Renal Evolution Revisited

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Annals of Anatomy 233 (2021) 151610

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Annals of Anatomy

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The struggle to equilibrate outer and inner milieus: Renal evolution revisited

∗

Laura Keogh, David Kilroy, Sourav Bhattacharjee

School of Veterinary Medicine, University College Dublin (UCD), Belﬁeld, Dublin, Ireland

a r t i c l e i n f o a b s t r a c t

Article history: The journey of life, from primordial protoplasm to a complex vertebrate form, is a tale of survival against

Received 26 February 2020

incessant alterations in climate, surface topography, food chain, and chemistry of the external environ-

Received in revised form

ment. Kidneys present with an ensemble embodiment of the adaptations devised by diverse life-forms to

14 September 2020

cope with such challenges and maintain a chemical equilibrium of water and solutes, both in and outside

Accepted 15 September 2020

the body. This minireview revisits renal evolution utilizing the classic: From Fish to Philosopher; the story

of our internal environment, by Prof. Homer W. Smith (1895–1962) as a template. Prof. Smith’s views

Keywords:

exempliﬁed the invention of glomeruli, or its abolishment, as a mechanism to ﬁlter water. Moreover,

Kidneys

with the need to preserve water, as in reptiles, the loop of Henle was introduced to concentrate urine.

Renal evolution

When compared to smaller mammals, the larger ones, albeit having loops of Henle of similar lengths,

Loop of Henle

Chemical equilibrium demonstrated a distinct packing of the nephrons in kidneys. Moreover, the renal portal system degener-

Glomerulus ated in mammals, while still present in other vertebrates. This account will present with a critique of the

current concepts of renal evolution while examining how various other factors, including the ones that

we know more about now, such as genetic factors, synchronize to achieve renal development. Finally, it

will try to assess the validity of ideas laid by Prof. Smith with the knowledge that we possess now, and

understand the complex architecture that evolution has imprinted on the kidneys during its struggle to

survive over epochs.

license (http://creativecommons.org/licenses/by/4.0/).

1. Introduction Being a crucial organ involved in homeostasis (Kotas and

Medzhitov, 2015; Modell et al., 2015; Stanger, 2015; Röder et al.,

Kidneys are indispensable in maintaining the chemical com- 2016), the evolution of kidneys has steadily attracted academic

position of extracellular ﬂuids (ECF) that continuously bathe scrutiny due to its role in chemical surveillance of the environ-

our internal organs to ensure health and survival (Youn and mental milieu organisms thrive. It is necessary to appreciate that

McDonough, 2009; Hoenig and Zeidel, 2014; Blaine et al., 2015; the environment, along with its countless interactions with living

Palmer, 2015; Stanhewicz and Larry Kenney, 2015). Renal anatomy cells—from simple unicellular organisms to complex multicellular

and physiology, in their existing forms, present with an astound- ones—are chemical processes that, at times, can be incompati-

ing level of complexity, incredible precision, and added to its role ble with life. It is thus imperative that our current anatomy is

in excretion, exhibit a spectacular ability to monitor, sustain, and the ensemble package of all such protoplasmic reactions, from

introduce alterations in the composition of ECF. Despite being only the moment of its emergence on earth to a gamut of environ-

1% of the body weight in humans, kidneys receive 20% of the cardiac mental stimuli received throughout the history of evolution. Being

output and contribute 10% to the entire oxygen consumption of the involved in the process of adaptation to an ever-changing envi-

body (Chevalier, 2017). In order to demonstrate such remarkable ronment, including varied habitats and ﬂuctuating food chains, as

feats, kidneys have emerged as one of the most perfused organs in an organ, kidneys have evolved drastically over epochs to support

vertebrates, especially in mammals, such as humans (Fig. 1), where life in its struggle to exist through uneasy geological vicissitudes,

the entire pool of blood is circulated multiple times daily through which at times, had been hostile. History of the earth as a stellar

them. body is anything but consistent, while it undergoes a circadian, and,

at times, unexpected catastrophic changes—as reﬂected in a con-

tinuous background level of extinction of terrestrial biomass with

∗ intercalated mass extinction events noted throughout the history

Corresponding author.

E-mail address: [email protected] (S. Bhattacharjee).

https://doi.org/10.1016/j.aanat.2020.151610

2 L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610

Fig. 1. (A) the human urinary system, (B) cross-section of a human kidney with its internal anatomy, and (C) structure of a typical mammalian nephron with a ﬁltering

mechanism.

of life on earth (Jablonski, 2001; McElwain and Punyasena, 2007; The objectives of this mini-review are: (i) to understand the

Carpenter and Bishop, 2009; Whiteside and Grice, 2016). discourse of renal evolution as a venture of sustaining life on this

With an estimated 10% of the global population now affected planet, and maintenance of an equilibrium of water, with dissolved

and millions of deaths registered each year, renal ailments, includ- solute, between the exterior and interior milieus of an animal body;

ing acute kidney injury (AKI), chronic kidney disease (CKD), and (ii) to examine the evolution of kidneys, from protovertebrates to

end-stage kidney disease (ESKD), are an ongoing pandemic (Kam mammals, with gradually increasing anatomical complexity; (iii)

Tao Li et al., 2013; Susantitaphong et al., 2013), while the crisis to assess how different geological vicissitudes, with intercalated

is aggravated further by the surge of hypertension and diabetes mass extinction events, has inﬂuenced the anatomy and develop-

cases in association to obesity. The Global Burden of Disease (GBD) ment of kidneys; (iv) to estimate the validity of concepts in renal

study conducted in 2015 by the World Health Organization (WHO) evolution, as formulated by Prof. Homer W. Smith, in the light of

reported a staggering 1.2 million deaths (Wetmore and Collins, current evidence, and scholastic arguments.

2016; Luyckx et al., 2018) and 19 million disability-adjusted life

years (DALYs) due to cardiovascular diseases caused by a com- 2. The troubled history of earth and evolution of life

promised glomerular ﬁltration rate (GFR). Even more worrying

news is that the mortality due to CKD recorded a 32% growth There remain plenty of gaps in the existing knowledge on the

from 2005–2015. Almost two million people, mostly from the USA, timeline of earth. Still, a widespread consensus is that the solar

Japan, Germany, Brazil, and Italy—are currently undergoing dialy- system was created almost 4.6 billion years ago from the condensa-

sis (Fig. 2). Such a spike in the number of patients suffering from tion of interstellar dust. Some of the superﬁcial rocks on earth were

renal diseases is causing a substantial ﬁnancial burden and human noted to be as old as 4.5 billion years, thus, comparable to the solar

suffering on a planetary scale. In the US only, the cost of treating system. Over many epochs, the composition of the earth, encased

CKD patients has already exceeded $48 billion per year (Damien within its spherical shape (Fig. 3A) and rich in varied landscapes

et al., 2016). Similarly, in the UK, the cost of providing health care with minerals often noticed as rocky lumps (Fig. 3B), has under-

to CKD patients is hefty, and more than the combined expendi- gone drastic reorganizations. Thus, the internal structure of the

ture of breast, lung, colon, and skin cancer cases (National Kidney earth is heterogeneous and displays layers of concentric spheres,

Foundation, Global facts). Given the clinical signiﬁcance of renal with heavier ones displaced more toward the core while the lighter

health, today, more than ever, a critical understanding of renal ones laid gradually on top of them. While moving from the surface

anatomy and physiology is necessary as our kidneys present with to core, terrestrial contents are roughly divided into the following

an embodiment of the struggle for survival and adaptation of life, layers (Boehler, 1996; Hawkesworth et al., 2017):

starting its journey as a simple protoplasmic mass to the complex

mammalian form that we now encounter.

(i) Crust: the thickness of 2–3 miles below the oceans, and 30–50

Published ﬁrst in the year 1953, the treatise: From Fish to Philoso-

miles beneath the continents.

pher; the story of our internal environment by famous American

(ii) Mantle: the overall thickness of ∼1800 miles with two distinct

physiologist, Prof. Homer W. Smith (1895–1962), based on the

layers: an outer basaltic layer and an inner layer of metal-

evolution of kidneys, is a cult classic within the community of phys-

lic oxides plus sulﬁdes. The continents, composed mainly of

iologists, zoologists and evolutionary biologists. With inimitable

granites, ﬂoat on the mantle as relatively lighter chunks.

lucid prose, the disquisition traced the evolution of kidneys—from

(iii) Core: a very dense layer composed mostly of heavy molten

archaic aquatic invertebrates to contemporary mammals—while

metals, such as iron and nickel.

correlating its ﬁndings to a series of environmental changes that

the planet had been through. The book is an indispensable the-

Unfortunately, such theories continue to rely on indirect exper-

sis for those who are interested in understanding kidneys as vital

imental evidence, such as the propagation velocities of seismic

organs, and even more importantly, as an archive of evolutionary

waves and, thus, leave room for interpretation and debate. More-

records (Smith, 1959).

over, the transition from the crust to the mantle is drastic, known as

L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610 3

Fig. 2. Cartoon showing: (A) the various renal pathologies, such as acute and chronic pyelonephritis, hydronephrosis, and glomerulonephritis, which are often the causes of

CKD or ESKD requiring (B) dialysis, or in certain cases, (C) biopsy, as performed by a Trucut biopsy needle.

Fig. 3. (A) Internal composition of the earth is arranged grossly in three concentric spheres, which from the surface to the core are: crust, mantle, and core, while various

terrestrial landscapes are provided as insets. (B) Various types of rocks, as clusters of minerals, are recovered from the crust of the earth and work as useful resources for

paleontological evidence, such as fossils.

the Mohoroviciˇ c´ discontinuity (Jarchow and Thompson, 1989; Cook distribution of granite in continental landmasses, the temperature

et al., 2010), or only Moho to the geologists, and eponymized after of the terrestrial surface had been less than the boiling point of

◦

the famed Croatian seismologist Andrija Mohoroviciˇ c´ (1857–1936). water, that is, 100 C (Santosh et al., 2017). The granite layer is less

It is established now that most of the time, and with heterogeneous flexible than semifluid or fluidic materials beneath it, which causes

4 L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610

Table 1

expansion, and at times, the ﬂow of molten materials under con-

Concentrations (mmol/L) of various electrolytes in the ECF of vertebrates compared

vection, causing an elevation of the superﬁcial basaltic layer into

to ocean water, while the sodium concentration is ﬁxed as 100 mmol/L (Schulte

mountainous landscapes. Initially, there was only one landmass,

et al., 2014).

the supercontinent, or Pangaea, which later was fragmented by a

Sodium Potassium Calcium Chloride

solar tide into different continental landmasses.

The mountain-building processes on earth, also known as oro- Ocean 100 2.17 2.19 116.4

Fish 100 1.95 1.87 89.6

genies (Gk. óros = mountains, genesis = creation), are closely related

Amphibia 100 3.03 1.74 91.6

to the evolution of life. Whenever there had been such phases of

Reptiles 100 4.14 2.22 68.5

mountain development, usually noticed at intervals of 30 million

Mammals 100 2.85 1.78 71.4

years, that is, Proterozoic (2500–541 Ma), Paleozoic (541–252 Ma),

Mesozoic (252–65 Ma), and Cenozoic (65 Ma–till now) eras, it left

longstanding evolutionary imprints. Newly formed mountains in of evolution and biodiversity on the planet signiﬁcantly with

some of these eras were rapidly eroded by multiple climatic factors, a disastrous effect for marine animals (Benton and Twitchett,

∼

such as wind, rain, and frost. At the same time, eroded materials, 2003; Benton, 2018). At the same time, 70% of the terres-

with subsequent collisions and friction, were gradually converted trial species, including the insects and mammal-like reptiles

into smaller pieces, while the debris was washed away to the seas (synapsids), became extinct (Shen et al., 2019).

by rivers and deposited as silt. (iv) Triassic–Jurassic (201 Ma): extinction of 23%, 48%, and 70%–75%

The weight of this massive layer of silt forced the basalt layer of all the families, genera, and species on earth, respectively,

beneath it to encroach below the lighter continental masses and with the extinction of most non-dinosaurian archosaurs, ther-

raise them higher than the sea levels. Such cyclical remodel- apsids, and large amphibia (Lucas and Tanner, 2015; Dunhill

ing of continental landmasses is continuing from antiquity—thus, et al., 2018). With little competition left, it rewarded dominance

climate change with periodic phases of mountain building and to the dinosaurs that continued for the next 135 Ma.

erosions have always been operational on this planet. Some of (v) Cretaceous–Paleogene (66 Ma): extinction of 17%, 50%, and 75%

the high mountains generated by such terrestrial upheavals have of all the families, genera, and species on earth, respectively,

disappeared entirely due to relentless erosion. However, some with the disappearance of all non-avian dinosaurs leaving space

have survived; for example, the Himalayas, Alps, and the Rocky for the mammals, and to a certain degree, birds, to dominate

Mountains were formed during the last Laramide (80–35 Ma) and that continues even today (Longrich et al., 2011; Witts et al.,

Cascadian orogenies. The times of terrestrial elevation were fol- 2018).

lowed by vast glaciation when the ice caps extended to the sea,

decreasing aquatic temperature temporarily and, thus, enticing Such extinction events, as per Prof. Smith, bear signiﬁcant rel-

marine animals to migrate and take refuge in warmer areas, such evance in the evolution of life as by the elimination of a dominant

as equatorial regions. species it provided an opportunity for new species to emerge and

On the contrary, at the times of low relief in terrestrial land- dominate. For example, by eliminating the dinosaurs from the

scapes, warm and saline oceanic water intruded into continental earth, the Cretaceous–Paleogene (66 Ma) mass extinction gave the

masses, paving ways for warm currents to spread inland—thus, mammals, including humans, an opportunity to dominate.

encouraging the migration of tropical species to even reach polar

regions now rich in vegetation due to the warmth introduced by 4. The emergence of protovertebrates

currents, in search of food. It can be stated that had there been no

such constant mountain-building processes or remodeling of the The provenance of life on this planet is still largely shrouded in

terrains, there is a high possibility that most, if not all, of the earth mystery. However, the consensus within evolutionary biologists is

would have been immersed in water. Thus, as per the theory of that the protoplasm was created in a marine environment almost

Prof. Smith, the urge to survive against environmental challenges 550 million years ago from dissolved minerals in seawater and cat-

would not have existed; and perhaps that would have also meant alyzed by the sunlight; thus ushering the Paleozoic (541–252 Ma)

a lack of biodiversity that we ﬁnd now with the absence of a large era, a watershed line in the history of earth marked by Charnian

variety of animals, including quadrupeds, birds, and warm-blooded revolution (Carney, 1999), also known as the Grand Canyon dis-

mammals. turbance. The primary ingredients of primitive protoplasm, that is,

carbon, hydrogen, nitrogen, sulfur, phosphorus, were imbibed from

the aquatic environment as the chemical composition of seawater,

3. The ﬁve major mass extinction events

along with its mineral content, has not changed much throughout

history (Table 1). The ﬁrst phases of evolution after the emergence

Current techniques have identiﬁed at least twenty extinction

of protoplasm remain obscure, partly due to the unavailability of

events with ﬁve major ones:

fossil records caused by the degradation of soft biological materials.

Most probably, the earliest forms of life, with or without

(i) Ordovician–Silurian (450–440 Ma): second largest of the ﬁve diversity, lacked typical prokaryotic or eukaryotic physiology

mass extinctions with the extinction of 27%, 57%, and 60%–70% characterized by dedicated mechanisms for respiration and

of all families, genera, and species on earth (Sheehan, 2001; metabolism. The Cambrian period (541–485 Ma), that is, the ﬁrst

Wang et al., 2019). of six periods of the Paleozoic era and succeeded by Ordovician

(ii) Late Devonian (375–360 Ma): extinction of 19%, 50%, and 70% of (485–444 Ma), Silurian (444–419 Ma), Devonian (419–359 Ma),

all the families, genera, and species on earth, respectively, that Carboniferous (359–299 Ma) and Permian (299–252 Ma) periods,

continued for ∼20 million years over multiple pulses (Sallan and showed unexpected ﬂourishment of biodiversity, known as Cam-

Coates, 2010; De Vleeschouwer et al., 2017; Carmichael et al., brian explosion (Valentine, 2002; Marshall, 2006; Zhang, 2014;

2019). Briggs, 2015; Zhuravlev and Wood, 2018), with abundant fossilized

(iii) Permian–Triassic (252 Ma): most signiﬁcant of the ﬁve mass evidence available to the delight of geologists and paleontologists.

extinctions—hence, also called the great dying, with the dis- It is intriguing that most animal phyla within marine inverte-

appearance of 57%, 83%, and 90%–96% of all families, genera, brates, that is, mollusks, coelenterates, ﬁshes, worms, arthropods,

and species on earth, respectively. It changed the discourse appeared during this period. The abundance of fossils from this

L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610 5

period and a striking void before it has bafﬂed paleontologists for the exterior. They thus have adapted relentlessly to gain control

long. It is argued that one of the signiﬁcant reasons to explain such over the complex chemistry of solutes and water (solvent) mov-

longevity of Cambrian fossils, or its absence before it, was the for- ing in and out of their bodies. Original forms of life that appeared

mation of robust chitin shells (Miller, 1991; Flannery et al., 2001; within the marine environment were simpler, often unicellular,

Bentov et al., 2016)—a nitrogenous polymer visible in crustaceans, and isotonic to marine water. Hence, they faced only limited dif-

but was absent in organisms before Cambrian period. fusion happening in or out of their bodies. Such archaic life-forms

Prof. Smith suggested an interesting theory to explain the emer- still imbibed some water with dissolved salt from the ingestion of

gence of such chitin-rich shells during the Cambrian explosion. It microscopic food, while most of the water was released back into

stated that the necessity of such robust shells emerged as a protec- the environment via pores, that is, celomostomes (Smith, 1947)

tive measure to newly evolved carnivores instigated by a shortage distributed symmetrically along the length of a ventrodorsally ﬂat-

of food due to a surge in numbers and diversity. In contrast, erst- tened body cavity (coelom), while the respiratory epithelia also

while invertebrates were soft, ﬂoating creatures vulnerable toward excreted part of the salt. It is worthwhile to note here that such

predators. The appearance of protective chitin shells also inspired celomostomes were also used as vents to release the gametes, that

the designing of custom-built apparatus, such as powerful jaws and is, sperm and ova, into the exterior—a fact which resulted in the

limbs, and augmented mobility due to elongated limbs formed by rivalry of shared anatomical afﬁliation between reproductive and

multiple adjoining smaller units—as seen in the eurypterids or the excretory systems that continues even today. Unfortunately, the

horse-shoe crab Limulus sp. Thus, mobility evolved as a crucial skill fate of such isosmotic creatures was reversed as they had to relo-

for survival. Such scavenger species became dominating and consti- cate back to fresh- or brackish-water environments as geography

tuted ∼60% of Cambrian biomass (Bambach, 1993; Schmitz, 2006; changed anew with a different challenge, and suddenly now the

Sperling et al., 2013). animal bodies were relatively hypertonic to its environment trig-

Another exciting component of Prof. Smith’s thesis is about the gering an inﬂux of water. Ostracoderms enjoyed an advantage over

emergence of invertebrate species, often with spindle-shaped, side- other life-forms due to natural body armor that resisted any inﬂux.

wise symmetrical and elongated bodies ﬂoating in freshwaters. An Still, especially in the creatures without shells, an urge was felt

argument put forward by Prof. Smith was that the characteristic toward developing an efﬁcient mechanism of losing excess water

invertebrate body shape and segmentation of musculature enabled that gained access into their bodies by diffusion. Initially, the mem-

rhythmic contractions conducive for swimming in unidirectional brane lining the celom and celomostomes was used to relinquish

water ﬂow, as found in the rivers, whereas water ﬂow in the sea is water into the environment via archaic nephric tubules. With grow-

uneven, and no creature with such a segmented musculature has ing complexity in anatomy, an organized nephric system gradually

ever evolved in a marine environment. Speculation here can be that evolved with a more compact structure known as the kidneys.

due to the continually changing landscapes and altering ratios of Unlike other abdominal organs, which develop in part from the

continental landmasses to seawater or even freshwater deposits, it endoderm, kidneys develop from mesoderm, the germ cell line

is likely that archaic invertebrates relocated into brackish or saline known to produce muscles.

water of estuaries or rivers. Hence, their evolution, especially the To ensure an adequate loss of water, Prof. Smith speculated that

morphology, was inﬂuenced by the dynamics of river water. If valid, perhaps nature arbitrated in favor of a water ﬁltration bed running

this migration marked an essential event in the evolution of life. on a pressure gradient to be an optimum and energy-efﬁcient way.

Such a chitin-rich exoskeleton also acted as a waterproof jacket for In contrast, the responsibility of exerting enough ﬁltration pressure

protovertebrates restricting the ﬂux of water, both in and out of was assigned to the heart. It gave rise to the glomerulus (glomus

their bodies. = ball), a tuft of capillary inserted into initial celomostomes, and

Moreover, such an armor made them massive creatures throughout evolution, was gradually pushed into the end of a tubule

dwelling into the depths of an aqueous ecosystem, groveling in to produce a more compact ﬁltration bed with a collection chamber

mud for food. The ostracoderm plates in such protovertebrates later (Bowman’s capsule). Thus, the archinephric ducts were formed. The

evolved into various useful structures, such as ﬁns in ﬁshes, and appearance of archinephric ducts provided a rationale for kidneys

the extremities from pectoral and pelvic ﬁns in tetrapods (Romer to be involved in a struggle for separation from the reproductive

and Williams, 1976; Janvier, 2010; Brazeau and Friedman, 2015). system, especially in the male gender, which continues even after

Some of these ostracoderm plates developed into teeth within jaws, 350 million years. The renal and reproductive systems are still

which themselves evolved from primitive gill arches. Such appear- interrelated in lower species. They continue to function as either

ance of teeth-bearing jaws provided a predatory advantage, which only renal system (e.g., hagﬁsh), only the reproductive system car-

in turn required sensory functions, for example, smell, hearing, and rying gametes (e.g., Australian lungﬁsh, frog), or a mix of both

vision, to anticipate the prey, and thus evolving into a developed, (e.g., shark, salamander). From reptiles onward, archinephric ducts

coordinated, and organized sensory center, that is, brain, in higher have preserved their reproductive function. Besides, the kidneys

vertebrates. have developed ureters, which as per Prof. Smith, explains why

the metanephric kidneys became positioned distant from testes in

the abdomen. In the female sex, this struggle for separation was

5. Kidneys for maintaining chemical balance and less intense, and ova were released into the abdominal cavity to be

producing hypertonic urine received by the oviducts.

Prof. Smith speculated further that emerging life-forms now

The emergence of vertebrates with complex anatomy and phys- faced another new obstacle, that is, loss of a large proportion

iology also warranted novel mechanisms to maintain the internal of useful soluble molecules and electrolytes (e.g., sodium, potas-

environment—a ﬂuidic construct to bathe organs and preserve sium, glucose, fructose, chloride, phosphate, sulfate, amino acid,

chemical equilibrium. The answer to such a complex challenge, vitamins) with the glomerular ﬁltrate. Kidneys developed a reab-

especially a way to maintain chemical equipoise throughout cat- sorption mechanism in the form of a loop of Henle and coupled it to

aclysmic environmental changes, ultimately culminated into an the glomeruli to restrict such losses. During evolution, the loop of

organ, the kidney. It is known that within an interface separating Henle also developed two distinct segments: a proximal convoluted

two different media, water moves by diffusion from hypotonic to tubule (PCT) involved primarily with the reabsorption of water

the hypertonic compartment (solvent follows the solute). Life-forms and solute, and a distal convoluted tubule (DCT) to secrete acid

have always tried to equilibrate their interior environments with (H ) and, thus, maintain acid-base balance. In some vertebrates,

6 L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610

the PCT and DCT are separated by a short and narrow intermediate process of laying eggs also evolved within the animal kingdom,

segment, rich in ciliated cells, to propel the ﬁltrate. Such a ﬁltration- where eggs encased within a brittle shell permeable to oxygen,

reabsorption mechanism might appear counterintuitive given the contained enough ﬂuid with optimized chemistry and nutrition,

fact that nature had to invent a new process, that is, reabsorption, provided an artiﬁcial sanctuary for the offsprings before they devel-

to retain >99% of ﬁltered water (with dissolved substances) in an oped into adulthood (Romer, 1957; Reisz, 1997). Unfortunately,

urge to curb the repercussions of its innovation, that is, ﬁltration; fossil-based evidence, particularly from the Devonian era (419–359

with a signiﬁcant workload now assigned to heart. Ma) when the amphibia most probably evolved, are scarce and

inadequate for a thorough evaluation. However, the available evi-

dence points out that by Permian era (299–252 Ma), amphibia were

6. Renal portal system

a prominent class with adaptations to survive, although the num-

bers started declining from the Mesozoic era (252–65 Ma), most

It is a venous portal system present in all vertebrates except

probably due to competition from the reptiles equipped with supe-

mammals, hagﬁsh, and lampreys, where glomerular ﬁltration is

rior survival skills (Roelants et al., 2007). In fact, from the Triassic

either absent or undermined due to a reduced GFR and maintains

period (252–201 Ma), the ﬁrst and shortest period of the Mesozoic

parallel blood ﬂow to convoluted tubules (Holz et al., 1997, 1999).

era, merely two signiﬁcant orders of amphibia survived: Anura, that

Anatomically, the renal portal veins are formed by the fusion of two

is, without a tail, as found in frogs; and Urodeles, that is, with tail,

posterior cardinal veins, or its analogs, draining the dorsal torso, tail

as in salamanders (Zardoya and Meyer, 2001). Amphibian kidneys

muscles, and inguinal regions, into the kidneys. They supply the

are glomerular and have low GFR to decrease ﬁltrate under arid

tubules, merge with renal veins, and drain into caudal vena cava.

conditions, with an additional mechanism of permeation via skin

It provides with an additional supply of blood to kidneys that are

to deal with an excess or scarcity of water, both these mechanisms

unable to produce hypertonic urine due to a lack of loops, such as

inﬂuenced by the pituitary gland (Jo and Harris, 1995; Hasegawa

in amphibia and reptiles, where the GFR is often downregulated by

et al., 2003; Ogushi et al., 2010).

the arginine-vasotocin (AVT) hormone (Dunham and Wilczynski,

Interestingly, the pituitary gland is present in all vertebrates,

2014; Wilczynski et al., 2017); thereby preventing the occurrence

while in lower ones, it is connected by nerves of the pineal gland,

of acute tubular necrosis (ATN). In mammals, the renal portal sys-

often termed as the third eye, and is associated with the pho-

tem is absent, while the tuft of afferent renal arteriole branches

toreceptors to regulate light-based physiologic (e.g., diurnal) or

further to supply tubules. However, the renal portal system can still

seasonal variations (Minneman and Wurtman, 1976; Borjigin et al.,

be noticed as the pampiniform plexus—a rich venous plexus around

1999; Maronde and Stehle, 2007). It is degenerated in most of the

the spermatic cord known to cause varicocele.

amphibia now, although it has evolved into the pineal gland in

mammals, including humans. The pituitary gland secretes antid-

7. The adaptation of glomerular kidneys iuretic hormone (ADH), which stimulates reabsorption of water

from convoluted tubules to minimize urinary output under arid-

7.1. Amphibia ity. Additionally, under dry conditions, the glomerular arteriole

undergoes vasoconstriction, further decreasing the GFR, while the

The evolution of amphibia was mired with the dilemma of renal portal system maintains just enough blood supply to ensure

choosing land or water as a primary habitat; thus, amphibian phys- the viability of tubular cells. Amphibian skin also contributes to

iology has adapted to survive under dry conditions, although only maintaining the homeostasis by losing or gaining water, mostly by

for short spans, just enough to reach the next aqueous habitat. passive diffusion, via the dermal pores that vary in size depending

Prof. Smith argued that the emergence of amphibia occurred in the on the environment, and are not controlled by the pituitary gland

Devonian (459–359 Ma) era characterized by widespread aridity (Dainty and House, 1966). Amphibian species can experience either

that forced some aquatic ﬁshes toward air-breathing (Romer, 1956; loss or gain of a considerable amount of water under desiccation or

Long and Gordon, 2004; George and Blieck, 2011). However, a more moist conditions within short periods, so much so that some Aus-

visible presence of the amphibia could be noticed in the Carbonifer- tralian aboriginal tribes still use water-loaded frogs as a source of

ous (359–299 Ma) era that experienced Acadian disturbance giving water. Apart from water, sodium ions (and not potassium, calcium,

rise to the Appalachian Mountains (Murphy and Keppie, 2005). or ammonia) are also absorbed via these pores.

Such cataclysmic geological events gave rise to new terrains where

the seabed was elevated to form mountains, while at times, the 7.2. Reptiles and birds

high-altitude areas merged into oceans. The climate, especially in

Europe and North America, which existed as a single continent then, The transition of the Pennsylvanian (324–299 Ma) to Permian

◦

was warm and humid, with average temperatures ∼20 C higher (299–252 Ma) period experienced a new upheaval, the Appalachian

than now. Changing of the continental landscape also caused an revolution, with considerable changes in global climate. The Per-

increase of vegetation in arctic regions, heavy showers across con- mian period experienced a drastic decrease in global temperature

tinents, and higher oxygen content in the atmosphere (Feulner, and the spread of deserts; thus, a cold arid climate gripped over

2017). There was an explosive growth in the insect population, the planet with a signiﬁcant fraction of landmasses now covered

some of them quite substantial in size due to the abundant oxygen in glaciers. Such cooling effect also invited different challenges

in the atmosphere (Dudley, 1998; Harrison et al., 2010), offering a for the amphibia on two fronts: hunt for food while resources

coveted resource for food that enticed some piscine life-forms to were shrinking and to survive under cold arid climate. Such chal-

migrate into the land—a transformation that took 50–100 million lenges were magniﬁed even more for the offsprings who were not

years and required multiple adaptations, such as the conversion of ready yet to handle such an extreme climate. Additionally, unlike

the pectoral and pelvic arches to extremities, strengthening of ver- ﬁshes, the amphibia laid a much lesser number of eggs. At the

tebral column enabling it to lift the torso, reconstruction of aortic same time, the offsprings required an aqueous environment at

arches, and the emergence of compartmentalized heart as the lungs the initial stages of their lives before developing proper amphib-

gradually replaced gills as the major respiratory organ. ian traits. In reptiles, birds, and mammals, that is, amniotes—the

The amphibian physiology, particularly its mechanisms to bal- eggs contained enough ﬂuid and nutrition reserve packed within

ance water while continually shifting habitats between land and three layers of membranes: amnion to provide an aqueous envi-

water are intriguing. Perhaps with the emergence of amphibia, the ronment for the embryo; allantois that connects to the embryonic

L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610 7

kidneys and acts as a reservoir for urine; and chorion that covered deprived areas can produce urine 2.0–2.5× concentrated than

the internal surface of shells. Fossilized evidence of the Jurassic plasma, whereas, for mammals, it can often go up to 5–10× . Some

ichthyosaurs demonstrated that ovoviviparity evolved already in mammals, such as Australian Hopping Mouse (Notomys alexis), liv-

reptiles by then (Shine, 1983), and continues to be noted in some ing under arid conditions, are even able to produce 30× more

species, such as rattlesnakes. Perhaps the warm-bloodedness, that concentrated urine than plasma (Braun, 1998). However, it is worth

is, homeothermia (homoios = like, therme = heat), appeared in birds noting here that mammals and birds react differently toward

and mammals as a survival mechanism while being exposed to water-deprivation. For example, the plasma osmolality in humans

∼

long spells of cold climate. In contrast, the reptiles remained cold- ( 300 mOsm/kg water) varies little with water-deprivation—thus,

blooded, that is, poikilothermic (poikilos = multicolored, therme = the U/Posm (urine-to-plasma osmolality) ratio can increase signiﬁ-

heat). cantly; whereas in the case of reptiles and birds, the osmolality of

More adaptations were deemed necessary to enable the adult both urine and plasma increases under dehydration, reptiles more

animals to cope with climatic challenges and deprivation of water. than birds, which can underestimate increase of U/Posm. While fac-

Hence, the permeable skin of amphibia was replaced by a thick ing water-deprivation, in birds with salt glands, when osmolality of

impermeable hide, from snout to tail, characterized by scales, urine reaches 400–450 mOsm/kg water, oliguria sets in while salt

scutes, or plates developed from a corniﬁed epidermis. However, glands start secreting more salt-rich ﬂuid under parasympathetic

such waterprooﬁng of the body required kidneys to take over as the control (Bindslev and Skadhauge, 1971; Harvey and Phillips, 1982).

sole organ of ensuring water balance. Reptiles also overhauled their Many reptiles, such as lizards, snakes, and tortoises, have similar

metabolic pathways to preserve water. Thus, instead of urea, the salt glands that participate in maintaining homeostasis under dry

signiﬁcant excretory nitrogenous metabolic waste in amphibia and conditions.

mammals; uric acid evolved as the major metabolic waste, and uri- Furthermore, unlike mammals, the signiﬁcant nitrogenous

cotelic behavior (Dantzler and Braun, 1980; Schmidt-Nielsen, 1988) metabolic waste in reptiles and birds, that is, uric acid, contributes

appeared, although a tiny amount of uric acid is also produced in little to urine osmolality. Apart from the structure of nephron,

mammals from the metabolism of nucleoproteins. The solubility of with or without loops, the osmotic gradient present between

◦

uric acid (∼60 mg/L at 20 C) is much less than urea (∼1080 g/L at 20 cortico-medullary junctions and medullary tips also determines the

◦

C) and carries twice more nitrogen per molecule; thus, osmotically capacity to concentrate urine. This gradient in mammals is deter-

requires only half the water than urea for an equivalent amount of mined by both sodium chloride and water (with trace amounts of

metabolized protein. urea), whereas it is only sodium chloride for birds. Another intrigu-

Additionally, uric acid, although less soluble, can produce ing point is the continuous pattern of avian CDs, where smaller

supersaturated, protein-rich, colloidal suspensions of 0.5–15 ␮m ducts fuse to form larger ones and ﬁnally end up as ureters, unlike

spherical particles (65% uric acid) in water, and subsequently pre- mammalian kidneys, where the CDs are discontinuous and termi-

cipitates as amorphous microscopic crystals that may accumulate nate in a large pore at tips of renal papillae. Reptilian kidneys, on the

and cause gout. The higher protein content of avian and reptilian other hand, are segmented and exhibit species variation. For exam-

urine ensures the stability of the colloidal suspension and, thus, ple, snakes (Ophidians) have bilateral, long, and narrow kidneys

both birds and reptiles pass up to 5 mg/L protein per day in the with the nephrons folded on itself for three times while traversing

urine. In contrast, mammals, including humans, pass very little or the entire thickness of lobules (Dantzler and Braun, 1980); whereas

none. The reptiles and birds utilize this uric acid and deposit it as the tetrapods (e.g., alligators, lizards, tortoises) have oval, ﬂattened

highly concentrated (as high as 21% in chickens) suspension in the and compact kidneys while their nephrons show ophidian folding,

cloaca, where uric acid is precipitated and defecated after that as although traversing only half of the full thickness of lobules (Davis

a white paste while the remaining water is reabsorbed back into et al., 1976). The CD in reptiles also merges at a right angle to the

the rectum by reverse peristalsis (Brummermann and Braun, 1995). ureter.

The ﬂux of water across rectal epithelia, unlike renal tubules, occurs

along an isosmotic, or slightly hyperosmotic (∼100 mOsm higher 7.3. Mammals

than blood plasma) gradient. Another adaptation as a response to

water deprivation was an intentional undermining of the glomeru- One unusual evolutionary mechanism in mammals against

lar apparatus to restrict water ﬁltration; although, reptilian and the cold arid Permian climate, apart from covering their bod-

avian kidneys are not strictly aglomerular. Prof. Smith anticipated ies in a heat-proof layer of hair similar to feathers in birds, is

that the presence of such rudimentary glomeruli ensured excretion homeothermia or warm-bloodedness (Crompton et al., 1978), as

of salts, such as sodium chloride, which the renal tubules in reptiles also visible in birds. Due to a lack of fossilized evidence, it is dif-

and birds were unable to secrete. However, a small fraction of salt ﬁcult to ascertain when such warm-blooded mammals and birds

was also excreted by salt glands when present. These rudimentary appeared. Moreover, neither feathers nor body hair was preserved

glomeruli might be there to provide just enough ﬂow of water to in fossils for further investigation. The earliest avian fossils, that

wash out the insoluble uric acid from tubules. is, Archaeopteryx and Archaeornis, are speculated to be warm-

The avian kidneys are intriguing as microscopically they rep- blooded creatures. Archaeopteryx, termed the “original bird” or

resent a hybrid between reptilian and mammalian kidneys with “ﬁrst bird” to highlight its transitional form between dinosaurs and

70%–90% of the nephrons without a loop of Henle; that is, birds, is often debated regarding how much of an avian species

are reptilian and located mostly in renal cortices; whereas, the it was (Cracraft, 1977). The Archaeopteryx was indeed covered

mammalian-type nephrons (10%–30%) have loops and are nested in feathers, and despite having lizard-like vertebrae or forelimbs

in renal medulla (Johnson and Mugaas, 1970; Braun and Dantzler, with claws and reptilian jaws, its hindlimbs were certainly adapted

1972; Braun and Reimer, 1988; Goldstein and Braun, 1989). The toward an avian life. If the creature was warm-blooded, it meant

reptilian, that is, loop-less nephrons enter medulla and drain that such homeothermic traits appeared already at an early Juras-

into collecting ducts (CDs) of mammalian-type, that is, looped sic (201–145 Ma), or even at a late Triassic (252–201 Ma) period. It

nephrons, thus leaving an isosmotic, or even hyposmotic urine is worth noting here that except for the similarity to mammals in

for further processing by countercurrent multiplication system being warm-blooded, birds have remained mainly related to rep-

(Dantzler et al., 2014). Apart from mammals, birds are the only tiles, particularly in physiological traits. Warm-bloodedness has

animals capable of producing concentrated urine, although the undoubtedly provided the mammals with evolutionary leverage

concentrating ability is reduced. Thus, birds from the water- while surviving cold, dry climate, which resonated well with the

8 L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610

emerging dominance of mammals from the Cenozoic (65 Ma–till as elephants or whales, have nephrons of comparable length to

now) era, often termed as “recent times.” Thus, the mammals had smaller mammals. What is intriguing in larger mammals is that

to wait for almost 100 million years, and a less understood dis- the nephrons, although similar in length to smaller mammals, are

appearance of mighty dinosaurs, to grab such an opportunity. Prof. more in number, and the number of nephrons does increase allo-

Smith speculated that warm-bloodedness helped the mammals not metrically with body weight. However, the nephrons are organized

only in acquiring better survival skills under freezing climate, but differently in kidneys. An explanation for such observation can be

also enhanced their capability to produce most concentrated urine the physics of ultraﬁltration at glomeruli, where the net pressure

∼

in the entire animal kingdom—a feat achieved by following two ( 10 mm Hg) of two opposing forces, that is, systolic pressure

mechanisms: favoring ﬁltration and colloid hydrostatic pressure exerted by the

proteins present in blood opposing it, determine the ultimate GFR.

(i) Remodeling of the tubules: the narrow segment between PCT and Thus, there is a limit to the permissible length of nephrons, depend-

DCT, rich in ciliated cells and visible in amphibia, was remod- ing on the cumulative frictional force exerted by it on the ﬂow

eled into a long, thin, and non-ciliated aqueduct; thus, instead of ﬂuid. Larger mammals have thus negotiated a compromise by

of only PCT and DCT, mammalian renal tubules exhibit three acquiring more nephrons, but of smaller lengths, and packed dis-

segments: proximal, thin and distal to form the characteristic tinctly within kidneys.

loop of Henle.

(ii) Disappearance of the renal portal system: the mammalian renal

8. A brief overview of molecular events during renal

portal system regressed due to stabilization of glomerular ﬁl-

development

tration under a relatively high systolic pressure caused by

warm-bloodedness which, unlike the amphibia and reptiles,

The development of metanephric kidneys emerges out of a

obviated the need of back-up blood supply in the form of renal

chain of interactions between mesenchyme and epithelial con-

portal system to counter a reduced ﬁltration pressure.

structs inﬂuenced by cell signaling pathways, and branching

of the primitive ureteric bud (UB), derived from embryonic

Human kidneys harbor a million nephrons, each with a com-

2 mesonephric/Wolfﬁan duct, into the renal matrix (Hyink and

bined ﬁltration bed of 0.76 m surface area, while the amount of

3 Abrahamson, 1995; Obara-Ishihara et al., 1999), also known as

glomerular ﬁltrate is ∼125 cm /min or ∼180 L/d. To sustain such a

3 the metanephric mesenchyme (MM). The interactions between UB

high ﬁltration rate, nearly 1200 cm /min, that is, ∼1700 L of blood

and MM, both derived from intermediate mesoderm (IM) spaced

is ﬁltered daily by the kidneys along with ∼1.1 kg sodium chlo-

between embryonic lateral and paraxial mesoderms, have attracted

ride dissolved in it. However, 95% of this ﬁltered salt is reabsorbed

attention. It is known that the UB invades MM, and once able

back, leaving only 5–10 g for urinary excretion. Similarly, ∼99% of

to intrude it, starts branching in a coordinated fashion to initiate

the ﬁltered sodium bicarbonate and glucose are also reabsorbed.

the process of nephrogenesis (Fig. 5). The expression of Pax-2 and

Experimental data suggest that ∼85% of the sodium chloride, along

Sim-1 genes, induced by bone morphogenetic protein-4 (BMP-4),

with available water thereof, is reabsorbed in PCT. In the presence

is essential for the formation of mesonephric/Wolfﬁan duct due

of ADH, sodium chloride is reabsorbed in the thin segment and

to a mesenchymal-epithelial (MET) transition (Saxén and Sariola,

increases the osmolality of interstitial ﬂuid. Thus, osmotically free

1987). It leads to the formation of nephrogenic cords (Torres et al.,

water is reabsorbed by passive diffusion across epithelia of the thin

1995) in association to the expression of multiple transcription fac-

segment as well as DCT and CD; hence, oliguria ensues in case of

tors (e.g., WT1, Osr1, Eya1, Six1, Sall1, Hoxc11, Hoxa11, and Hoxd11)

dehydration, and vice versa.

as renal development progresses via pronephric, mesonephric and

metanephric phases (Fig. 5B; Costantini and Kopan, 2010). The

7.3.1. Mammalian kidneys: overall morphology

growth of UB is triggered by secretion of glial cell-derived neu-

Morphology of mammalian kidneys displays wide variation

rotrophic factor (GDNF) from MM (Reidy and Rosenblum, 2009)

across the spectrum of species, although a unipapillate bean-

and the resulting activation of Gfr␣1/Ret receptors; thus, the Ret-

shaped kidney remains the prototype, especially in mammals

positive cells in mesonephric/Wolfﬁan ducts start developing, and

with a weight of <5 kg. However, such standard architecture of

visible as swelling in mouse embryos on an embryonic day (E)

mammalian kidney varies, and following four dominant renal mor-

10–10.5 (Meyer et al., 2004). At E11, the swelling, appearing more

phologies have evolved with a gradual increase in renal size (Fig. 4;

like a bud now with a lumen encased in the basement membrane

Braun, 1998):

(Chi et al., 2009), follows the GDNF signal and reach MM. Depend-

ing on the patterns of gene expression, UB differentiates into two

(i) Unipapillate bean-shaped: found typically in the smaller mam-

distinct regions: CD develops from the distal end, while ureter and

mals, and characterized by fused cortex and medulla, e.g., cats

renal pelvis from its trunk (Shakya et al., 2005). The following sig-

and dogs.

naling cascades are involved in nephrogenesis:

(ii) Crest shaped: found in larger mammals, and although the

medulla is undivided, it has a decreased depth and increased

anteroposterior dimension, e.g., larger dogs and cats, camels, (i) Wnt: these glycoproteins play a crucial role in renal develop-

wildebeests. ment (Kispert et al., 1996, 1998; Lin et al., 2001; Carroll et al.,

(iii) Compound multireniculate: the medulla is divided into mul- 2005), and are expressed both in UB (Wnt5a, Wnt5b, Wnt6,

tiple pyramids, although cortex remains fused, e.g., humans, Wnt9b, Wnt11) and MM (Wnt2b, Wnt4, Wnt5a). Notably, the

elephants, bears, rhinoceros, bison, and cattle. Wnt4, expressed in MM and both comma- and S-shaped bod-

(iv) Discrete multireniculate: the largest of kidneys, while both the ies of renal vesicles, plays a signiﬁcant role (Stark et al., 1994).

cortex and medulla are segmented, and found in marine mam- The expression of Wnt7b, from E13.5 onward in the epithe-

mals, e.g., seals and whales. lium of CD, establishes a renal cortico-medullary axis, along

which nephrons and CDs are oriented in developed kidneys (Yu

A study into the relationship between the length of nephrons et al., 2002, 2009); while the Wnt9b is known to participate in

and mammalian body mass delivered intriguing facts (Greenwald, nephrogenesis. The Wnt5a plays a crucial part in nephrogen-

1989). For example, it was noted that the length of nephrons did not esis, and its absence causes diseases, including renal cancers

increase allometrically with body weight. Larger mammals, such (Li et al., 2013; Nishita et al., 2014; Yun et al., 2014). Both

L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610 9

Fig. 4. The species variation in mammalian kidneys: (A) equine with heart-shaped right and near bean-shaped left kidneys, (B) bovine kidneys with lobulated cortex but

fused medulla, and, (C) canine bean-shaped kidneys with fused cortex and medulla.

Wnt7b and Wnt9b are involved in ensuring adequate cell pro- although the trunk continues elongating further to form papilla,

liferation with proper orientation of the mitotic spindles and medulla, and CD (Pepicelli et al., 1997; Mikels and Nusse, 2006;

act via a non-canonical WNT/PCP pathway (Fig. 6; Dudley and Michael et al., 2007). The patterns of gene expression at tips and

Robertson, 1997; Takada et al., 2006). Additionally, the Wnt7b, trunks of UB vary depending on the phase of growth. Further signals

in association with Hgf, Egf, and laminin, is essential for the from the progenitor/stem cells at UB-tips induce MET in surround-

survival of cells in CD (Kreidberg et al., 1996; Liu et al., 2009). ing cap mesenchyme by triggering the formation of pre-tubular

(ii) GDNF/Ret: these are important for the development of UB and aggregates (PTAs) at close vicinity of tips, whereas the MM at a dis-

its branching (Sweeney et al., 2008; Zhang et al., 2009; Chi tance from tips remains largely undifferentiated (Saburi et al., 2008;

et al., 2011), while Ret signals receive feedback from various Georgas et al., 2009). The progenitor cells are known to stimulate

pathways, e.g., ERK MAP kinase, PI3K, PLC␥ (Watanabe and various pathways (e.g., Eya1, Hox11, Osr1, Pax2, WT1) and induce

Costantini, 2004; Ihermann-Hella et al., 2014). Additionally, MET, whereas genes like Six2 and Sall1 help to replenish progenitor

GDNF/Ret signaling also upregulates the expression of speciﬁc cells and sustain growth (Wellik et al., 2002; James et al., 2006; Self

genes at tips of UB, e.g., Ertv4, Etv5, Met, Mmp1, and Wnt11 et al., 2006; Park et al., 2012; Basta et al., 2014). Further activation

(Basson et al., 2005; Lu et al., 2009). of Wnt9b from the UB stimulates PTAs to differentiate further and

(iii) Fibroblast growth factor (FGF): the FGF receptors (Fgfr1 and gradually form renal vesicles after passing through comma (,) and

Fgfr2) are expressed in MM and UB of mouse embryos on E10.5 S-shaped stages (Fig. 7) due to polarization (inﬂuenced by Notch2

and 11.5, respectively (Okazawa et al., 2015); and are essential signaling forming the podocytes and proximal tubules, while LIM

for the expression of Pax2, Six2, and Sall1 at later stages of renal homeobox 1/Lhx1 gene dictates the development of distal tubules)

development. and elongation (Kobayashi et al., 2005). S-shaped renal vesicles

(iv) Miscellaneous: The Six1, a homeobox protein expressed in MM, then fuse with UB-tips to form nephrons followed by the forma-

participates at the early stages of renal development, while tion of PCTs, DCTs, CDs, and loops of Henle (regulated by Pou3f3

Sall1, a multi-zinc ﬁnger transcription factor and expressed in gene). The Bmp7 is later expressed at progenitor cells, both within

MM from E10.5 onward, works in coordination with Six1 (Xu UB and cap mesenchyme, while most of the following nephroge-

et al., 2003). nesis happens in Six2-positive cells. Furthermore, proximal ends

of developing nephrons are vascularized to form glomerulus under

the guidance of Foxc2 and Vegfa that recruit angioblasts from neigh-

Approximately 350–400 tips are generated (E11.5–E15.5) after

boring mesenchyme to form capillaries (Eremina et al., 2003, 2007)

nine such branching cycles of UB, where the ﬁrst branching is a

with further inputs from Bmp4 in podocytes and PdgfB/Pdgfrb path-

bifurcation followed by a trifurcation at one of the previous two

ways (Lindahl et al., 1998).

tips; while the remaining branching progresses through bifurca-

tion after that (Majumdar et al., 2003; Cebrián et al., 2004; Short

et al., 2010). The cells located at UB-tips are highly proliferative and 9. The theory of recapitulation in renal evolution

facilitate the growth of UB-trunks. However, cells at the UB-tips

remain mostly undifferentiated, while the ones at UB trunks differ- It is undeniable that many mammalian kidneys demonstrate

entiate to form CDs. The extracellular matrix (ECM), particularly the successive stages of its evolutionary history, aligning to its aquatic

integrin, laminin, and collagen proteins in it with their expression origin. However, on scrutiny, it can be stated that although it is

regulated by genes, such as Lamc1 for laminin, provide robust sup- true in general, such a notion falters in explaining much of the del-

port for nephrogenesis and offer a conducive microenvironment for icate and minute adaptive changes in kidneys. Thus, the theory of

cellular proliferation (Müller et al., 1997; Smyth et al., 1999; Yang recapitulation, that is, “Ontogeny recapitulates phylogeny,” (bio-

et al., 2011). The rate of branching at tips of UB falls after E15.5, genetic law), coined by Ernst Haeckel (Haeckel, 1868, 1876) based

10 L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610

Fig. 5. (A) Cartoon showing the presence and role of different genes, such as Wilm’s tumor 1 (WT1), Sall1, Pax2, Six2, and Hoxd11 to ensure survival and renewal of MM. The

BMP4 and BMP7 induce apoptosis and differentiation of MM, respectively, via the BMP-pSMAD pathway. The WT1 exerts inﬂuence on the BMP-pSMAD pathway by regulating

its inhibitor, that is, BMP binding endothelial regulator (Bmper) gene, and activation of FGF pathways through Fgf20/Fgf16 and Gas1 expression. (B) Scheme showing the

different events in nephrogenesis, both within UB and MM, while marking the genes associated with them within oval shapes.

on the Meckel-Serres law deduced by Étienne Serres and Johann development is inﬂuenced by many cues, both environmental and

Meckel (Meckel and Serres, 1827) with further critical evaluation genetic, that ﬁnally shape adult animals. For example, the number

by Paul Pirlot (Pirlot, 1969) and Alfred Romer (Romer, 1962, 1968) of nephrons in humans at birth is roughly similar, although, with

in the 20th century, is over-simplistic and fails to recognize the further development and age, it varies. Even in the same human,

complexity of evolution or its multidimensionality. Moreover, the the nephrons differ from each other.

theory of recapitulation already faced staunch criticism after its Similarly, in marine teleosts, nephrons have devised novel

publication by contemporaries of Haeckel, such as Karl Ernst von adaptations to restrict the efﬂux of water and sodium, such as a

Baer (von Baer, 1828), Wilhelm His Sr. (Murray and Turner, 2014), reduction in the number of glomeruli and secretion of solutes (e.g.,

2+ 2+ 2−

and Frans Julius Keibel (Keibel, 1897). It is known that embryonic Mg , Ca , SO4 ) with novel molecular mechanisms to survive in

a hyperosmotic environment. Thus, realistically it is improbable for

L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610 11

Fig. 6. Scheme providing an overview of the Wnt signaling pathways. (A) In the absence of bound Wnt, ␤-catenin (B-cat) is degraded due to phosphorylation by GSK3␤.

(B) In canonical signaling, binding of Wnt with its receptors Fz and LRP induces accumulation of ␤-catenin into cellular cytoplasm before translocating into the nucleus and

activate transcription of Wnt target genes with support of TCF/LEF cofactors. (C) In the planar cell polarity (PCP) pathway, Rho, Rac, and Cdc42 located downstream to Dsh

rearrange the actin cytoskeleton and establish cellular polarity.

Fig. 7. Cartoon showing various cellular events resulting in nephrogenesis.

an embryo to depict all such changes within a short developmen- we might never know enough about it. Thus, it is irrational to the-

tal span. The embryo, in its nascent stages, exhibits some general orize the recapitulation of an unknown and highly complex chain

features, which can hint toward at least some of its evolutionary of events. It is also unclear why remnants of ancestral structures

stages. However, at later phases, the development follows its trajec- keep reappearing even after millions of years without an appar-

tory as inﬂuenced, and to a certain extent, determined by different ent evolutionary advantage. Various theories have been proposed

environmental and genetic factors. Various developmental stages to explain this conundrum, although none of them has succeeded

of the mammalian kidney indeed give us an idea of the different in convincing the critics with robust evidence. Modern techniques

phases of evolution with subtle hints toward its struggle to cope have enabled video recording of even minute details of embryolog-

with the changing chemistry of the exterior in ways of striking a ical development in different species and conclusively rejected any

balance between gained and lost water. Still, plenty of delicate ﬁnd- such recapitulation of phylogenetic stages. Finally, the embryonic

ings in renal evolution, particularly in internal anatomy, remain drawings based on which Ernst Haeckel formulated his biogenetic

unchecked and emerge at later stages of development with traces law were later found to be misleading, simplistic, at times manipu-

lost in the discourse of development, thus recapitulated neither by lative, and more ﬁction than fact. Thus, the validity of recapitulation

embryos nor by kidneys. theory, while analyzing the evolutionary impact on morphology

Visible phases of ontogeny present with a superﬁcial and and organogenesis, remains unestablished.

simplistic representation of the developmental phases and do

not depict the complexity of vertebrate development, including 10. The validity of Prof. Homer Smith’s theory

organogenesis. Therefore, an external similarity of embryos cannot

be extrapolated toward a recapitulation of all phylogenetic stages, The concepts laid by Prof. Homer Smith provided an excel-

which, to begin with, is already quite uncertain, convoluted, while lent thesis toward understanding renal evolution or anticipate

12 L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610

evolutionary urges that shaped kidneys. The importance of such However, researchers like Robert W. Grifﬁth (Grifﬁth, 1987) has

concepts, such as sustenance of water-solute balance with the exte- proposed an anadromous origin of vertebrates, a sort of middle-

rior, toward understanding structural and functional attributes of ground between the limnic and marine origin theories, based on

the kidney is undeniable, and it did offer an inclusive vantage to following arguments (and assumptions): (i) the marine protochor-

various stages of renal development. However, the views of Prof. date ancestors of vertebrates visited brackish waters of estuaries

Smith also suffered from an over-simpliﬁcation of facts. It failed to during Cambrian explosion in search of food, which in turn required

recognize the contributions made by multiple other factors in renal ultraﬁltration of water that ultimately culminated into glomeruli

evolution, for example, genetic ones, which are an indisputable and mechanisms to preserve ions like sodium; (ii) the ancestral

component not only in renal development but are equally impor- vertebrates slowly migrated toward freshwater for reproduction

tant from a pathological point-of-view. An in-depth understanding as it provided a more safe environment, with less predators and

of genes and how they work in organogenesis was rudimentary in competitors, for vulnerable larvae; (iii) due to lack of food in fresh-

the 1950s, which might have contributed to such lapses. water, the migrated protovertebrates survived in meager amounts

Additionally, our understanding of biodiversity and how differ- of food—a trait noticed even today for the lampreys, and few other

ent life-forms have evolved in synchrony, and often as a response teleosts; (iv) the evolution of vascular spongy bones in ﬁshes is

to cope with successive cycles of climatic changes, continues to be a testimony of such anadromy exercised by ancestral vertebrates,

inadequate. It is difﬁcult, if not impossible, to retrace evolutionary and acted as a vital resource of calcium, phosphoprotein, and other

pathways over hundreds of millions of years across the astounding minerals, both for a protovertebrate leaving upstream for spawn-

speciation. The terrestrial topography, land-to-mass ratios, con- ing while on little food, and developing embryo; (v) anadromy

tinental landscape, and planetary ﬂora-and-fauna have changed required the protovertebrates to develop senses of vision, olfac-

drastically over millions of years. Naturally, the challenges faced tion, ability to detect electric current, magnetic ﬁeld and location to

by life-forms and resources available to them have also remod- facilitate swimming upstream, while a coordination of such senses

eled heavily over such periods. It is still unclear how to deal with ultimately resulted in the evolution of brain.

such an immense amount of data, which, to begin with, is already Finally, scientists who support the origin of the protovertebrates

quite challenging to gather, identify and quantify, or interpolate in estuarine brackish water, such as Hans Ditrich (Ditrich, 2007),

the environmental factors into mathematical terms—and that too place the following evidence: (i) ammonia—the major nitrogenous

with overwhelming biodiversity that exists today. The in silico tools waster product in both aquatic vertebrates and invertebrates—is

provide a new resource, although such emerging analytic suites highly water-soluble and diffuses freely through epithelial sur-

are still at nascent stages and need plenty of improvement before faces; thus, there is no need for a separate organ like kidney

dealing with such hyperdimensional datasets. The views of Prof. to evolve in vertebrates and excrete it; (ii) the major function

Smith, albeit providing an overall comprehension of renal evo- of kidney is not to ﬁlter excess water but to reclaim lost ions

2+ 2+

lution based on major physico-chemical drivers, from a modern from body, mostly divalent ones (e.g., Ca , Mg ), which are cru-

scientiﬁc perspective, were limited by scope due to its primary cial for development of osseous and nervous system; and organic

focus on environmental cues. As a result, it failed to include the macromolecules (e.g., glucose, peptides) via ATP-dependent active

conceptual depths of many unanswered questions in renal evolu- transport; (iii) evolution of such energy-consuming processes indi-

tion, reveal granular details, or include the inventory of missing cate that protovertebrates were isotonic (∼350 mOSm) but not

elements, such as genotypic constraints, before ﬁtting them into a isoionic to their external environment—thus the external environ-

broader evolutionary picture. ment must have been brackish; (iv) the glomeruli developed to

An interesting topic to demonstrate the various counter- facilitate this major function of kidneys, that is, reabsorption of ions

arguments placed against many ideas proposed by Prof. Smith is and macromolecules, by providing enough ﬂuidic ﬁltrate; (v) the

the origin of protovertebrates in fresh or seawater—a dispute that current marine vertebrates have spectacular capability to get rid of

has remained unsettled among the zoologists. Prof. Smith was an excess salt which is unlikely to have been present in protoverte-

ardent supporter of the theory that protovertebrates originated brates, and makes little sense that such sophisticated mechanisms

in freshwater. Such a limnic origin, as per him, gave rise to the were devised by nature to enable living in an environment with

glomeruli as an effective water ﬁltration mechanism and get rid similar salinity; thus a marine origin of protovertebrates seems

of excess water that the protovertebrates, with a hypertonic inner improbable; (vi) anadromy, is a relatively rare phenomenon and

environment, imbibed in a hypotonic environment. However, the mostly a derived condition and, hence, making such a theory of

theory of freshwater origin in protovertebrates has now received origin uncertain.

signiﬁcant criticism. Simultaneously, other theories claiming the

origin of protovertebrates in a marine environment, brackish water

of estuaries, and even under anadromous conditions, have been 11. Summary and outlook

proposed. It would be relevant to have a glance over the arguments

supporting the alternative theories. In summary, we have used the concepts of Prof. Homer Smith as

Proponents of the marine origin of vertebrates, including Alfred a template to revisit and assess realms of renal evolution. Despite its

Romer (Romer, 1949), base their claim on the following argu- simplistic interpretation, the scholastic value of the book with its

ments: (i) the three protochordate groups, viz., Cephalochordata, lucid style of explaining critical facts toward maintaining water-

Hemichordata, and Urochordata, are all marine; (ii) the earliest salt balance inside the body, as exhibited by various life-forms

vertebrate fossils belong to Ordovician period and are always recov- throughout the discourse of evolution in pursuit of survival, cannot

ered from marine sediments; (iii) the salinity and ionic strength of be stressed enough. The parlance of this book, particularly its nar-

Ordovician seawater were similar to modern times, which refutes rative, sets a precedent enabling us to assess the kidneys not only

the theories of evolution based on seawaters of low salinity; (iv) as a vital organ but instead dissects its evolution into current forms.

invertebrate marine ancestors of the ostracoderms and placoderms The major conclusions that distill out of the study are: (i) the

are common, and there is no evidence to suggest any other habi- geologic events, including upheavals, with frequent mass extinc-

tat than marine for them; (v) the kidneys of marine myxinoids and tions, provide with a useful template to understand various stages

elasmobranchs, with an inner isosmotic environment to seawater, of renal evolution; (ii) the urge of life to survive on earth through-

are glomerular which rules out the argument that emergence of out its disturbing history as a terrestrial body, while searching

glomeruli is a freshwater adaptation. ways to strike a chemical equilibrium with an unpredictable exter-

L. Keogh, D. Kilroy and S. Bhattacharjee / Annals of Anatomy 233 (2021) 151610 13

nal environment, is a major determinant of renal evolution; (iii) Carpenter, P.A., Bishop, P.C., 2009. A review of previous mass extinctions and historic

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