Renal Physiology

RenalCJASN Physiology ePress. Published on May 1, 2014 as doi: 10.2215/CJN.08860813 Homeostasis, the Milieu Inte´rieur, and the Wisdom of the Nephron Melanie P. Hoenig and Mark L. Zeidel Abstract The concept of homeostasis has been inextricably linked to the function of the kidneys for more than a century when it was recognized that the kidneys had the ability to maintain the “internal milieu” and allow organisms the “physiologic freedom” to move into varying environments and take in varying diets and fluids. Early ingenious, Division of Nephrology, Beth albeit rudimentary, experiments unlocked a wealth of secrets on the mechanisms involved in the formation of Israel Deaconess urine and renal handling of the gamut of electrolytes, as well as that of water, acid, and protein. Recent scientific Medical Center, advances have confirmed these prescient postulates such that the modern clinician is the beneficiary of a rich Harvard Medical understanding of the nephron and the kidney’s critical role in homeostasis down to the molecular level. This School, Boston, review summarizes those early achievements and provides a framework and introduction for the new CJASN Massachusetts series on renal physiology. ccc–ccc Correspondence: Clin J Am Soc Nephrol 9: , 2014. doi: 10.2215/CJN.08860813 Dr. Melanie P. Hoenig, Division of Nephrology, Department of Introduction advance our understanding. In this overview, we Medicine, Beth Israel Critical advances in our understanding of renal phys- will describe, all too briefly, the ingenious methods Deaconess Medical iology are unfolding at a rapid pace. Yet, remarkably, used by early investigators and the secrets they Center Clinic, Fa 8/ the lessons learned from early crude measurements and unlocked to help create the in-depth understanding 185 Pilgrim Road, careful study still hold true; indeed, classic articles still Boston, MA 02215. of renal physiology and pathophysiology that we Email: MHoenig@ serve as the basis for introductory textbooks on renal enjoy today. Additional details will follow in the bidmc.harvard.edu physiology and provide a solid working knowledge to new CJASN series of review articles on the physiology clinicians. Drawings with just a handful of transporters of the kidney. at each nephron segment, known for more than half a century, are sufficient to understand basic mechanisms of autoregulation, clearance, and the effects of The Milieu Inte´rieur and the Kidney’s Essential diuretics—the tools needed to care for patients. Yet we Role clinicians also benefit from a treasure trove of subse- In the early 1800s, Darwin’s Theory of Evolution quent scientific advances, which have given us a de- combined with the recognition that the body chemis- tailed and comprehensive understanding of how the tries of many disparate species were remarkably kidney maintains stable body chemistries and volume similar led Claude Bernard to develop his theory balance. of the Milieu Intérieur: “The constancy of the inter- Thelayersofcomplexityandthemysteriesthat nal environment is the condition of a free and in- continue to unravel make it difficult to stay abreast dependent existence” (3). By this, he meant that the of current research. Still, the modern nephrologist is ability of our ancestor organisms to leave the oceans in good company. In 1959, a medical student wrote required that they develop the ability to “carry the to Homer Smith, the uncontested patriarch of modern oceanwiththem” in the form of an internal ocean, nephrology at the time, to inquire about his recti- bathing their cells constantly in fluids that resemble linear depiction of the nephron (Figure 1) and why the very seas from which they evolved. This concept, he failed to mention the counter current theory in although reminiscent of the notion of bodily humors his famous 1956 textbook, the Principles of Renal (4,5), marked an enormous advance because Bernard Physiology (1,2). Indeed, the structure of the loop described both the features of bodily fluids and the of Henle had been well known since the mid- need to maintain that internal milieu. Maintenance of 1800s, but the importance of that eponymous struc- the internal milieu was first called the “wisdom of ture, the gradient that it generated, and its role in the body” by Starling (6), who recognized that or- the final product urine was only just elucidated at ganisms must maintain the constancy of this internal thetimeofthestudent’s correspondence. Before ocean despite great fluctuations in diet, fluid intake, this, Homer Smith felt that the hairpin turn was and other environmental conditions. The term homeo- just a vestige of embryology. This student’smis- stasis was later coined by behaviorist Walter Cannon sive was a curiosity, rather than a criticism. Care- to describe the physiologic processes that, in ag- fully framed questions have always served to gregate, maintain the constancy of the internal www.cjasn.org Vol 9 July, 2014 Copyright © 2014 by the American Society of Nephrology 1 2 Clinical Journal of the American Society of Nephrology Figure 1. | Study of the kidney requires consideration of both the role of each segment and the three-dimensional architecture. (A) Homer Smith’s rectilinear nephron mimics the straight trajectory of the fish nephron. (B) The human nephron is more intricate; the distal nephron greets its own glomerulus before it returns to the environs established by the loop of Henle. TX, treatment. A is modified from reference 1, with permission. chemistries, as well as BP, body temperature, and energy Studies performed in frogs, rabbits, and dogs in the early balance (7). 1900s showed that the constituents of blood and urine The earliest insights into renal physiology came from the differed because urine contained urea, potassium, and assiduous study of anatomy because, to a large degree, renal sodium salts, whereas blood contains protein, glucose, and function follows structure. Meticulous drawings and histo- very little urea. Furthermore, balance studies suggested logic study of the animal and human kidney from William that the volume and constituents of urine changed depend- Bowman (8,9), Jacob Henle (10), and others, complete with ing on changing intake or experimental infusions. In his capsule, capillaries, and convoluted tubules were available “The Secretion of Urine” monograph published in 1917, in Bernard’s time, yet the mechanisms for the formation of Cushny summarized the available literature to date and urine and the kidney’s role in homeostasis were not em- described the brisk diuresis that followed sodium chloride braced until the next century. Until the 1920s, a debate raged infusions. He also reported findings that showed that the on the mechanism of urine formation. Some researchers kidney produced acid urine in humans and the carnivora, championed a filtration doctrine and others ascribed secre- whereas the herbivora had alkaline urine unless fed a pro- tory power to both the glomerulus and tubules (11,12). The tein diet (14). Despite this careful review and his presen- secretory theory was more popular, however, because the tation of the “modern view” that acknowledged that both sheer volume of blood that would first need to be filtered filtration and secretion could exist, Cushny struggled with and then reabsorbed by the kidney was enormous. Homer the data and felt that the theories were “diametrically op- Smith noted that the filter-reabsorption strategy “seemed posed” because secretion and reabsorption would result in extravagant and physiologically complicated” (2). opposing currents along the renal epithelium. Clearly, methods were needed that could allow direct measure- ment of the filtrate and its modification along the nephron. Early Investigations Form the Framework When Wearn and Richards introduced the micropunc- An interest in comparative physiology and the advent of ture technique to the study of the kidney (first in amphibia, the marine biologic laboratories that studded the Atlantic which had large renal structures amenable to manipula- coast at the turn of the century helped frame an early tion), the debate on the formation of urine was resolved understanding of the kidney and its role in evolution. (11,15). By sampling the fluid elaborated from the glomer- Remarkably, increasingly complex fish with salty interiors ular capsule of a frog, the team demonstrated a protein- adapted to fresh water, whereas amphibians rose from the free filtrate that was otherwise similar to blood. By contrast, sea to face the challenges mandated by scarce water. In his the frog bladder urine had a different composition from famed opus, Smith summarized the observations to date the blood and was free of glucose. These findings, in light and waxed poetic (and philosophic), declaring, “Superfi- of earlier data, supported the notion that urine is formed cially, it might be said that the function of the kidneys is to by glomerular filtration, and the urine is then modified in make urine; but in a more considered view, one can say the tubules, by a combination of reabsorption and secre- that the kidneys make the stuff of philosophy itself” (13). tion. Subsequent studies by Walker and others inserted oil This impression, the sense of wonder at the intricate deal- “plugs” or “blocks” in various segments of the nephron ings of the kidney, permeates the scientific writings from and distal to the sampling pipette so that the investigators that time to this day. could avoid contamination but still study urine from Clin J Am Soc Nephrol 9: ccc–ccc, July, 2014 Homeostasis

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