A Homeric view of kidney evolution: A reprint of H.W. Smith's classic essay with a new introduction

Authors

  • Peter D. Vize

    Corresponding author
    1. Department of Biological Science, University of Calgary, Alberta, Canada
    2. Department of Biochemistry and Molecular Biology, University of Calgary, Alberta, Canada
    • Departments of Biological Science and Biochemistry and Molecular Biology, University of Calgary, 2500 University Drive NW, Alberta T2N 1N4, Canada
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In From Fish to Philosopher (1953), Homer W. Smith melds his groundbreaking physiological studies with geological and evolutionary musings to present an amazingly integrated view of how adaptation of a single organ may have contributed to the evolution of man. A condensed version of this thesis was presented in a lecture to the School of Medicine at the University of Kansas in 1943 and later published by the University of Kansas Press (Smith,1943). This holistic view of how selection led to adaptation of the kidney in response to the move from salt- to freshwater, and in the example of the elasmobranchs and bony fishes back to saltwater again, is an extraordinary piece of evolutionary exposition. Knowledge has advanced since 1940 but as a work of integrative logic, and a beautiful piece of writing, it has few rivals.

This essay begins with the cooling of the earth four billion years ago. The cooling of the crust produced periodic upheavals that had major effects on the earth's atmospheric conditions, which in turn led to changes in selective pressure. Smith describes how the migration from the oceans to freshwater challenged the physiology of invertebrates and protovertebrates and proposes how these pressures were dealt with through the evolution of the kidney. As upheavals drove the early freshwater-inhabiting vertebrates either back to the sea or onto the land, once again physiological barriers had to be overcome, largely by the kidney. Some of Smith's early physiological studies were conducted on the African lungfish and the changes that occur as these animals escape drought through estivation (summer sleep: the opposite of winter hibernation) in mud burrows. These animals can survive for years without food when encased in dry mud. In this state, the animal needs to adapt from a situation in which water influx and excretion are dominant processes to one in which there is absolutely no water intake and no production of urine. The lungfish therefore cyclically deals with similar physiological pressures to those faced by vertebrates in the course of evolution and musing on these changes probably contributed enormously to the thesis presented in the essay reproduced here.

As a researcher investigating development of the kidney, I find this vision of evolution modifying organogenesis (and organogenesis modifying physiology) to be extremely useful. A wealth of comparative systems exist in nature that could allow us to link genetic change to developmental adaptation. One particularly useful example outlined by Smith is the aglomerular kidney's of certain marine fishes. Which of the genes postulated to be essential for glomerular development are no longer expressed during organogenesis in these animals? One such gene, WT1, is still present in the genome of the aglomerular (Marshall,1929) pufferfish (Miles et al.,1998), but has changes that may render it non- or partially functional. As the genomes of both glomerular (zebrafish) and aglomerular (Fugu) fish are now available, this problem is ripe for exploration. Amphibians initially live in an aqueous environment, but in many species spend large amounts of adult time terrestrially. These animals switch kidneys along with environments during metamorphosis with larval pronephroi dedicated to excreting water and adult mesonephroi dedicated to retaining it (Vize et al.,2003). What developmental adaptations are associated with this transition? How do the permanently aquatic water excreting mesonephric kidneys of zebrafish differ from those of the water-retaining amphibians? Both Danio and Xenopus genomes will soon be completely sequenced and provide powerful tools for investigating such questions. Smith's essay provides a framework for thinking about how genetic change may drive physiological specialization and brings to light a wealth of interesting material and experimental possibilities.

If readers enjoy this essay, they will be even more impressed by the expanded detail offered in From Fish to Philosopher (1953). Other excellent works by Smith include a semifictional account of his adventures obtaining lungfish for physiological studies in Kamongo (1932); an edited collected works, Homer William Smith: His Scientific and Literary Achievements (1962); and the philosophical Man and His Gods (1952), with a foreword by Albert Einstein.

Evolution of the Kidney

HOMER W. SMITH

A reprinting from “Lectures on the Kidney,” University Extension Division, University of Kansas, Lawrence Kansas (1943).

Seventy-odd years have elapsed since Claude Bernard first apprehended the fact that the true medium in which we live is neither air nor water, but the blood, the internal medium that bathes our muscles, glands and brain. This internal environment, as he called it, is a cosmos elaborately isolated from the external world and protected by a variety of physiological devices to the end that its composition shall remain unaffected by the sudden and sometimes severe changes that beset the other and unstable cosmos that lies outside our skins.2

During the 7 decades since Bernard formulated this concept, there has been discovered feature after feature in our milieu intérieur to which his concept of physiological regulation must be applied. Vital phenomena involve the interplay of so many physical-chemical factors that only a beginning can be made toward enumerating them. The most important one is, of course, water itself, the chief constituent of the blood and tissues; then there are the numerous inorganic salts: sodium, potassium, magnesium, calcium, chloride, phosphate and bicarbonate, the delicate and precisely balanced acid and basic components, glucose and amino acids. This list, though incomplete, is long enough to emphasize the biological importance of the mixture as a whole. The lungs serve to maintain the composition of the blood with respect to oxygen and carbon dioxide, and with this their duty ends. The responsibility for maintaining the composition of the blood in respect to other constituents devolves largely upon the kidneys. It is no exaggeration to say that the composition of the blood is determined not by what the mouth ingests but by what the kidneys keep; they are the master chemists of our internal environment, which, so to speak, they synthesize in reverse. When, among other duties, they excrete the ashes of our body fires, or remove from the blood the infinite variety of foreign substances which are constantly being absorbed from our indiscriminate gastrointestinal tracts, these excretory operations are incidental to the major task of keeping our internal environment in an ideal, balanced state. Our glands, our muscles, our bones, our tendons, even our brains, are called upon to do only one kind of physiological work, while our kidneys are called upon to perform an innumerable variety of operations. Bones can break, muscles can atrophy, glands can loaf, even the brain can go to sleep, without immediately endangering our survival, but when the kidneys fail to manufacture the proper kind of blood neither bone, muscle, gland nor brain can carry on. To quote Bernard again, “In proportion as we ascend the scale of living beings, the organism grows more complex, the organic units become more delicate and require a more perfected internal environment.” It was the view of this physiologist that we achieve a free and independent life, mentally and physically, because of the constancy of the composition of our blood. Recognizing that we have the kind of blood we have because we have the kind of kidneys that we have, we must acknowledge that our kidneys constitute the major foundation of our physiological freedom. Superficially, it might be said that the function of the kidneys is to make urine; but in a more considered view one can say that the kidneys make the stuff of philosophy itself.

Taken as a whole, the human kidney appears to be extraordinarily complex, but on anatomical analysis this complexity is reducible to fairly simple terms. Each of the two kidneys, which are of about the same size, is made up of slightly more than one million microscopic units, or nephrons. These nephrons are all essentially alike and consist of a filtering bed composed of a capillary tuft, or glomerulus, which drains directly into a long, elaborate tubule. These million-odd glomerular-tubular units empty into common collecting ducts which through confluent union finally deliver the urine into the pelvis of the kidney, whence it flows down the ureter into the bladder. In the two million-odd glomeruli, i.e., in the renal filtering bed where the formation of urine begins, the blood is literally spread out over a great surface by being divided among the innumerable capillary channels. The total surface of the glomerular capillary bed in the two human kidneys exceeds 1.0 square meter. Through this bed there are filtered off in each minute's time about 125 cc of water, or about 0.01 cc per square centimeter per minute, which is a rate of filtration well below that of the ordinary laboratory filters. But this capillary bed is still a filter in the ordinary laboratory sense for it permits everything in the plasma to pass through it except the blood cells, the plasma proteins and similar large molecular aggregates. To supply this 125 cc of filtrate 1,200 cc of blood are perfused each minute through the capillary bed of the glomeruli.

After leaving the glomerulus the blood passes into a second set of capillaries surrounding the tubule; here an opportunity is afforded for the tubule cells to transfer various substances from blood to tubular urine, or from tubular urine back into the blood, and here is where all specific chemical operations are carried out. For as the glomerular filtrate passes down the tubules valuable substances such as glucose, sodium, chloride, amino acids, etc., are reabsorbed and returned to the blood by various processes of tubular reabsorption. At the same time certain waste products and foreign substances are taken from the blood by the tubule cells and transferred to the tubular urine. These excreted substances and such waste products and foreign compounds as are present in the original filtrate but are themselves not reabsorbed, remain in the tubular fluid to be excreted in the urine. Of all substances reabsorbed by the tubules water is reabsorbed to the greatest extent: out of the 125 cc of filtrate formed each minute, on the average 124 cc of water are reabsorbed, leaving only 1.0 cc to be excreted as urine. In consequence of this extensive reabsorption of water, such substances as are filtered through the glomeruli but are themselves not reabsorbed by the tubules appear in the final urine in a highly concentrated form.35

In requiring how the renal tubule elaborates the glomerular filtrate into urine it will be noted that this tubule is cytologically differentiated into three segments: a proximal segment, an intermediate thin segment, and a distal segment with drains into an arborized system of collecting tubules. The proximal segment appears to be a jack-of-all-trades, capable of reabsorbing valuable constituents, notably glucose and chloride, from the glomerular filtrate, and at the same time capable of transporting many waste products and foreign substances from blood to urine. On rather indirect evidence it has been inferred that the thin segment is responsible for the final reabsorption of water and the production of a highly concentrated urine. The function of the distal segment remains something of a mystery, but there are reasons to believe that it is responsible for the adjustment of the acidity of the urine, for the conservation of the alkali reserve of the blood, and perhaps for the chemical formation of ammonia. In the present stage of our knowledge it would be dangerous to be dogmatic about details, and in any case it is not my intention to discuss the finer points of renal function. We are concerned here only with the general pattern of structure and function in this nephric unit, and with the inquiry, How did our kidney come to have the architecture that it does? In pursuit of this inquiry we must digress from the structure of the kidney to the general evolutionary history of the vertebrates, which history must itself be prefaced by a brief discussion of the structure of the earth.

According to the geologist the continents upon which we live are but irregular slabs of granite some 15 to 40 miles thick, floating like isolated islands upon a bed of basalt, the rock which makes up the oceanic floor. Under this bed of basalt, which is only some 700 miles thick, is a zone of semifluid magma extending to a total depth of about 1,800 miles. Innermost is a core of iron, some 4,000 miles in diameter, which is raised far above incandescent heat (6,000°C) by the enormous pressure existing at the center of the earth. It is now generally agreed by the geologist and the astronomer that the earth was separated from the sun about 2,000 million years ago through disruption of the parent body by a passing star, but the daughter planet remained molten and homogeneous for only a short time, quickly acquiring its present stratified structure as it cooled and crystallized.

The continents float above the average level of the earth's crust because their granite is lighter than the basaltic bed upon which they rest; as their exposed masses weather down and the silt is deposited in the sea along their edges, the added weight of this deposit causes the plastic basalt to flow beneath the land masses and to float them higher in the air. It is these slow adjustments to maintain isostatic equilibrium between the continents and the oceanic floor that sometimes cause abrupt movements of the land.6, 21 But all the earthquakes of historic time are trivial when compared with the disturbances of the past, which have extended not over days or weeks, but millions of years.

As measured, quite accurately it is now believed, by the radioactive clock within its rocks, the earth has had its present cold and semisolid form for about 1,800 million years. During this period it has been cooling and shrinking as a whole, having decreased in diameter something between 200 and 400 miles. Under the stresses resulting from this cooling process, and more particularly in consequence of the alternate fusion and solidification of the basaltic crust, this shrinking has been intermittent rather than uniform, so that at recurrent intervals of roughly 30 million years the continental masses have been wrinkled and folded into great mountain chains. During the intervening periods of geologic quiescence, the mountains raised by the preceding diastrophic movement have been largely if not entirely worn away to sea level by the slow erosion of wind and rain. Schuchert30 (1929) estimates that the total continental depth eroded in this manner since the opening of the Paleozoic exceeds 75 vertical miles, or more than 20 ranges of mountains like the present European Alps or the American Rockies.

These periodic revolutions, as the geologist calls them, have made us what we are. Because they have changed the form and size of the continents and seas and at times submerged great areas of land beneath the water, because they have diverted oceanic currents, altered the dust and water vapor in the atmosphere, raised barriers to moisture-laden winds and otherwise interfered with the basal forces that control the weather, these revolutions have been accompanied by marked and protracted changes in climate over the entire surface of the earth. In general, periods of mountain building have been accompanied by marked refrigeration so that in some instances glaciers have descended to sea level in equatorial latitudes; while in the quiescent intervals, after erosion had leveled the recently formed mountains to mere hills, warm shallow seas have transgressed widely over the low-lying lands, and even Arctica and Antarctica have enjoyed a climate that was warm and humid.29

According to modern experimental biology, the vis a tergo of evolution is the production of new varieties in consequence of random mutations in the chromosomes; such of these varieties as are unfitted to survive are pruned away by natural selection, leaving the better-fitted mutants to get along as best they can. Mutation is fundamental to evolution, but mutation itself would be of little avail to modify organic pattern did not the vis a fronte of natural selection foster the survival of exotic individuals, of the new mutations, by offering them a special environment in which their unique characters are advantageous, by preserving them from genetic extinction through backbreeding with the unmutated forms, and probably in other ways. We may believe that in the shaping of the final evolutionary product as we see it now, mutation and environment have played balanced and equal roles. Though we cannot assign to either mutation or selection any teleological direction, they tend within certain limits to have one result: after a few million years, when many millions of mutations have occurred and most of them have become extinct, we can expect to find among the surviving organisms some that are much better fitted to endure severe environmental changes than was the parent form. It is only here, in the accidental development of increased independence of environment, of increased physiological freedom in Bernard's sense of the word, that we can speak of evolution as being upward, rather than just sideways.

The paleontological record reveals that evolution has not been a continuous process, but an intermittent one. In Lull's22, 23 descriptive terms, it has been a tide of organic specialization moving forward in marked pulsations invariably synchronous with the great upheavals of the earth's crust. It was probably one of these pulsations, synchronous with the Cambrian Revolution, that gave the vertebrates their start. The more important steps in the phylogenetic history of these forms, with special reference to those events that have a close bearing upon the evolution of the kidney, are depicted graphically in Figure 1.

Figure 1.

Synopsis of the evolution of the vertebrates in relation to saltwater (darkly shaded) and freshwater (lightly shaded) habitat. The irregular curve illustrates mountain-building episodes (geologic revolutions) which have influenced this evolutionary history. The time scale is such that the Pleistocene era and recent time are compressed.

The problem of the origin of the first chordates remains more or less where it was left by the great biologists of the past century—in a sadly unsatisfactory state. A few years ago there was consensus of opinion on at least one point: that the chordates shared with the echinoderms, the acorn worms, Branchiostoma (Amphioxus) and the tunicates, a common marine ancestor, a frail-bodied, ghostly form, similar perhaps to the Dipleurula larva of the echinoderms.27 The most important features of this hypothetical ancestor were that it possessed a bilateral symmetry comparable to that of Branchiostoma, and like Branchiostoma it kept one end foremost as it swam slowly and feebly through the archaic seas. But the right of this ghostly form, the like of which no one has ever seen, to spawn the great vertebrate phylum has recently been questioned on the ground that the chordates, as they first appear in the fossil record, were depressed, bottom-living, heavily armored and sluggish animals as far removed in appearance from Branchistoma as one can imagine. This fact is in part responsible for the suggestion of Torsten Gislén,10 which has been seconded by Gregory,15, 16 that the first chordates may have been evolved from a free-swimming Paleozoic crinoid, or sea lily. To this perennial debate we will add one more confusing argument of our own in a later paragraph.

As we cannot say from what forms the first chordates were evolved, neither can we with any certainty name the time of their evolution. Some would assign this evolution to the Ordovician Period, and some to the Cambrian. The opening of the Cambrian was marked by one of the most violent periods of mountain building the earth has ever known. These mountains have long since been washed away, but the sediment to which they were reduced is to be seen in the several vertical miles of red- and yellow-banded rocks through which the Colorado River has cut the Grand Canyon, and from which scenic chasm the geologic revolution takes its name. The biologist has repeatedly asserted that the truly unique features of the vertebrates consist, broadly speaking, of bilateral symmetry: of a stiffened and yet flexible internal backbone with an articulated skeleton for the support of muscles so arranged as to produce powerful lateral motions of the body, the backbone, skeleton and muscles being made up of regularly repeated segments; of paired, fin-like expansions of the skin to resist the thrust of these muscles and to maintain an even keel as the animal shoves itself forward in the water; and of major sense organs located in the anterior end of the body. These features are just such as to endow the organism with considerable swimming power, to enable it to move swiftly through the sea, or, as an alternative, to live in a swiftly flowing river. According to one theory, first propounded by Chamberlain5 and substantially supported by Barrell,1 the sluggish ancestors of the chordates had already migrated from the sea into the quiet brackish or freshwater lagoons of the Cambrian continents when the Grand Canyon revolution overtook them: the tilting of the land accelerated the motion of the rivers and this accelerated motion fostered the evolution of the dynamic, chordate form. But another theory, offered by Moody,25 has it that the prochordates appeared in freshwater somewhat later, being literally driven into the rivers and lakes in Ordovician time by the attacks of the giant marine cephalopods that had then risen to supremacy in the seas.

Whichever theory we accept, it is now agreed that it was in the freshwaters of the Paleozoic continents, and not in the sea, that the first chordates, and from them the ostracoderms and early fishes, were evolved. When, in 1930, Professor E.K. Marshall and I reviewed the comparative anatomy of the kidney and on the question of the habitat of the early vertebrates followed the freshwater thesis as set forth by Chamberlain5 and Barrel,1 we were conscious of treading on uncertain ground.24 But since that time the subject has been carefully reviewed by Romer and Grove,28 and in the face of this new evidence the freshwater hypothesis can no longer be denied.

Now, the very matrix of life is water, and the evolution of the kidney is essentially the story of the evolution of the regulation of the water content of the body. Marine invertebrates—worms, starfish, mollusks, etc.—are generally in osmotic equilibrium with the sea, and they therefore face no problem of water regulation. And it may safely be assumed that in the Cambrian or Ordovician prochordate ancestor of the vertebrates the kidney was little, if at all, concerned with the excretion of water, but wholly with the excretion of nitrogenous waste.

Judging from the evidence of comparative anatomy, the marine ancestor of the chordates had in each of the middle segments of the body a pair of open tubules which connected the primitive body cavity, or coelome, with the exterior; these segmental tubules were probably originally gonaducts serving to carry the eggs and sperm out of the coelomic cavity. Possibly before the chordate stage the coelomic membrane had come to play a part in excretion, and the segmental gonaducts which connected it with the exterior, and which were themselves formed by an evagination of the coelomic membrane, perhaps participated in the regulation of the composition of the blood by reabsorbing valuable substances from the coelomic fluid, or by secreting waste products into this fluid as it passed out of the body.

With this rather meager equipment of a coelomic membrane and a number of segmental ducts the first chordates essayed to enter the freshwaters of the Paleozoic continents. In migrating from the sea to brackish estuary and thence up the rivers to the inland lakes these chordates were probably following a protoplasmic impulse to search for peace, but they were destined never to have that impulse satisfied. They encountered trouble, as is obviously revealed by the defensive armor which they soon evolved. The first vertebrates to appear in abundance in the fossil record, the Silurian and Devonian ostracoderms, the arthrodires, antiarchs and the earliest shark-like forms bearing jaws, the acanthodians, and even the later advanced fishes, were typically encased from snout to tail in apparently impregnable armor which took the form of bony plates, scutes or scales. Any sample of the vertebrate population of Silurian-Devonian times from Pennsylvania to Spitzbergen suggests that some death-dealing enemy, swift, merciless and irresistible, lurked in every corner of the world.

Why all this heavy armor? Romer27 has pointed out that the only visible enemies of the ostracoderms and early fishes were the eurypterids that shared with them the continental waterways. Admittedly some of these eurypterids were much larger than the ostracoderms and fishes, and possessed strong claws, but they were primarily sluggish mud crawlers and unless they struck with their pointed tails, as does their enfeebled descendant, Limulus, or injected poison, as do their offspring, the scorpions, their fearsomeness may have been more apparent than real. The thesis that the armor of the early vertebrates served primarily to protect them from predacious enemies is perhaps open to question. May I offer an alternative suggestion: these vertebrates had an enemy which they could not see, but one which pursued them every minute of the day and night, and one from which there was no escape though they fled from Pennsylvania to Spitzbergen—a physical-chemical danger inherent in their new environment. When the first migrant from the sea took up residence in freshwater, its blood and tissues, bearing the physical-chemical imprint of its marine home, were rich in salts: for we may on straight extrapolation assume that at the opening of either Cambrian or Ordovician time the sea had one-half or better of its present salinity. This saline heritage might be in part erased, but it could not wholly be cast aside without reorganizing every nerve and muscle cell. The evolution of a regulated internal environment, if it had not yet begun, was imperatively imminent. For in the new freshwater habitat the salts and proteins of the tissue cells drew water osmotic pressure so that by degrees the organism tended to pass from excessive hydration to edema and in extremis to swell to death. We may confidently assert that were the osmotic infiltration of water not arrested, survival in freshwater would be impossible. The first step toward arresting the infiltration of water would naturally be to insulate the body as far as possible by a waterproof covering. Why not believe that the ever present armor of the fossilized vertebrates of Silurian and Devonian time was a defense against the osmotic invasion of freshwater rather than against the claws and tail spines of the eurypterids?

In the history of evolution we see repeated instances where some adaptation is carried to absurd and disadvantageous overdevelopment, and perhaps an insulation serving primarily to repel freshwater may have been the genesis of spines and tubercles and other armored absurdities as would later serve to ward off strong-jawed, sharp-toothed predators such as had not yet been evolved. It seems that it was from certain of these protuberant spines that the fins were evolved. If we take this path of interpretation, we must conclude that what started out to be merely a waterproof insulation was destined to supply the fishes with fins for swimming and with spines and other armament for battle, and the tetrapods with legs with which to crawl about on land.

But to invest the body in waterproof armor entailed important changes in internal anatomy as well. The multiple segmental openings of the archaic coelomic tubules had to be obliterated, and these tubules had to be arranged to drain into the one posterior member which still pierced the now armored skin. Thus the evolution of the first archinephric duct may have been fostered by the waterproofing of the body. Moreover, with most of the body covered by armor, a few posterior skeletal muscles had to be selected and developed in order to concentrate leverage in a powerful tail; this emphasis on the posterior segmental muscles, together with compression of the middle segments of the body cavity beneath one or a few armor sheets, would tend to obliterate the primitive segmental divisions of the coelome and to foster the development of pericardial and splanchnic cavities as they appear in the higher vertebrates. The evolution of an armored body, the remote, articulated parts of which had to be moved in a coordinated manner, would foster the evolution of a central nervous ganglion or brain, which stood in close functional relationship to the anterior, distance receptors. The development of armor about the head would foster the cranial articulation of mouth parts and the evolution of jaws, which, absent in the ostracoderms, are first discoverable in the mailed acanthodians of Silurian time. But these interesting speculations, and they are nothing else, lie apart from our main theme, namely, that it was in seeking protection against freshwater that the first vertebrates to be preserved in the fossil record, the ostracoderms, came to be depressed, bottom-living armored creatures far removed from the hypothetical dynamic, fast-swimming prototype of classical theory. For even under their best efforts at free swimming the early armored vertebrates found it easier to sink to the bottom and wiggle upon the mud, where indeed most of them remained until the close of the Devonian. If the ostracoderms are viewed as a consequence of evolution in freshwater they offer less difficulty to the dynamic theory, which is recommended on so many grounds.**

Yet even thus encased in a waterproof covering, the gills, the mouth and the intestinal tract still afforded routes by which excessive quantities of water could be absorbed. The ostracoderms and early fishes had to compensate for this excessive influx by increasing the excretion of this substance. Their battle against freshwater was only half won. Evolution frequently works by adapting old things to new uses, and it seems that no better way could be devised to get the surplus of water out of the body than to have the heart pump it out; and the easiest way to do this was to prepare a filtering device by bringing the preexisting arteries into close juxtaposition with the preexisting coelomic tubules, to form the coelomate glomerulus which, as a lobulated tuft of capillaries, still hangs free in the pericardial cavity of some of the lower vertebrates. Later a direct connection was effected between arteries and tubules outside the coelomic cavity, to form the typical glomerulas as found in mesonephros and metanephros of the higher animals. But in many recent fishes and Amphibia, the mesonephric tubules still retain their ancient connection with the body cavity. The essential point is that the renal glomerulus was evolved independently of and long after the evolution of the renal tubule. And it will be recalled that in the ontogenetic development of the human embryo the glomerulus is not brought into conjunction and connected with the tubule of the metanephros until some time after this tubule has been formed; it is possible that this interval between the development of the tubule and the glomerulus is an ontogenetic recapitulation of the phylogenetic interval which separated their evolution.

But the very nature of a high-pressure filtration system permits not only water to be pumped out of the body, but also most of the osmotically active constituents of the plasma, which means all the valuable constituents except the proteins—glucose, chloride, phosphate, etc.—for if these did not pass through the filtering bed the great osmotic pressure which they exert would effectively prevent the heart from pumping any water through this bed. Hence, with the advent of the glomerulus it was necessary to so modify the tubules that they could reabsorb these valuable constituents from the filtrate. Moreover, there was such an excess of water over salt to be excreted that the urine had to be almost pure water, i.e., it had to have a substantially lower osmotic pressure than the blood. Thus, as a concomitant of the evolution of the glomerulus, there came into existence a tubule capable of reabsorbing large quantities of glucose and similar valuable substances, and capable of elaborating, by the reabsorption of the salt, a urine that was hypotonic to the blood.

To whatever extent this new freshwater kidney was adequate to its time, times changed. The restless earth began to heave again. At the close of the Silurian another diastrophic movement disturbed its crust; no great mountains were raised in North America, but a ridge higher than the Alps was wrinkled up in northern Europe, of which the low Calendonian mountains of Scotland are all that now remain. Other continental areas were extensively submerged beneath the sea, and what land escaped was plagued by extremes of climate swinging between excess of rain and drought. The fishes of the early and middle Devonian found themselves forced to choose between the invading saltwater marshes and the isolated freshwater pools which periodically contracted into stagnant swamps or hard mud flats. Some of the more powerful elasmobranchs, perhaps now better fitted to compete with the cephalopods and other marine invertebrates, sought sanctuary by turning toward the sea; the fate of these, the first fishes to live in saltwater, will be noted in a later paragraph. The more advanced of the fishes, however, in order to survive in the stagnant waters of the continents, took to swallowing air and thus invented lungs and prepared the way for the evolution of the terrestrial vertebrates.

At the close of the Devonian the earth suffered its third major upheaval in vertebrate history; the periodic dry spells of the Devonian were replaced by protracted and widespread desiccation and many of the air-breathing fishes followed the example of the Silurian elasmobranchs and abandoned freshwater for refuge in the sea where they founded the Paleozoic-Mesozoic dynasties of marine teleosts. But certain of the freshwater fishes, the Crossopterygians, learned to use their fins for feet with which to crawl from one pool to another, and thus founded the Carboniferous and Pennsylvanian Amphibia which needed to return to the water pools only occasionally to drink and to lay their eggs.

For a moment let us consider what must have happened to the bony fishes that took up life in the sea in the Carboniferous. Actually, none of these Mesozoic forms survives today, all the recent marine teleosts having been evolved since the opening of the Cenozoic era; but the physiology of recent forms is adequate to illustrate the difficulties of changing one's habitat from fresh- to saltwater.

With the migration from fresh- to saltwater the osmotic relations between organism and environment are reversed; the body tissues are less concentrated than the sea and, unless the composition of these tissues is completely overhauled, they must tend constantly to suffer osmotic dehydration and ultimate desiccation and collapse. The marine bony fishes face not a perpetual excess of water, like their freshwater ancestors, but a perpetual deficit of it. In theory they could maintain the accustomed proportion of salt and water in the body by excreting a highly concentrated urine, but in practice they cannot do this for the fish kidney is unable to elaborate a urine which is osmotically more concentrated than the blood. Their lot would be as unhappy as that of the Ancient Mariner were it not that, unlike that thirsty man, they have the happy advantage of possessing gills, and the gill is the only organ in the lower vertebrates capable of doing hypertonic osmotic work. Had the Ancient Mariner possessed such a marvelous organ he could have lived like a fish by drinking the briny sea; he could have separated the salt from the water by excreting the salt out of his gills in a concentrated form, leaving the water free for his tissue, or for the formation of urine. But with the limitations of the fish kidney he still would have had cause to deplore his lot, since for every liter of urine formed he would be forced to concentrate a liter of seawater by 66%. It is not surprising that the marine fishes, rather than spend their precious energy in making more concentrated the already concentrated sea, naturally became conservative in the matter of urine formation and excreted no more urine than was required to remove waste products from the body.32 When the bony fishes migrated from freshwater to the sea, the high-pressure filtering device of the glomerulus was no longer an asset, but a liability. They shut the filtering bed down as far as possible, and with the passing years the glomeruli grew smaller and smaller, fewer and fewer; to examine the glomeruli in a series of marine teleost kidneys reminds one of the old-fashioned Herpecide advertisement: Going—going—gone! Nearly all the marine teleosts show some evidence of glomerular degeneration, and in certain of them (the toadfish, midshipman, goosefish, batfish, sea horse, pipefish, and in certain deep-sea fishes) the kidney has become entirely aglomerular.3, 12, 13, 14, 24 There is no constant rule by which the aglomerular condition is reached; Grafflin11 has shown that in the “daddy” sculpin the glomeruli cease to function between the young and the adult stage, while Armstrong (personal communication) has shown that in the toadfish and pipefish a glomerulus does not develop even in the embryo. Though evolution is not reversible, the marine teleosts are indirectly converting their kidneys back to the purely tubular form possessed by the prochordate ancestor which left the sea in Cambrian or Ordovician time.

But there is more than one way of solving physiological difficulties, including that faced by the Ancient Mariner and the marine teleosts. Let us return to the elasmobranchs, who had first made the marine migration in the Devonian. These more primitive fishes solved the problem of living in saltwater in an entirely different way. The four orders of the subclass Elasmobranchii—the sharks, rays, skates and chimeras—separated from the parent stem and from each other in or shortly after the Devonian period; that is to say, the Devonian is the most recent time at which we can assign to all four orders a common ancestry. Yet all four orders possess a common and surprisingly unique adaptation for living in seawater; they have changed the composition of their blood by deliberately bringing themselves, as it were, into a perpetually uremic state; they reabsorb from the glomerular filtrate as it passes down the tubules such urea as is present in this fluid (urea being the chief product of nitrogen combustion) much as the Ordovician-Silurian fishes learned to reabsorb glucose and chloride. They return this otherwise inert waste product to the blood until it reaches concentrations of 2,000 to 2,500 mgm.%. The presence of this urea raises the osmotic pressure of the blood above that of the surrounding seawater and causes water to move from the sea into the body, through the gills; and thus, pure water, free from salt, moves continuously inward at a sufficient rate to afford a vehicle for the urinary excretion of waste products and such excess salt as is present in the food.33, 34. Where the bony fishes must continuously drink seawater in a steady stream, in the elasmobranchs this fluid serves only to wet the gills.

A unique tubular segment is present in the elasmobranch kidney, just distal to the glomerulus, which is thought to be the site of the active reabsorption of urea from the glomerular filtrate. None of the elasmobranch fishes, in spite of their long residence in the sea, is aglomerular; having always had abundant water available for filtration, there has been no need to abandon their glomeruli.

It is especially interesting that the method of reproduction in this subclass is highly specialized, the majority of the Elasmobranchii being viviparous, the rest producing an egg enclosed in a relatively impermeable egg case. The latter is apparently the more primitive mode of reproduction. Both the viviparous forms and those that have a cleidoic or “closed” egg utilize internal fertilization, for which purpose there exist claspers in the male and accessory reproductive glands in the female. One supposes that this specialized mode of reproduction is concerned with the conservation of urea in the young embryo until such time as its kidneys and its respiratory and integumentary membranes are organized. The Cladoselachii of the Devonian apparently lacked claspers, but these were present in the Carboniferous and Permian hybodonts and pleuracanths and in all the Jurassic sharks. Further paleontological research may, in the above view, be able to reveal to us the exact time at which the uremic habitus, as an adaptation to saltwater, was acquired.

Returning now from the fishes to the main evolutionary tree: during the coal ages the low-lying lands were heavily clothed in tropical and subtropical vegetation. There was a high rainfall, the air was humid, the world was a swampy paradise inhabited by spiders, scorpions, centipedes and snails, and lorded over by Amphibia that lived half in water and half on land. But on the whole life was as stagnant as the swamps in which it lived. It was too comfortable, and in comfort the living organism comes to rest, its evolution stops or regression begins.

The moist paradise of the coal ages lasted until the Permian; then in the great Appalachian Revolution a majestic range of mountains, 3 to 4 miles high, was corrugated in the region that now lies between Newfoundland and Alabama. The Southern Hemisphere passed into a severe glacial period, and in the Northern Hemisphere the warm moist climate of the Carboniferous was replaced by aridity and seasonal chilliness. The cycads, equisetums, clubmosses and tree ferns of the coal measures were exterminated; all the great families of the marine elasmobranchs were destroyed along with most of the marine and freshwater teleosts; and the stagnant Amphibia changed slowly toward more terrestrial forms. It was the sheer pressure of worldwide Permian desiccation that fostered the evolution of the reptiles, which were driven in extremis to living permanently on land. These new reptiles had tough hides and relatively long legs with which to crawl from one water hole to another; the egg, for the first time in vertebrate history, was encased in a waterproof shell and contained within it the allantoic sac to receive the waste products of the embryo; a multitude of adaptations, most of which concern the preservation of the internal environment, had to be effected to liberate the organism from its primeval aquatic environment. One of the most important of these adaptations consisted in a subtle change in the method of protein combustion. Instead of degrading protein nitrogen to urea, as had the fishes and Amphibia, the reptiles overhauled their metabolic machinery and degraded their protein nitrogen to uric acid. Uric acid is a very peculiar substance: it is almost insoluble in water, and yet it readily forms highly supersaturated solutions; the reptiles secrete it in the tubular urine as a concentrated, supersaturated solution; then, as the tubular urine passes to the cloaca, the uric acid precipitates out, leaving most of the water in the urine free to be reabsorbed into the blood, while the uric acid itself is expelled as an almost dry paste. This same uric acid adaptation, like so many other reptilian characters, is found in the birds,20, 36 for the birds are but warm-blooded reptiles with feathers and wings.

When the teleosts risked desiccation in the briny sea many of them completely discarded their glomeruli as extravagant routes of water loss. In view of the fact that in the arid-living reptiles and the marine birds the need for water conservation is equally extreme one might expect some of them to be aglomerular too, but no aglomerular reptile or bird has thus far been described. The reptilian-avian kidney is, however, headed in that direction, for the once elaborate glomerular tuft is reduced to a few, in some cases only two, capillary loops, and contains a great amount of inert connective tissue. It is as though these animals, having found the glomeruli largely superfluous but needing to flush the uric acid-rich secretion of the tubules down to the cloaca, had stopped short of the complete obliteration of the glomeruli and retained a vestige of the filtering bed in order to supply the tubules with a feeble, irrigating stream.

At this point you are probably wondering if the title of this discourse is not misrepresenting, since so much of it has been devoted to the lower vertebrates and so little of it to the mammals or to man. I would defend this apparent unfairness by pointing out that all the mammals together constitute but a small fraction of the vertebrates, and man himself but one mammalian species among thousands. The geological age of truly human forms is at most 1,000,000 years, a slight interval indeed out of the 500 to 600 million years which we must apprehend if we are to see the human organism in the proper perspective. But apart from this aspect of the problem I must confess that at this point in the story of the evolution of the kidney there is a serious hiatus in our knowledge, namely, the circumstances surrounding the evolution of the first mammalian forms.

The mammals have added the only important patent to the kidney since Devonian time: the capacity to excrete urine that is markedly hypertonic, or osmotically more concentrated than the blood. As pointed out in an earlier paragraph, the elaboration of this hypertonic urine is in part effected by the unique, intermediate thin segment which is present in the tubule of all mammalian forms.

We must inquire, How did this capacity to excrete a hypertonic urine come to be evolved? And we may go on to ask, Since the mammals were evolved from reptilian forms, why do they not excrete uric acid like the reptiles and the birds? And since the mammals do not generally live in freshwater, since in fact some mammals, such as the kangaroo rat, can live indefinitely upon dry oatmeal, while others, such as the whales and seals, can live indefinitely in the sea without ever taking a drink of freshwater, why have they not lost their glomeruli? Why, on the contrary, have the glomeruli reached their fullest development in the order Mammalia?

Let us review briefly what is known about early mammalian evolution. Through all the Mesozoic the mammals remained in the background and let the reptiles have the stage. During the desiccation of the Permian these thick-skinned animals, their legs ever growing longer, began to crawl on their bellies all over the world and to establish their reputation for grotesquerie. In the Triassic, which was, like the Permian, a period of aridity but one lacking marked seasonal extremes of heat and cold and generally warm enough to permit the luxuriant growth of ferns, tree ferns and equisetums, reptilian peculiarities began to reach extremes. The more advanced took to walking on their hind legs and strutted about like the lords of the universe. In the Jurassic the climate reverted to subtropical humidity, and the reptilian paradise was but slightly disturbed by the diastrophic movement that raised the Sierra Nevadas and ushered in the Cretaceous. Here reptilian evolution culminated, on the one hand, in the great dinosaurs, the most magnificent creatures and probably the dumbest per kilogram of body weight that the earth has ever seen, and, on the other hand, in the flying reptiles whose jaws were still filled with teeth and whose wings were still tipped with claws. Then, at the end of the Cretaceous, when the Rocky Mountains and the Andes were rising slowly, the curtain is rung down on this Mesozoic scene with a suddenness that is almost dramatic. The dinosaurs disappeared, the birds lost their teeth and shaped their forelimbs into delicate wings, and a host of new actors, in the form of the Cenozoic mammals, rushed upon the stage as though they had long been waiting impatiently behind the scenes.

Where these mammals had been throughout the long and fantastic period of the Mesozoic is still a mystery. The oldest known mammalian fossils date from the late Triassic or early Jurassic periods, and these were already advanced and specialized creatures; no remnants of a stock which could have been ancestral even to the Cretaceous forms have been discovered.31 However, it must be believed that truly mammalian types were in existence in the early Triassic, and probably even in the Permian, while the reptiles themselves were still in a relatively primitive stage. Certain Triassic reptiles, the cynodonts, resembled the mammals in such features as the posterior jaw elements, the teeth, and the structure of the shoulder girdle, and they stood with their limbs well under the body, and it may be supposed that the cynodont reptiles and the mammals were evolved out of a common Permian stock. It need not be supposed, however, that this common ancestral stock was warm-blooded, nor need it be supposed that it had acquired the reptilian habit of excreting uric acid; rather it may have been a semiaquatic type that degraded its protein nitrogen to urea, as we may suppose was the case in the Pennsylvanian Amphibia.

Proceeding from this premise, it is to be noted that there were two environmental stresses operating in Permian time: intense aridity and intense frigidity. The Permian was one of the greatest ice ages of all time. Frigidity—the cold nights of the desert and the long, cold, seasonal winters—placed a high premium upon the ability to be continuously active, even as aridity placed a premium upon the ability to travel overland from one water hole to another. A nascent, evolving stock could adapt itself to one of these stresses ahead of the other. Let us suppose that the protomammalian forms got off to warm-bloodedness first, in adaptation to frigidity, rather than to uric acid excretion, in adaptation to aridity. The progressive evolution of warm-bloodedness entailed a marked increase in the circulation of the blood, which in turn entailed a corresponding increase in arterial blood pressure; this increased blood pressure resulted in an increased rate of filtration through the glomeruli, and this entailed an increased need for conserving water by reabsorbing it from the tubules. Thus rapid elevation of body temperature would foster increased reabsorption in the tubules by accentuating the very need for it. It is plausible, therefore, that the accentuated capacity of the mammalian tubule for reabsorbing water was simply a sequel of the evolution of the warm-blooded state, which evolutionary step may have been taken before the habitus of uric acid excretion had become fixed in the general reptilian stock. Once the definitive mammalian kidney had been evolved as an adaptation to frigidity, it served as an adaptation to aridity as well, for the enhancement of water conservation which it effected enabled the mammals to compete, dry spell for dry spell, with the more sluggish reptilian forms. Into whatever dry spot the reptiles could radiate the mammals could follow them, and when the desert night descended and forced the cold-blooded reptiles into sleep the warm-blooded mammals remained active and alert. But more important, perhaps, was the change in temperature that marked the Laramide Revolution; it may have been the inability of the reptiles to endure this period of refrigeration and desiccation that led to their almost total extinction,26 while the furry warm-blooded mammals, equipped to meet both vicissitudes, could carry on.

This interpretation receives support in the fact that in the bird kidney the tubules are of a mixed type, some resembling the reptilian tubule in lacking a thin segment, some resembling the mammalian tubule in possessing such a segment. Functionally the bird kidney is intermediate between the reptiles and the mammals, the bird retaining the uric acid habitus of the former, although it can under certain conditions elaborate a distinctly hypertonic urine.20 The similarity to the mammalian kidney in the last respect is probably a case of convergent evolution fostered by the common character of warm-bloodedness, for the birds were evolved from reptiles that were far removed from the mammalian stem.

When, at the close of the Cretaceous, the dinosaurs became extinct, the mammals began to populate the earth. In the Paleocene the lemuroids took to living in the trees and became the Eocene tarisioids who looked forward with both eyes at the same time and depended upon the sense of sight rather than upon smell or hearing. In the Oligocene a tarisioid or lemuroid stock gave rise to the monkeys which in the Miocene in turn spawned the Dryopithecine apes that roamed over Europe, Africa, and Asia. Then the rising Himalayas buckled Central Asia into an uninhabitable mountain chain, and such of the Dryopithecine apes as survived were driven to abandon the trees and to seek their living in the southern plains. From Asia a Dryopithecine descendant migrated into Africa, to spawn there in the Pliocene such forms as Australopithecus africanus, discovered by Dart,7 and Plesianthropus transvaalensis and Paranthropus robustus, recently discovered by Broom,3, 4 and declared by their discoverers and by Gregory and Hellman17 to be truly neither ape nor man. [For a general discussion of the origin of man see Wilder.37]

The kidney is not identical in structure and function in all mammalian forms, but the human kidney differs only in details from that organ in the dog, cat, and rabbit. It is not surprising that in function the human kidney has its closest homologue in the kidneys of the great apes, who can claim with man a common ancestor back somewhere in the Miocene.

Examining the pattern of the human kidney, we must not be surprised to find that it is far from a perfect organ. In fact, it is in many respects grossly inefficient. It begins its task by pouring some 125 cc of water into the tubules each minute, demanding for this extravagant filtration one quarter of all the blood put out by the heart. Out of this stream of water, 99% must be reabsorbed again. This circuitous method of operation is peculiar, to say the least. At one end, the heart is working hard to pump a large quantity of water out of the body; at the other end the tubules are working equally hard to defeat the heart by keeping 99% of this water from escaping. Thus heart and kidney are literally pitched in constant battle against each other—our lives depend on neither one of them ever winning out. Nature frequently opposes two forces against each other in order to maintain a steady state, but the opposition in this instance takes on an aspect of sheer extravagance. Paradoxically, the kidney has to do its greatest work when it excretes the smallest quantity of urine; as the urine flow increases it does less and less work, and if the urine flow were to increase to the colossal figure of 125 per minute—170 liters per day—the kidney, in respect to the excretion of water, would be doing no work at all.

In consequence of the circuitous pattern of the filtration and reabsorption of water, nearly half a pound of glucose and over 3 pounds of sodium chloride per day, not to mention quantities of phosphate, amino acids and other substances, must be saved from being lost in the urine by being reabsorbed from the tubular stream. There is enough waste motion here to bankrupt any economic system—other than a natural one, for Nature is the only artificer who does not need to count the cost by which she achieves her ends.

The chief waste product which the kidney is called upon to excrete is urea. The glomeruli remove each minute such urea as is contained in 125 cc of blood, but because of the way the tubules are put together 50% of this urea diffuses back into the blood again, so that in terms of the total renal blood flow (1,200 cc per minute) the overall efficiency of the excretion is only about 5%. There are certain foreign substances, however (diodrast, hippuran, phenol red, etc.), which have been synthesized only within the past few years, which the kidney excretes with almost 100% efficiency. Is it not strange that, in spite of the fact that it has never before encountered them, the kidney should be able to excrete such artificial, synthetic compounds 20 times as efficiently as it excretes the principal nitrogenous waste product naturally formed in the body, and which it has been excreting for millions and millions of years?

The kidney is receiving more attention today than ever before. These scientific problems range from local organic pathology to such subtle matters as the relation of the internal environment and its multiplicity of chemical factors to personality and mental disease. Certainly, mental integrity is a sine qua non of the free and independent life. As intermittent rays of light blend into moving images on the cinematographic screen, so the multiform activities within the brain are integrated into images of consciousness and brought into an unstable focus to form that fleeting entity which we call personality, or self. But let the composition of our internal environment suffer change, let our kidneys fail for even a short time to fulfill their task, and our mental integrity, our personality, is destroyed.

There are those who say that the human kidney was created to keep the blood pure, or more precisely, to keep our internal environment in an ideal balanced state. I would deny this. I grant that the human kidney is a marvelous organ, but I cannot grant that it was purposefully designed to excrete urine, or even to regulate the composition of the blood, or to subserve the physiological welfare of Homo sapiens in any sense. Rather I contend that the human kidney manufactures the kind of urine that it does, and it maintains the blood in the composition which that fluid has, because this kidney has a certain functional architecture: and it owes that architecture not to design or foresight or any plan, but to the fact that the earth is an unstable sphere with a fragile crust, to the geologic revolutions that for 600 million years have raised and lowered continents and seas, to the predacious enemies, and heat and cold, and storms and droughts, the unending succession of vicissitudes that have driven the mutant vertebrates from sea into freshwater, into desiccated swamps, out upon the dry land, from one habitation to another, perpetually in search of the free and independent life, perpetually failing for one reason or another to find it.

It is more than an antiquarian impulse that leads me to close this lecture by two quotations. About the Fifth Century, a Persian philosopher who is well known to all of you remarked:

“Myself when young did eagerly frequent Doctor and Saint, and heard great argument about it and about: but evermore Came out by the same door where in I went.”

Many centuries later, specifically in 1804, a French chemist named Fourcroy,9 who presented the first comprehensive exposition of the nature and physiological importance of urine in a volume entitled A General System of Chemical Knowledge, said:

“The urine of man is one of the animal matters that have been the most examined by chemists and of which the examination has at the same time furnished the most singular discoveries to chemistry, and the most useful applications to physiology, as well as the art of healing. This liquid, which commonly inspires men only with contempt and disgust, which is generally ranked amongst vile and repulsive matters, has become, in the hands of the chemists, a source of important discoveries and is an object in the history of which we find the most singular disparity between the ideas which are generally formed of it in the world, and the valuable notion which the study of it affords to the physiologist, the physician and the philosopher.”

Acknowledgements

I thank Antone Jacobson for introducing me to the work of Homer W. Smith; F. Woodward, S. White, K. Curry, and the University of Kansas Extension School and Press and N. Taylor of New York University Press for their help in reproducing this work; Margaret Krzyzanska for typing the article.

  • **

    The essential principle of this thesis—that the exoskeleton of the ostracoderms served as insulation against freshwater, and that it was from this exoskeleton that there were evolved the spikes and other forms of armor, and later the locomotor organs, jaws, teeth, etc., of the higher fishes—has been accepted by Gregory and Raven (1941) in their paper.

  1. 1

    The following list is not so much intended to encompass the literature in this .eld as to indicate a few articles or books of special interest to the student of general biology.

Ancillary