Alexander Leaf: in memoriam

Kidney International (2013) 83 771 Dennis A. Ausiello1 and Qais Al-Awqati2 1Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA; 2Department of Medicine, Columbia University, New York, New York, USA Correspondence: Dennis A. Ausiello, Massachusetts General Hospital, Bulfinch 127, 55 Fruit Street, Boston, Massachusetts 02114-2621, USA. E-mail: dausiello@partners.org A lex Leaf died at the age of 92 on 24 December 2012. He was a long-time faculty member of the Massachusetts General Hospital (MGH) and Harvard Medical School, where he served as chief of the Department of Medicine at MGH (1966–1981), and as the Jackson Professor of Clinical Medicine and later the Ridley Watts Professor of Preventive Medicine at Harvard Medical School. Alex Leaf first came to MGH in 1944 as an intern, left to finish his residency at the Mayo Clinic, and returned to MGH in 1949 as a fellow in medicine, working with famed endocrinologist Fuller Albright, MD. A superb investigator, Dr. Leaf was tapped by Howard Means, MD, then chief of medicine, to help create MGH’s first renal laboratory. He went on to serve as chief of the Renal Unit from 1951 until 1983. Alexander Leaf was one of the founders of the scientific basis of nephrology. That most of his contributions are now textbook knowledge is perhaps the reason why most nephrologists today would not know what he achieved. His early work, similar to that of the other founders of our discipline, examined the mechanism by which the kidney controls salt excretion. He defined a critical role for adrenal steroids, before the identification of aldosterone. His studies on water metabolism also led to many insights into the mechanism of action of vasopressin. In fact, he demonstrated (with Bartter) that when humans were given continuous doses of vasopressin and drank large volumes of water, they diluted their body fluids and developed volume expansion leading to salt excretion, showing the primacy of the role of sodium balance in the control of extracellular fluid volume.1 When a patient with a lung tumor was found to resemble these research subjects (some of whom were the authors of the paper!), it was clear that the syndrome of inappropriate antidiuretic hormone secretion was described. In fact, some Europeans began calling this syndrome the Leaf–Bartter syndrome. Leaf ’s interests in defining cellular mechanisms of ion transport were stimulated by a sabbatical stay at Oxford in the laboratory of Hans Krebs. He decided to study the regulation of the ionic composition of cells by testing what was then considered the critical paradigm in this process, active water transport. Several investigators in the late 1940s showed that cells swelled when they were poisoned. Such studies were interpreted to mean that cells were hyperosmotic to the extracellular fluid. By that time, it was shown that isotopic water could readily exchange across cell membranes, and hence it was concluded that the continuous influx of water must be balanced by its active transport out of the cell. In a series of compelling studies, Leaf proved this idea false. First he showed that ingestion of large volumes of water readily equilibrated with the total-body water, diluting the extracellular space. He then found that cell swelling in poisoned tissues was due to the entry of not just water, but also solutes (NaCl). When one divided the number of osmoles of solutes accumulated by the amount of water taken up, there was isotonic expansion of the intracellular space consistent with the now recognized passive movement of water down an osmotic gradient.2 Returning to Boston, Leaf used the first instrument developed to measure the freezing point depression of these tissues.3 This osmometer showed that the intracellular osmolality of a variety of mammalian tissues was the same as that of blood, except for the kidney medulla. The latter finding laid the groundwork for the understanding of the mechanism of urinary concentration. But these studies also established Alexander Leaf, already a distinguished renal physiologist, as a major figure in the nascent field of cell physiology. During his stay in Krebs’s laboratory, Leaf got to hear and meet Hans Ussing, who had just begun to examine active sodium transport across frog skin. On his return to Boston, Leaf established the toad urinary bladder as a model membrane for studying the cellular mechanisms of salt and water transport. In parallel with Ussing’s group, he established that transepithelial sodium transport occurs across two ratelimiting steps; entry into the cell from the lumen was passive and down an electrochemical gradient, while exit was active, requiring an input of energy into the Na,K-ATPase. These landmark studies showed that hormones Alexander Leaf: in memoriam