Frederic Bartter

Biographical Timeline

• 1914 – Born September 10 in Manila, Philippines, to an English Anglican missionary father and an American mother. Grew up in Baguio, a remote mountain village in the Philippines.
• 1927 – Sent to the United States at age 13 to attend the Lenox School in Massachusetts.
• 1935 – Graduated BA from Harvard College.
• 1940 – Earned MD from Harvard Medical School.
• 1941 – Internship at Roosevelt Hospital, New York City.
• 1940s – Served in the U.S. Public Health Service during World War II, working on blood products and tropical diseases such as onchocerciasis.
• 1946–1951 – Research fellow and later clinical staff with Fuller Albright (1900–1969) at Massachusetts General Hospital. Contributed major observations in calcium metabolism, adrenal hyperplasia, sex steroids, and HPA axis function.
• 1951 – Appointed Chief of the Endocrine Branch, National Heart Institute (NIH), later renamed the Endocrine-Hypertension Branch. Held this position until 1978.
• 1957 – Co-described the syndrome of inappropriate antidiuretic hormone secretion (SIADH) with William B. Schwartz (1922–2009).
• 1962 – Described Bartter syndrome, a form of juxtaglomerular hyperplasia with hypokalaemia, hyperaldosteronism, and normal blood pressure.
• 1970–1976 – Clinical Director of the National Heart, Lung, and Blood Institute (NHLBI).
• 1978 – Moved to University of Texas Health Science Center, San Antonio, as Associate Chief of Staff for Research and Professor of Medicine.
• 1979 – Elected to the U.S. National Academy of Sciences.
• 1983 – Died May 5 suffering a cerebral haemorrhage, while attending a NAS conference.
• 1986 – American Society for Bone and Mineral Research establishes the Frederic C. Bartter Award in his honour.

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Medical Eponyms

Bartter Syndrome (1962)

Bartter syndrome refers to a group of renal tubulopathies characterized by hypokalaemic metabolic alkalosis, elevated renin and aldosterone levels, and normal or low blood pressure. First described in 1962 by Frederic Bartter and colleagues as a distinct clinical entity with juxtaglomerular hyperplasia and secondary hyperaldosteronism without hypertension. The condition fundamentally challenged prevailing models of sodium and volume regulation.

1962 – Bartter et al published Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Their careful clinical and pathological correlation established that juxtaglomerular cell hyperplasia was likely compensatory to chronic sodium wasting, leading to persistent stimulation of the renin-angiotensin-aldosterone system.

We have described two patients who appear to represent examples of a new syndrome characterized by hyperplasia of the juxtaglomerular complex of the kidney, secondary hyperaldosteronism, hypokalemic alkalosis, and normal or low blood pressure…
Despite striking activation of the renin-angiotensin-aldosterone system, both patients remained normotensive and showed no evidence of increased vascular reactivity.

Bartter, 1962

Pathophysiology and Classification: Subsequent genetic discoveries have classified Bartter syndrome into at least five types, each linked to transport defects in the thick ascending limb of Henle

• Type I – SLC12A1 (NKCC2)
• Type II – KCNJ1 (ROMK)
• Type III – CLCNKB
• Type IV – BSND (often with sensorineural deafness)
• Type V – MAGED2 (X-linked, transient antenatal form)

Clinical Subtypes:

• Classic Bartter syndrome – Onset in childhood with polyuria, growth failure, and salt craving.
• Antenatal Bartter syndrome – Ppolyhydramnios, postnatal severe hypokalaemia and metabolic alkalosis.

Therapeutic Development:

Initially managed with potassium and sodium supplementation, along with spironolactone. Later shown to benefit from NSAIDs (e.g. indomethacin) that reduce renal prostaglandin-mediated salt wasting. Current strategies focus on individualized electrolyte repletion, prostaglandin blockade, and long-term growth monitoring in children.

Bartter’s identification of this paradoxical form of normotensive hyperaldosteronism fundamentally altered understanding of renal sodium handling and volume regulation. The syndrome remains a key model for salt-losing nephropathy and has illuminated the roles of renal transporters in genetic hypertension and electrolyte disorders.

Summary

Comparative Context:

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Schwartz–Bartter syndrome (1957) (SIADH)

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) is a disorder of impaired water excretion caused by inappropriate secretion or action of antidiuretic hormone (ADH), leading to hyponatraemia and hypo-osmolality despite relative euvolaemia.

1957 – First described by William Schwartz and Frederic Bartter in patients with bronchogenic carcinoma, marking the beginning of understanding paraneoplastic endocrine syndromes.

We have studied a syndrome of impaired water excretion that is characterized by hyponatremia, urinary sodium loss, and continued antidiuresis despite hypotonicity… The disorder is best explained by a sustained inappropriate secretion of ADH.

Schwartz and Bartter 1957

This case series demonstrated a unique combination of hyponatraemia, concentrated urine, and low serum osmolality in the absence of hypovolemia or oedema, despite continuous antidiuresis. It laid the foundation for diagnostic criteria that remain largely unchanged.

1967 – Bartter and Schwartz then proposed a diagnostic criteria that remain largely unchanged today.

The diagnosis of this disorder should rest upon six major findings… hyponatremia, hypo-osmolality of the plasma, continued renal excretion of sodium, urine osmolality exceeding that of plasma, absence of clinical evidence of volume depletion, and normal function of adrenal and thyroid glands

Bartter and Schwartz, 1967

These six cardinal criteria form the enduring framework for SIADH diagnosis and remain widely used in clinical and academic settings.

• Hyponatraemia (Na⁺ <135 mEq/L)
• Low plasma osmolality (<275 mOsm/kg)
• Urine osmolality >100 mOsm/kg despite hyponatraemia
• Euvolaemic clinical state
• No adrenal, thyroid, pituitary, or renal insufficiency
• Reversal with fluid restriction

Pathophysiology: SIADH results from increased ADH secretion (central or ectopic) or enhanced renal response, independent of serum tonicity. Causes include:

• Malignancy – especially small cell lung carcinoma (ectopic ADH production)
• CNS disturbances – stroke, trauma, infection
• Pulmonary disease – pneumonia, tuberculosis
• Medications – SSRIs, carbamazepine, cyclophosphamide, vincristine
• Post-operative states and pain
• Hereditary SIADH – gain-of-function V2 receptor mutations

Clinical Features: Symptoms stem from cerebral oedema due to hyponatraemia with nausea, confusion, seizures, and coma. Treatment includes:

• Fluid restriction (first-line)
• Hypertonic saline for severe symptoms
• Loop diuretics + salt tabs (in chronic cases)
• Vasopressin receptor antagonists – e.g., tolvaptan, conivaptan

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Key Medical Contributions

Mushroom Toxicity and Water Intoxication

Among Bartter’s more unusual research interests was the role of toxic mushroom ingestion in hyponatraemic syndromes, especially in the context of water retention and ADH dysregulation. His animal studies and toxicological investigations explored how certain mushroom species could trigger a SIADH-like state.

Bartter investigated water intoxication induced by mushroom ingestion, hypothesising that certain mycotoxins could provoke inappropriate ADH secretion or disrupt renal handling of water. Though largely anecdotal and published in toxicology forums, his studies contributed to the understanding of environmentally induced hyponatraemia.

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Güllner Syndrome (Familial Hypokalaemic Alkalosis with Prostaglandin Excess)

Güllner syndrome is a rare familial disorder characterised by hypokalaemic metabolic alkalosis, elevated renin and aldosterone levels, increased urinary prostaglandins, and normal blood pressure, but not conforming to classical Bartter syndrome. The syndrome highlights the possibility of a distinct hereditary renal tubular defect associated with prostaglandin overproduction.

1979 – Original Description by Güllner, Bartter et al in A familial disorder with hypokalemic alkalosis, hyperreninemia, aldosteronism, high urinary prostaglandins and normal blood pressure that is not “Bartter’s syndrome.”

Unlike Bartter’s, juxtaglomerular hyperplasia was absent, suggesting the defect lies elsewhere in the nephron. The markedly elevated urinary prostaglandin excretion suggested an intrinsic defect in prostaglandin regulation or metabolism, possibly upstream in the renal tubular epithelium. The syndrome might represent a “prostaglandin‑driven tubulopathy”, which secondarily stimulates renin-angiotensin-aldosterone cascade without overt sodium-wasting severe enough to lower blood pressure.

Güllner syndrome remains exceptionally rare, with few documented pedigrees or molecular follow-ups. It is sometimes cited in reviews of “Bartter-like syndromes” that fall outside classical genetic classifications.

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Major Publications

• Bartter FC, Albright F, Forbes AP, Leaf A, Dempsey E, Carroll E. The effects of adrenocorticotropic hormone and cortisone in the adrenogenital syndrome associated with congenital adrenal hyperplasia: an attempt to explain and correct its disordered hormonal pattern. J Clin Invest. 1951 Mar;30(3):237-51.
• Leaf A, Bartter FC, Santos RF, Wrong O. Evidence in man that urinary electrolyte loss induced by pitressin is a function of water retention. J Clin Invest. 1953 Sep;32(9):868-78.
• Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med. 1957 Oct;23(4):529-42. [Schwarz-Bartter syndrome][SIADH]
• Schwartz WB, Tassel D, Bartter FC. Further observations on hyponatremia and renal sodium loss probably resulting from inappropriate secretion of antidiuretic hormone. N Engl J Med. 1960 Apr 14;262:743-8.
• Bartter FC, Pronove P, Gill JR Jr, MacCardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med. 1962 Dec;33:811-28 [Bartter syndrome].
• Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. 1967 May;42(5):790-806. [Schwarz-Bartter syndrome][SIADH]
• Gill JR Jr, Bartter FC. Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of Henle as a proximal cause of Bartter’s syncrome. Am J Med. 1978 Nov;65(5):766-72.
• Güllner HG, Gill JR Jr, Bartter FC, Chan JC, Dickman PS. A familial disorder with hypokalemic alkalosis, hyperreninemia, aldosteronism, high urinary prostaglandins and normal blood pressure that is not “Bartter’s syndrome”. Trans Assoc Am Physicians. 1979;92:175-88. [Güllner syndrome]
• Güllner HG, Gill JR Jr, Bartter FC. Correction of hypokalemia by magnesium repletion in familial hypokalemic alkalosis with tubulopathy. Am J Med. 1981 Oct;71(4):578-82.
• Güllner HG, Bartter FC, Gill JR Jr, Dickman PS, Wilson CB, Tiwari JL. A sibship with hypokalemic alkalosis and renal proximal tubulopathy. Arch Intern Med. 1983 Aug;143(8):1534-40.

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References

Biography

• Luft R. Mannen bakom syndromet. Frederic C. Bartter: den svampälskande endokrinologen som lämnade föga åt slumpen [The man behind the syndrome. Frederic C. Bartter: the mushroom-loving endocrinologist who left little to chance]. Lakartidningen. 1991 Oct 30;88(44):3669-70.
• Wilson JD, Delea CS. Frederic C. Bartter: September 10, 1914-May 5, 1983. Biogr Mem Natl Acad Sci. 1990;59:3-24.
• Loriaux DL. Frederic C. Bartter (1914–1983). The Endocrinologist 2006; 16(4): 187-188
• Slater JDH. Frederic Crosby Bartter. RCP Inspiring Physicians

Eponymous terms

• Unwin RJ, Capasso G. Bartter’s and Gitelman’s syndromes: their relationship to the actions of loop and thiazide diuretics. Curr Opin Pharmacol. 2006 Apr;6(2):208-13.
• Konrad M et al. Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders. Kidney Int. 2021 Feb;99(2):324-335.