SECTION 2: DISORDERS OF RENAL DEVELOPMENT

CHAPTER

Structural and Functional

Development of the Kidney
Tino D. Piscione and Aoife M. Waters

The kidney presents in the highest degree the

phenomenon of sensibility; the power of reacting to
various stimuli in a direction which is appropriate for
the survival of the organism; a power of adaptation
which almost gives one the idea that its component parts
must be endowed with intelligence.
E. H. Starling, 1909
As recognized by Starling, the mammalian kidney, through
evolution, has developed adaptive regulatory mechanisms
such as conservation of water, excretion of waste, maintenance of electrolytes, and acid-base homeostasis. As a result,
such regulatory function requires the coordinate development of specic cell types within a precise pattern so that
body uid composition can be closely monitored and regulated. The developmental program that controls this precise
patterning is a highly dynamic process involving interplay
between genetic and cellular factors. Defects in developmental programming of the kidney result in a spectrum of structural and functional disorders that are discussed in other
chapters in this book. To provide a framework for understanding the developmental origins of these disorders, the
structural and functional development of the kidney is outlined here.

PART 1: ANATOMIC DEVELOPMENT

OF THE KIDNEY
Tino D. Piscione

OVERVIEW OF HUMAN
KIDNEY DEVELOPMENT
rons
once
nephrogenesis
is completed.2,4
Consequently the number of functioning nephrons
formed at 32 to 34 weeks gestation
may have
important implications for long-term renal outcome.
Semakin bertambahnya bukti yang menunjukkan bahwa
regulators of nephrogenesis (reviewed in
infants born prematurely or by de novo generation of neph-

banyaknya nefron yang terbentuk seelah lahir, menentukan

fungsi ginjal di masa akan datang.
There is increasing evidence that the number of nephrons
formed at birth is a determinant of renal function later in life.
This concept is supported by the association of renal failure
in humans with oligomeganephronia5,6 and by the demonstration of reduced glomerular number in humans with primary
hypertension and chronic kidney disease.7,8 Quantitative
analyses in humans and rodents using stereologic methods of
glomerular counting in renal autopsy specimens have revealed
a direct relationship between birth weight and glomerular
number.9,10 The latter data are consistent with the Barker
hypothesis, which proposes that adult disease has fetal origins
and is based on epidemiologic studies showing a correlation
between birth weight and the incidence of cardiovascular
disease.11,12 Consequently mechanisms that control structural
and functional kidney development are likely to be crucial
for programming long-term, as well as short-term, renal
survival.

MORPHOLOGIC STAGES OF HUMAN

KIDNEY DEVELOPMENT
Our understanding of the morphologic stages of human
kidney development is largely based on histologic descriptions of microdissected human fetal kidney autopsy specimens
performed
by
Edith
Potter
and
Vitoon
Osathanondh.1,13,14
Their seminal work was complemented by analyses of mouse
kidney development performed by Lauri Saxen.15 These
studies revealed conserved mechanisms of nephrogenesis
between humans and mice, and formed the basis for utilizing
the murine embryonic kidney as an ideal system to study
mammalian kidney development. Advances in human genomics and mammalian developmental genetics have further
accelerated the tempo of new discovery in the eld of developmental nephrology. Consequently this research has resulted
in a clearer understanding of the original morphologic descriptions of kidney development and the identication of key
16,17
). The morpho91
logic stages of mammalian kidney development are summa-

Chapter 6

Structural and Functional Development of the Kidney

rized in the following section. Cellular events that underlie

these morphologic changes are discussed in Part 2 under
Sodium Transport in the Developing Kidney. Current knowledge of genetic and molecular regulation is then reviewed
in Potassium Transport in the Developing Kidney, also in
Part 2.

OVERVIEW OF MAMMALIAN
KIDNEY MORPHOGENESIS
The mammalian kidney derives from two parts of the metanephros, its embryonic precursor. The rst part is the ureteric
bud, which originates as an epithelial outgrowth of the wolfan duct. The ureteric bud gives rise to the collecting duct
(CD) system, including cortical and medullary CDs, renal
calyces, renal pelvis, ureter, and trigone of the bladder.2,15
Development of the CD system involves an embryonic
process termed branching morphogenesis, dened as the formation of branched tubules.18 As a developmental process,
branching morphogenesis is essential in the formation of
several tissues, including kidney, lung, mammary tissue, exocrine pancreas, and salivary glands (reviewed in18). In kidney
development, renal branching morphogenesis may be considered a sequence of related events, which include (1) outgrowth of the ureteric bud, (2) iterative branching of the
ureteric bud and derivation of its daughter CDs, (3) patterning of the cortical and medullary CD system, and (4) formation of the pelvicalyceal system.
The second part of the metanephros that forms the mammalian kidney is the metanephric mesenchyme. Metanephric
mesenchyme originates as undifferentiated cells located in
the posterior intermediate mesoderm adjacent to the metanephric duct. Differentiation of metanephric mesenchyme
gives rise to all epithelial cell types that make up the mature
nephron, including the visceral and parietal epithelium of the
glomerulus, the proximal convoluted tubule, the ascending
and descending limbs of the loops of Henle, and the distal
convoluted tubule.2,15 Metanephric mesenchymal differentiation involves a process termed mesenchymal-epithelial transformation (MET). MET results in conversion of loosely
associated, nonpolarized mesenchymal cells into tightly associated, polarized epithelial cells that form primitive tubules.
Further differentiation of epithelial cell types within these
primitive tubules occurs in a spatially organized proximaldistal pattern, resulting in formation of the glomerular and
tubular segments of the mature nephron.

Ureteric Bud Induction

92

Genetic and molecular control of ureteric bud outgrowth are

discussed in greater detail in the section Ureteric Bud Induction later in the chapter. Here we focus on morphogenetic
events of ureteric bud induction, such as the number and
position of ureteric buds that form at the onset of kidney
development.
Ureteric bud formation may be considered the initial step
in mammalian kidney development (Figure 6-1, A). The ureteric bud forms as an outgrowth of the wolfan duct in
response to external cues provided by surrounding metanephric mesenchyme. The wolfan duct, also known as the mesonephric or nephric duct, is a paired embryonic epithelial

tubule extending in an anterior-posterior orientation on either

side of the midline. It is divided into three segmentsthe
pronephros, mesonephros, and metanephros. At its anterior
end the pronephros forms the renal anlage in sh19 and frogs20
but degenerates in mammals. The midportion of the wolfan
duct, the mesonephros, gives rise to male reproductive organs,
including the rete testis, efferent ducts, epididymis, vas deferens, seminal vesicle, and prostate.21 In females the mesonephric portion of the wolfan duct degenerates. The caudal
portion, the metanephros, gives origin to the ureteric bud
on its lateral aspect. The posterior segment of the duct
communicates with the cloaca to form the trigone of the
bladder.21
Ureteric bud formation is initiated at week 5 of human
fetal gestation and at embryonic day 10.5 (E10.5) in mice.
Signals from the metanephric mesenchyme induce the ureteric bud to form, elongate, and invade the mesenchyme.
Failure to induce ureteric bud outgrowth results in renal
agenesis, which occurs unilaterally or bilaterally if the ureteric bud fails to form on one or both wolfan ducts, respectively.16 Additional signals are required to restrict the number
of ureteric buds induced to form from the wolfan duct, as
revealed by the demonstration of severe renal and urogenital
malformations in humans and mice when ectopic outgrowth
of multiple ureteric buds from a single wolfan duct is
observed.22 Moreover, the relative position of ureteric bud
outgrowth from the wolfan duct appears to be crucial to
formation of a single ureter and competent vesicoureteral
junction. A relationship between ectopic positioning of ureteric bud outgrowth and vesicoureteral reux is largely supported by evidence from Mackie and Stephens, who described
defects in vesicoureteral junction formation in patients with
ureteral duplications.23 On the basis of their observations,
they postulated that when outgrowth of the ureteric bud
occurs at an ectopic site, the nal site of the ureteral orice
in the bladder will be ectopic.23 These data are supported by
phenotypic analyses of mice with mutations in Bmp4,24
Robo2,25 and components of the renin-angiotensin cascade,26,27
which show ureteral duplications or vesicoureteral reux and
demonstrate ectopic placement of ureteric bud formation on
the wolfan duct.

Renal Branching Morphogenesis

Renal branching morphogenesis commences between the
fth and sixth week of gestation2 in humans, and at E11.5 in
mice15 when the ureteric bud invades the metanephric mesenchyme and forms a T-shaped, branched structure (Figure
6-1, B). This T-shaped structure subsequently undergoes
further iterative branching events (Figure 6-1, C) to generate
approximately 15 generations of branches. In human kidney
development, the rst 9 generations of branching are completed by approximately 15 weeks gestation.2 During this
time new nephrons are induced through reciprocal inductive
interactions between the newly formed tips of the ureteric
bud and surrounding metanephric mesenchyme. By week 20
to 22 of gestation, ureteric bud branching is completed, and
the remainder of CD development occurs by extension of
peripheral (or cortical) segments and remodeling of central
(or medullary) segments.2 During these nal stages new
nephrons form predominantly through the induction of

Chapter 6

Induction

Structural and Functional Development of the Kidney

MET

Ureteric
bud tips

Stroma

Ureteric
bud

Condensed
mesenchyme

Renal vesicle

Collecting
duct

Proximal
tubule
Collecting
duct

Efferent
arteriole
Afferent
arteriole

Distal
tubule
Proximal
tubule

Branching

Glomerulus

Endothelial
cells

Distal
tubule

Podocytes
Parietal
glomerular
epithelium

Thick
ascending
limb

Henles loop
S-shaped body

Nephron

Figure 6-1 Stages of nephrogenesis. A, Induction of the metanephric mesenchyme by the ureteric bud promotes aggregation of condensed mesenchyme
around the tip of the ureteric bud. B, Polarized renal vesicles subsequently develop as the mesenchyme undergoes epithelial transition. Fusion of renal vesicles
occurs with the collecting ducts. C, Stromal cells secrete factors that inuence cell fate choices in neighboring nephrogenic structures and collecting ducts.
D, A cleft forms in the renal vesicle, giving rise to the comma-shaped body. The development of the S-shaped body involves formation of a proximal cleft
that is subsequently invaded by angioblasts and starts the process of glomerulogenesis (E). (Image redrawn from Dressler GR: The cellular basis of kidney
development, Annu Rev Cell Dev Biol 22:509-29, 2006.)

approximately four to seven nephrons around the tips of

terminal CD branches that have completed their branching
program while retaining the capacity to induce new nephron
formation.2,15
Throughout renal branching morphogenesis, the branching
ureteric
bud recapitulates a patterned, morphogenetic
sequence. This sequence includes (1) expansion of the
advancing ureteric bud branch at its leading tip (called the
ampulla), (2) division of the ampulla causing the formation
of new ureteric bud branches, and (3) elongation of the newly
formed branch segment. Analysis of renal branching morphogenesis in organ culture systems employing kidneys of transgenic mice expressing the uorescent reporter (known as
enhanced green uorescent protein, or EGFP) in the ureteric
bud lineage have been informative regarding the sequence
and pattern of branching events that occur following the
formation of the initial T structure.28,29 Accordingly, all terminal branching begins with formation of a swollen ampulla
at the tip, expanding to two to three times the diameter of
the parental trunk before it is clear how many daughter
segments will be generated. The majority of bifurcations
are symmetric wherein the ampulla attens and extends in
two opposite directions, resulting in terminal bifurcation.
However, trid branching (i.e., three daughter branches
arising from one ampulla) and lateral branching (i.e., de novo

branch formation arising from a ureteric bud truncal segment)

resulting in asymmetric branching have also been described.28
When asymmetric branching occurs, the ampulla rst grows
in one direction, forming an L rather than a T shape. In the
case of a trifurcation, the ampulla forms three distinct humps,
each of which forms a new segment. Regression of trid
branches is frequently observed,28,30 suggesting that dynamic
remodeling occurs during renal branching morphogenesis.
Morphometric analyses of individual branch growth parameters reveal a conserved hierarchic pattern of diminishing
nal length achieved for successive ureteric bud branch generations such that sixth generation branches are shorter than
fth generation branches, etc.28 However, in kidney organ
culture, asymmetric branching has been described in which
branches forming in the posterior region of kidney explants
elongate at a slower growth rate compared with branches
formed in anterior regions.31 Presumably, mechanisms that
promote asymmetric renal branching morphogenesis may be
crucial to achieving the nal nonspheric shape attained by the
fully formed kidney.

Corticomedullary Patterning and Formation of

the Pelvicalyceal System

Between weeks 22 and 34 of human fetal gestation,2 or

E15.5-birth in mice,15 morphologic changes result in the

93