorimetrische Bestimmung der Keimdrusenhormone. Ztschr. Physiol. Chem., 245: 47, 1936.

7. Peterson, R. E., Karer, A. and Guerra, S. L. Evaluation of Silber-Porter procedure for determination of plasma hydrocortisone. Anal. Chem., 29: 144, 1957.

8. Bartter, F. C. The role of aldosterone in the regulation of body fluid volume and composition. Scandinav. J. Clin. & Lab. Invest., 10: 50, 1957.

9. Lee, B. In: The Microtomist’s Vade Mecum, 10th ed., p. 308. Edited by Gatenby, J. B. and Painter, T. S. Philadelphia, 1946. The Blakiston Co.

10. Pitcock, J.A. and Hartroft, P.M. The juxtaglomerular cells in man and their relationship to the level of plasma sodium and to the zona glomerulosa of the adrenal cortex. Am. J. Path., 34: 863, 1958.

11. Bowie., D. J. Cytological studies of the islets of Langerhans in a teleost, Neomacnis griseus. Anat. Rec., 29: 57, 1924.

12. Albright, F., Burnett, C.H., Parson, W., Reifenstein, E. C. and Ros, A. Osteomalacia and late rickets. Medicine, 25: 399, 1946.

13. Pines, K. L. and Mudge, G. H. Renal tubular acidosis with osteomalacia. Am. J. Med., 11: 302, 1951.

14. Gill., J. R., Jr., Bell, N. H. and Bartter, F. C. Correction of renal sodium loss and secondary aldosteronism in renal tubular acidosis with bicarbonate loading. Clin. Res., 9: 201, 1961.

15. Schwartz, W. B. and Relman, A. S. Metabolic and renal studies in chronic potassium depletion resulting from overuse of laxatives. J. Clin. Invest., 32: 258, 1953.

16. Kliman, B. R., Bell., N. H. and Bartter, F. C. Albumin infusion. A new test for primary aldosteronism. Clin. Res., 9: 182, 1961.

17. August, J. T., Nelson, D. H. and Thorn, G. W. Response of normal subjects to large amounts of aldosterone. J. Clin. Invest., 37: 1549, 1958.

18. Rosenberg, E. Personal communication.

19. MacCardle, R. C. Unpublished observations.

20. Delorme, P. and Genest, J. Primary aldosteronism. A review of medical literature from 1955 to June 1958. Canad. M. A. J., 81: 893, 1959.

21. Oliver, J., MacDowell, M., Welt, L. G., Holliday, M. A., Hollander, W., Jr., Winters, R. W., Williams, T. F. and Segar, W. E. The renal lesions of electrolyte imbalance. I. The structural alteration in potassium-depleted rats. J. Exper. Med., 106: 563, 1957.

22. Gross, F., Loustalot, P. and Meier, R. Production of experimental hypertension by aldosterone. Acta Endocrinol., 26: 417, 1957.

23. Hartroft, P. M. and Hartroft, W. S. Studies on renal juxtaglomerular cells. I. Variations produced by sodium chloride and desoxycorticosterone acetate. J. Exper. Med., 97: 415, 1953.

24. Tobian, L., Thompson, J., Twedt, R. and Janecek, J. The granulation of juxtaglomerular cells in renal hypertension, desoxycorticosterone and post-desoxycorticosterone hypertension; adrenal regeneration hypertension, and adrenal insufficiency. J. Clin. Invest., 37: 660, 1958.

25. Dunihue, F. W. and Robertson, W. Van B. The effect of desoxycorticosterone acetate and of sodium on the juxtaglomerular apparatus. Endocrinology, 61: 293, 1957.

26. Tobian, L., Janecek, J. and Tomboulian, A. Correlation between granulation of juxtaglomerular cells and extractable renin in rats with experimental hypertension. Proc. Soc. Exper. Biol. & Med., 100: 94, 1959.

27. Deane, H. W. and Masson, G. Adrenal cortical changes in rats with various types of experimental hypertension. J. Clin. Endocrinol., 11: 193, 1951.

28. Kuhn, C., Hartroft, P. M. and Pitcock, J. A. Effects of renal extracts on juxtaglomerular cells, renin content, and zona glomerulosa. Fed. Proc., 20: 404, 1961.

29. Gross, F. Adrenocortical function and renal pressor mechanisms in experimental hypertension. In: Essential Hypertension, p. 92: Berlin, 1960. Springer Verlag.

30. Pasqualino, A. and Bourne, G. H. Histochemical changes in kidneys and adrenals of rats made hypertensive by the Goldblatt method. Nature, London, 182: 1426, 1958.

31. Bartter, F. C., Casper, A. G. T., Delea, C. S. and Slater, J. D. H. On the role of the kidney in the control of adrenal steroid production. Metabolism, 10: 1006, 1961.

32. Carpenter, C. C. J., Davis, J. O. and Ayers, C. R. Relation of renin, angiotensin II, and experimental renal hypertension to aldosterone secretion. J. Clin. Invest., 40: 2026, 1961.

33. Mulrow, P. J. and Ganong, W. F. Stimulation of aldosterone secretion by angiotensin II. Yale J. Biol. & Med., 33: 386, 1961.

34. Kalpan, N. M. and Bartter, F. C. The effect of ACTH, renin, angiotensin II, and various precursors on biosynthesis of aldosterone by adrenal slice. J. Clin. Invest., 41: 715, 1962.

35. Genest, J. Angiotensin, aldosterone and human arterial hypertension. Canad. M. A. J., 84: 403, 1961.

36. Laragh, J. H., Angers, M., Kelly, W. G. and Lieberman, S. Hypotensive agents and pressor substances J. A. M. A., 174: 234, 1960.

37. Elaut, L. La structure de l’artere afferente du glomerule renal chez le chien hypertendu. C. R. Soc. Biol., 115: 1416, 1933.

38. Goormaghtigh, N. Histological changes in the ischemic kidney with special reference to the juxtaglomerular apparatus. Am. J. Path, 16: 409, 1940.

39. Kaufmann, W. The morphological aspect of the Goormaghtigh cells (juxtaglomerular apparatus) in the normal and diseased human kidney. (Abstract). Am. J. Path., 17: 620, 1941.

40. Bartter, F. C. and Biglieri, E. G. Primary aldosteronism: Clinical Staff Conference at the National Institutes of Health. Ann. Int. Med., 48: 547, 1958.

41. Bock, K. D., Dengler, H., Krecke, H. J. and Reichel, G. Untersuchungen uber die Wirkung von synthetischem Hypertensin II auf Elektrolythaushalt, Nierenfunktion and Kreislauf beim Menschen. Klin. Wchnschr., 36: 808, 1958.

42. Gill, J. R., Jr. and Bartter, F. C. Unpublished observations.

43. Friedman, M., Freed, S. C. and Rosemann, R. H. Effect of potassium administration on (1) peripheral vascular reactivity and (2) blood pressure of the potassium-deficient rat. Circulation, 5: 415, 1952.

44. Tobian, L. Interrelationship of electrolytes, juxtaglomerular cells and hypertension. Physiol. Rev., 40: 280, 1960.

45. Biron, P., Koiw, E., Nowaczynski, W., Brouillet. J. and Genest, J. The effects of intravenous infusions of valine-5-angiotensin II and other pressor agents on urinary electrolytes and corticosteroids including aldosterone. J. Clin. Invest., 40: 338, 1961.

46. Slater, J. D. H. and Bartter, F. C. Unpublished observations.

47. Bryan, G. T. and Bartter, F. C. Unpublished observations.

AUTHOR COMMENTARY

John R. Gill Jr.

National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, Maryland

Patient M.W. was admitted to Duke Hospital in 1956 because it was thought that he might be an example of a new disorder recently described by Dr. Jerome Conn–primary aldosteronism. I was a medical resident on the ward at the time and was amazed by his story. He worked “pulling tobacco” in the hot sun despite a serum potassium that was consistently below 2 mEq/L! Our excitement at the prospect of treating an exotic disease in the unit faded to dismay when the results of urinary aldosterone, measured by a commercial laboratory, came back normal.

In the summer of 1957, I moved to the National Heart Institute to join Fred Bartter. The centerpiece of my introductory tour was a trip to the unit to visit a fascinating diagnostic dilemma–C.J. I was struck by the extent of the similarity between C.J. and M.W. and suggested that it might be worthwhile to study them together. Fred was delighted at the prospect of studying a second patient that, perchance, might be similarly afflicted.

As our article indicates, C.J. and M.W. did indeed exhibit similar features, and we considered it likely that they had the same disorder. Both patients had normal blood pressure associated with increased activity of the renin-angiotensin-aldosterone systems; both had diminished pressor responsiveness to angiotensin II. As a working hypothesis, we suggested that a resistance of the vasculature to the pressor action of angiotensin, of unknown etiology, was the proximal cause of the abnormalities we observed.

To our surprise, the article occasioned a rapidly increasing number of publications reporting observations on the condition that was quickly coming to be known as Bartter’s syndrome. It is of interest that Fred himself initially resisted this classification, preferring to refer to the syndrome as juxtaglomerular hyperplasia. After partially relenting to “so-called Bartter’s syndrome,” he eventually capitulated and joined the rest of the medical world.

The advent of the prostaglandin era in the 1970s led to new insights about the pathogenesis of Bartter’s syndrome and, more importantly, changed the focus from the vasculature to the renal tubule as the principal player in the etiology of the disorder.

Patients with Bartter’s syndrome overproduced prostaglandins; when they were treated with a prostaglandin synthase inhibitor, their renin-angiotensin-aldosterone systems returned to normal. Their blood pressure, unaffected by the treatment, then responded normally to angiotensin II. In contrast to the improvement noted above, hypokalemia persisted. These observations, together with the demonstration that experimental potassium depletion increased prostaglandin formation and reproduced most of the clinical features of the syndrome, led to the conclusion that potassium loss by the kidney, rather than a defect in the vasculature, was the cause of the syndrome.

With regard to the kidney, I cannot explain why the presence of nephrocalcinosis in patient M.W. was not further pursued initially. When we got around to measuring urinary calcium, it was high. In only two of the many other patients with the syndrome that we had an opportunity to study was urinary calcium high. In fact, in all of the other patients urinary calcium was either low or undetectable. The low urinary calcium was usually associated with a high urinary magnesium and hypomagnesemia. Patient C.J. had a low serum magnesium that would place him in this far larger group.

Thus, in retrospect, C.J. and M.W., although they share many of the same clinical features, probably do not have the same disorder. More likely, each has a distinct tubular transport abnormality that is different from the other.

The pioneering studies of Dr. Richard Lifton and his associates, using the powerful tools of molecular biology, represent a watershed period in the history of Bartter’s syndrome. These scientists have been able to identify the defective renal transporters responsible for two varieties of Bartter’s syndrome and the gene defects that give rise to them.

I am grateful for the publication of our article in the series “Milestones in Nephrology.” It has provided a wonderful opportunity for me to reflect on a most fascinating journey from phenotype to genotype, in which so many have participated over the past four decades. Little did we realize that this uncommon condition would occasion so much interest and contribute as much information as it has.

GUEST COMMENTARY

Richard P. Lifton

Yale University School of Medicine, New Haven, Connecticut

“If I have seen further it is by standing on the shoulders of giants.”

- Sir Isaac Newton

Newton’s comment in a letter to Robert Hooke in 1675 captures one of the principal strengths of the scientific method–the ability of contemporary science to build upon a solid foundation of prior work.

The past 10 years has witnessed a revolution in the understanding of the pathogenesis of inherited human disease, owing to development of powerful new tools for molecular genetic analysis. Equally important are the careful clinical observations of previous investigators, as well as their detailed work on fundamental aspects of normal and disease physiology. These studies have set the stage for implementation of modern genetic approaches.

This manuscript by Bartter and colleagues exemplifies the contribution that physicians with a keen eye and an ability to perform detailed clinical evaluation have made to both clinical medicine and basic science. Beginning with the recognition of two patients with unique constellations of clinical findings, the authors performed a careful and detailed evaluation of the physiologic features of these patients, which formed the basis for the eventual molecular understanding of these disorders. Since publication of this paper, more than 700 articles investigating the physiology of patients with features similar to those of these patients have been published, documenting a diverse and sometimes bewildering range of clinical and physiologic features of patients with spontaneous hypokalemic alkalosis. The recognition that these disorders are inherited as autosomal recessive traits has recently permitted the application of molecular genetic approaches to these traits, leading to determination of the molecular basis of inherited hypokalemic alkalosis.

We now recognize that patients with what is now called Bartter’s syndrome often present as critically ill neonates with severe intravascular volume depletion, frequently as the preterm offspring of mothers with polyhydramnios. These patients have hypokalemic alkalosis, normal serum magnesium levels, and hypercalciuria, often complicated by nephrocalcinosis. In contrast, patients with what we now refer to as Gitelman’s syndrome typically present at older ages with prominent neuromuscular signs and symptoms. These patients have hypokalemic alkalosis in conjunction with hypomagnesemia and hypocalciuria.

Our laboratory has been investigating the molecular genetics of human blood pressure variation. Previously, we determined the molecular basis of three single gene forms of either hyper-or hypotension: glucocorticoid-remediable aldosteronism, Liddle’s syndrome, and pseudohypoaldosteronism type 1. All of these disorders changed blood pressure by altering renal sodium reabsorption due to altered activity of the renal epithelial sodium channel. These observations led us to consider what phenotypes would result from mutation in other pathways mediating renal salt handling.

David Simon, then a fellow in the laboratory and now a faculty member at Yale, had been working on the genetics of pseudohypoaldosteronism type II, another mendelian form of hypertension that we thought might be caused by increased activity of the thiazide-sensitive Na-Cl cotransporter of the distal convoluted tubule. He had gone to considerable effort to clone and characterize the human gene encoding this transporter, which ultimately permitted him to exclude this gene in the pathogenesis of pseudohypoaldosteronism type II. With necessity being the mother of invention, David then decided to pursue the alternative hypothesis that loss of function mutation in this same gene could be a cause of recessive hypokalemic alkalosis. This hypothesis was tested by collecting families with this phenotype, followed by analysis of genetic linkage comparing the inheritance of these diseases with the inheritance of specific chromosome segments, followed by analysis of specific genes for mutations.

The results have been conclusive in demonstrating mutations causing both Gitelman’s and Bartter’s syndromes. Gitelman’s syndrome is caused by a mutation in the thiazide-sensitive Na-Cl cotransporter [1] , whereas Bartter’s syndrome can be caused by mutation in any of three different genes: the Na-K-2Cl cotransporter itself [2] , the potassium channel ROMK [3] , which recycles potassium entering cells of the thick ascending limb (TAL) back into the tubule lumen, or the chloride channel CLCNKB [4] , which we now believe mediates the exit of chloride from cells of the TAL into the blood stream.

These findings established that Bartter’s and Gitelman’s syndromes are caused by primary defects in renal salt conservation. This salt wasting leads to activation of the renin-angiotensin system, resulting in hypokalemic alkalosis due to increased sodium reabsorption via the renal epithelial sodium channel. All of the other features of these diseases must be secondary consequences of these primary defects. The precise mechanisms linking salt wasting from the TAL to calcium wasting, and conversely salt wasting from the distal convoluted tubule to increased calcium conservation, are not yet understood in detail. More surprising still is the observation that impaired salt reabsorption in the distal convoluted tubule leads to marked renal magnesium wasting, a finding that would not have been predicted by previous knowledge of renal magnesium handling. These findings indicate gaps in our knowledge of the basic mechanisms of renal physiology.

In addition, these studies of patients with Bartter’s syndrome have validated two new targets for development of new pharmaceutical agents. The in vivo phenotypes of patients with loss of function of ROMK or CLCNKB indicate that specific antagonists of these channels would be potent diuretic antihypertensive agents that do not have significant extrarenal effects.

During a period of explosive growth in our understanding of the molecular basis of inherited human disease, it is particularly appropriate to acknowledge the key contributions made by physicians performing detailed clinical investigation of patients with rare diseases. As the molecular bases of these diseases are uncovered, one anticipates that there will be important new opportunities for further investigation of the physiology of these and related diseases based on new molecular insights. Recognition of this opportunity, however, also raises the concern of whether a cadre of physicians will still exist with the training, time, and resources to conduct these studies with the same skill and care exemplified by this Milestone article.

Journal of the American Society of Nephrology
Volume 9 Number 3 March 1998
Copyright 1998 American Society of Nephrology
Pacita Pronove M.D., John R. Gill Jr. M.D., Ross C. Maccardle Ph.D., with the technical assistance of Esther Diller. With comments by John R. Gill Jr., Richard P. Lifton
Bethesda, Maryland Abridged and modified by original author from Am. J. Med. 33: 811-828, 1962

Manuscript received July 10, 1962.

REFERENCES
1. Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet F, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitelman HJ, Lifton RP: Gitelman’s variant of Bartter’s syndrome, inherited hypokalemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter, Nat Genet 12: 24-30, 1996

2. Simon DB, Karet FE, Hamdan JH, Di Pietro A, Sanjad SA, Lifton RP: Bartter’s syndrome, inherited hypokalemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet 13: 183-188, 1996

3. Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, Lifton RP: Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 14: 152-156, 1996

4. Simon DB, Bindra RS, Mansfield TA, Nelson-Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez-Soriano A, Morales AM, Sanjad SA, Taylor CM, Pilz C, Brem A, Trachtman H, Griswold W, Richard GA, John E, Lifton RP: Mutations in the chloride channel gene, CLCNKB, cause Bartter’s syndrome type III. Nat Genet 17: 171-178, 1997

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