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Ernest Henry Starling (1866-1927) on the Glomerular and Tubular Functions of the Kidney
Abstract
Around the turn of the 20th century, Ernest Henry Starling (1866-1927) made many fundamental contributions to the understanding of human physiology. With a deep interest in how fluid balance is regulated, he naturally turned to explore the intricacies of kidney function. Early in his career he focused upon the process of glomerular filtration and was able to substantiate the view of Carl Ludwig that this process can be explained entirely upon the basis of hydrostatic and oncotic pressure gradients across the glomerular capillary wall and that the process can be regulated by alterations in the tone of the afferent and efferent arterioles. To explore renal tubular function he employed a heart-lung-kidney model in the dog and was able to infer that certain substances are reabsorbed by the tubules (e.g. sodium chloride) and certain by tubular secretion (e.g. uric acid, indigo carmine dye). By temporarily blocking tubular function using hydrocyanic acid he was able to conclude that secreted substances must be taken up on the peritubular side of the cell and concentrated within the cell to drive the secretory process. Finally, he was able to appreciate that the kidney is an organ which is regulated according to the needs of the organism and that the processes of glomerular filtration, tubular secretion and reabsorption are all subject to regulatory influences, which have evolved to conserve the normal chemical composition of the cells and fluids of the body. © 2014 S. Karger AG, Basel.
... [55] Dilation of either the afferent or efferent arteriole achieves potent augmentation of peritubular capillary hydrostatic pressure, blunting the reabsorption of sodium. [56] We accordingly deduce coordinate dilatation of the afferent and efferent arterioles maintains a relatively constant proportionality between glomerular filtration rate and renal plasma flow and generates profound enhancement of tubular blood flow and peritubular capillary hydrostatic pressure, resisting proximal convoluted tubular reabsorption of sodium. [56] Reciprocally, coordinate constriction of the afferent and efferent arterioles maintains a relatively constant proportionality between glomerular filtration rate and renal plasma flow and generates profound reductions of tubular blood flow and peritubular capillary hydrostatic pressure, enhancing proximal convoluted tubular reabsorption of sodium. ...
... [56] We accordingly deduce coordinate dilatation of the afferent and efferent arterioles maintains a relatively constant proportionality between glomerular filtration rate and renal plasma flow and generates profound enhancement of tubular blood flow and peritubular capillary hydrostatic pressure, resisting proximal convoluted tubular reabsorption of sodium. [56] Reciprocally, coordinate constriction of the afferent and efferent arterioles maintains a relatively constant proportionality between glomerular filtration rate and renal plasma flow and generates profound reductions of tubular blood flow and peritubular capillary hydrostatic pressure, enhancing proximal convoluted tubular reabsorption of sodium. [56] Atrial natriuretic peptide, elaborated by significant stretch placed on the atrial walls, disfavors the reabsorption of anion-complexed sodium salts by the proximal convoluted tubule and promotes natriuresis. ...
... [56] Reciprocally, coordinate constriction of the afferent and efferent arterioles maintains a relatively constant proportionality between glomerular filtration rate and renal plasma flow and generates profound reductions of tubular blood flow and peritubular capillary hydrostatic pressure, enhancing proximal convoluted tubular reabsorption of sodium. [56] Atrial natriuretic peptide, elaborated by significant stretch placed on the atrial walls, disfavors the reabsorption of anion-complexed sodium salts by the proximal convoluted tubule and promotes natriuresis. [57] ...
Rationale:
Hyponatremia occurs frequently in the hospital setting and may be attributable to a host of etiologies. Drugs are frequently implicated. Trimethoprim-sulfamethoxazole (TMP/SMX) represents a well-recognized pharmacologic precipitant of drug-induced hyponatremia, with several reports extant in the retrievable literature. Nephrologists thus debate the mechanisms giving rise to TMP/SMX-induced hyponatremia and the precise mechanism by which treatment with TMP/SMX generates reductions of serum sodium concentration remain controversial. The agent has a well-known effect of antagonizing the effects of aldosterone upon the distal nephron. Renal salt wasting and the syndrome of inappropriate antidiuretic hormone secretion represent implicated mechanistic intermediaries in TMP/SMX-induced hyponatremia.
Patient concerns:
The patient endorsed no explicit concerns.
Diagnoses:
We describe the case of an 83-year-old female clinically diagnosed with pneumonia found to have an initial serum sodium in the range of 130 to 134 mEq/L consistent with mild hyponatremia upon admission. Sputum cultures grew Achromobacter xylosoxidans susceptible to TMP/SMX. The patient's serum sodium concentration precipitously decline following institution of treatment with TMP/SMX to 112 to 114 mEq/L during the course of 5 days.
Interventions:
Severe hyponatremia proved recalcitrant to initial therapy with supplemental salt tabs and standard doses of the vasopressin receptor antagonist tolvaptan.
Outcomes:
Escalating doses of tolvaptan increased the patient's sodium to 120 to 124 mEq/L. The patient was transferred to another hospital for further management. During her stay, the patient did not exhibit frank or obvious clinical features consistent with hyponatremia nor readily appreciable evidence of volume depletion.
Lessons:
TMP/SMX represents a frequent, though underreported cause of hyponatremia in the hospital setting several authors believe natriuresis may represent the most common mechanism underlying TMP/SMX-induced hyponatremia. Evidence implicating natriuresis to be mechanistic in TMP/SMX-induced hyponatremia include clinically appreciable hypovolemia and resolution of hyponatremia with oral or intravenous salt repletion. Salt repletion failed to monotherapeutically enhance our patient's hyponatremiadisfavoring renal salt wasting as originately mechanistic. Contemporaneous refractoriness of serum sodium to fluid restriction nor standard doses of tolvaptan confounded our initial attempts to mechanistically attribute the patient's hyponatremia to a specific cause. Clinical euvolemia and rapid response of hyponatremia to exceptionally high doses of tolvaptan strongly favors syndrome of inappropriate antidiuretic hormone to represent the chief mechanism by which TMP/SMX exacerbates hyponatremia.
... This has implications on cardiovascular disease and therapeutics [36]. His study on kidney function in 1924 demonstrated that the water, chlorides, bicarbonates, and glucose, lost in the excretory filtrate, are reabsorbed at the lower end of the kidney tubules of the nephron [37]. ...
Human physiology is the basis of any rational system of medicine. Experimental physiology gives insights into fundamental homeostatic and adaptive responses in health and further the knowledge of pathological mechanisms in diseases. Traditionally, a great deal of experimental physiology is done with mammalian and sub-mammalian vertebrates, frogs and toads but, increasing use is being made of experiments on human subjects, including the students themselves. The results of clinical investigations of hospital patients may also yield more detailed and relevant information than can be obtained from animal preparations. The interaction and collaboration between the scientist who aims to understand the functioning of the human body and the physician who aims to treat the malfunction is mandatory in modern medicine. This is corroborated by the fact that medicine is an art based on science.
An in vitro approach to the study of single nephron function in uremia has been employed in evaluating the control of fluid reabsorption by the renal superficial proximal straight tubule (PST). Isolated segments of PSTs from the remnant kidneys of uremic rabbits (stage III) were perfused in vitro and their rate of fluid reabsorption compared with normal PSTs and with PSTs derived from the remnant kidneys of nonuremic rabbits (stage II). All segments were exposed to a peritubular bathing medium of both normal and uremic rabbit serum thereby permitting a differentiation to be made between adaptations in function which are intrinsic to the tubular epithelium and those which are dependent upon a uremic milieu.Compared with normal and stage II PSTs, there was significant hypertrophy of the stage III tubules as evidenced by an increase in length and internal diameter, and a twofold increase in the dry weight per unit length. Fluid reabsorption per unit length of tubule was 70% greater in stage III than in normal and stage II PSTs, and was closely correlated with the increase in dry weight. Substitutions between normal and uremic rabbit serum in the peritubular bathing medium did not affect fluid reabsorption significantly in any of the three groups of PSTs. Perfusion of the tubules with an ultrafiltrate of normal vs. uremic serum likewise failed to influence the rate of net fluid reabsorption. It has previously been observed that net fluid secretion may occur in nonperfused or stop-flow perfused normal rabbit PSTs exposed to human uremic serum. Additional studies were thus performed on normal and stage III PSTs to evaluate whether net secretion occurs in the presence of rabbit uremic serum. No evidence for net secretion was found. These studies demonstrate that fluid reabsorption is greatly increased in the superficial PST of the uremic remnant kidney and that this functional adaptation is closely correlated with compensatory hypertrophy of the segment. Humoral factors in the peritubular environment do not appear to be important mediators of the enhanced fluid reabsorption.
Ernest Starling (1866-1927) was pre-eminent in the golden age of British Physiology. His name is usually associated with his "Law of the Heart,? but his discovery of secretin (the first hormone whose mode of action was explained) and his work on capillaries were more important contributions. He coined the word hormone one hundred years ago. His analysis of capillary function demonstrated that equal and opposite forces move across the capillary wall--an outward (hydrostatic) force and an inward (osmotic) force derived from plasma proteins. Starling's contributions include: Developing the "Frank-Starling Law of the Heart," presented in 1915 and modified in 1919. The Starling equation, describing fluid shifts in the body (1896). The discovery of secretin, the first hormone, with Bayliss (1902) and the introduction of the concept of hormones (1905).
This chapter reviews three themes, namely, medical education, the development of University College of London, and the growth of physiology that prevailed during the nineteenth century in the British Empire. Until about the middle of the nineteenth century, English medical education was in a dire state. A good deal of the blame for this can be held at the door of the two English universities, Oxford and Cambridge, which did not acknowledge science to be a suitable subject for a university education. In 1858, the Medical Act was passed, and the Medical Register was established, which contained a list of people recognized as medical practitioners by the state. A central body—the General Medical Council—was created, among whose tasks was to ensure uniform standards of medical qualification. The establishment of University College of London faced enormous resistance from detractors and the annual target for the college was not achieved until well into the twentieth century. Physiology—the study of the normal activity of the body—was in a very poor state in England, and people believed that science could never explain life in materialistic terms. However, the emergence of physiological science in England was accompanied by a corresponding increase in the activities of Victorian antivivisectionists.
Ernest Henry Starling laid the groundwork for our modern understanding of how the interstitial fluid, which he referred to as 'lymph', is regulated. Together with his colleague, William Bayliss, he provided the crucial insight into how fluid is driven out of the capillary to form interstitial fluid. That was to measure (estimate) the capillary pressure in different parts of the circulation and to relate changes in these pressures to altered lymph formation. In addressing how interstitial fluid re-enters the circulation, he was able to show that this occurs not only via the lymphatics, but also by re-entering the capillaries, mediated by the oncotic pressure of the plasma proteins. Starling's discoveries put to rest all notions that the processes of filtration and reabsorption of fluid are mediated by the 'vital activity' of cells. They could be explained entirely on the basis of physic-chemical forces. Based upon his insights from animal experiments, he was able to explain the genesis of edema (dropsy) in a number of disease states, including venous obstruction, cardiac disease and inflammatory conditions. © 2014 S. Karger AG, Basel.