.-14 - The renal system.pdf

Introduction 643 14
14The renal system
Girish Namagondlu, Alistair Chesser
Introduction 643
Functions of the kidney 643
Urine volume and composition 643
Balance of fluid intake and loss 644
Renal failure 644
Anatomy of the kidney 645
Gross structure 645
The nephron 645
Renal vasculature 646
Nerve supply to the renal tract 649
Development of the kidney 650
Permanent kidney 650
Renal function 650
Glomerular filtration and the production of
primary urine 651
Functions of the proximal convoluted tubule 653
Renal function tests 657
Renal control of fluid balance 661
Renal control of sodium balance 666
Diuretics 671
Renal control of acid–base balance 673
The urinary tract 676
Ureters 676
Gross structure of the bladder 678
Control of micturition 678
Renal diseases 679
General classification of renal disease 679
Onset of renal disease 680
Acute kidney injury 680
Chronic kidney disease 682
Renal replacement therapy 683
INTRODUCTION
The kidney is an essential organ for life and plays a central role in
homeostasis. Homeostasis, originally defined by the great French
physiologist Claude Bernard, refers to the stability and maintenance of
the internal environment of the body – the so-called ‘milieu intérieur’
(see Ch. 1). Key renal functions may be deduced from what happens
when the kidneys cease to function or fail.
Functions of the kidney
The functions of the kidneys may be summarised as:
• Homeostasis – consisting of filtration, when the blood is
filtered to remove waste products of metabolism and toxic
substances but retains essential nutrients, which is followed
by reabsorption and secretion of water and essential
electrolytes, to maintain acid–base balance, water (fluid) and
electrolyte balance as well as normal blood pressure. Urine is
produced in the process.
• Hormone secretion – independent of the endocrine system,
the kidneys secrete erythropoietin to stimulate red cell
production, renin as part of the blood pressure control
mechanism and the active form of vitamin D.
Therefore, the kidney:
• Controls the volume, osmolarity and acid–base balance of the
plasma and extracellular fluid (ECF)
• Controls the level of electrolytes in blood and ECF
• Recovers all the small molecules filtered by the nephron, such
as sugars and amino acids
• Excretes nitrogenous waste and ‘fixed’ acid from protein
metabolism, mainly urea, uric acid and creatinine
• Excretes a variety of toxic metabolites and excess electrolytes
and water
• Maintains red cell production by the secretion of the hormone
erythropoietin
• Produces the active form of vitamin D and hence maintains
calcium balance
• Controls blood pressure over the long term.
Urine volume and composition
In a healthy person the kidneys form approximately 1.5–2 L of urine
every 24 hours, which is equivalent to 1 mL/min entering the bladder.
Urine composition differs from plasma:
• First, the levels of urinary nitrogenous waste products, mostly
in the form of urea and ammonia, are much higher, whereas
levels of protein, glucose and amino acids are all very much
lower
• Second, although in any given 24 hours the total amount of
any urinary constituent, such as salts (NaCl, KCl, NaHCO3) and
urea, are excreted at a fairly constant rate, the volume of
water in which they are contained can vary widely, so that the
amount of solute excreted is independent of the volume of
urine.
Normally, urine is a slightly acidic, pale yellow fluid, with a pH of
approximately 6. However, when large volumes of water are ingested,
it can rapidly change to an almost colourless fluid, the excreted
volume matching the intake and the osmolarity falling to a minimum
of 50 mOsm. In contrast, if sweating is increased by hard exercise
or if the water intake is restricted, the volume of urine will fall and
a dark concentrated fluid is produced with an osmolarity which can
rise to 1400 mOsm (Information box 14.1). Plasma has a constant
osmolarity of approximately 285 mOsm.
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644 The renal system
14
measuring GFR. Over the years, calculation methods have become
more accurate and have lesser bias. A commonly used method, which
is easy and reasonably reliable, is estimating GFR by the chronic
kidney disease epidemiology collaboration formula (CKD-EPI), which is
based on age, sex, race, and serum creatinine; it is popularly known
as estimated glomerular filtration rate (eGFR). In healthy individuals,
the GFR is a very large volume of fluid – 125 mL/min in the young
male (equivalent to 180 L/24 h).
Blood urea and serum creatinine are commonly measured but
are surrogate and late markers of renal failure (Fig. 14.1). Levels
only increase in the blood when 50% of kidney function is lost.
For a healthy person on a mixed diet, the level of plasma urea is
approximately 5 mM and it does not begin to change until the GFR has
fallen by approximately 75%. However, this response does depend on
diet – a high protein intake in a meat eater would cause the plasma
urea to rise more rapidly in renal disease, whereas a vegetarian diet
would delay this rise until an even greater loss of renal function had
occurred. Often, prior to the rise in plasma urea, the blood pressure
begins to increase to high levels at rest (hypertension) and this
can be an early warning sign of renal problems (Clinical box 14.2).
Balance of fluid intake and loss
In a healthy human, the daily intake of water roughly equals loss in
the steady state. The principal source of water is drinking water and
other fluids and in food (oral), and most of the loss is in urine, via the
kidneys. Some water is lost as ‘insensible loss’, via respiration, skin,
sweating and faeces. Table 14.1 shows the approximate balance of
the total intake and loss of water by the body over 24 hours and the
electrolyte balance, and the factors that can disturb this balance.
Renal failure
In a person whose kidneys are beginning to fail, there is at first no
detectable sign or symptom of damage because humans have a
massive over-capacity in renal function. Few changes are seen until
three-quarters of the normal renal function is lost (Clinical box 14.1).
Symptoms appear late in renal failure and are usually:
• A result of waste product accumulation, mainly urea (uraemia),
such as loss of appetite, lethargy, nausea, vomiting, weight
loss, itching (uraemic frost), muscle cramps etc.
• The inability to excrete water (fluid overload), resulting in
breathlessness, orthopnoea, oliguria and peripheral oedema.
An early feature of renal failure is a drop in the glomerular filtration
rate (GFR) by all the nephrons (see later). There are several ways of
Information box 14.1 Osmolarity
Osmolarity measures the concentration of ‘particles’ that are capable of
exerting osmotic pressure, so that the osmolarity of a solution reflects the
number of ‘particles’ in a given volume of fluid that can exert an osmotic
pressure across a membrane. The kidneys are vital in keeping the
osmolarity of blood and the extracellular fluid (ECF) constant. The kidneys
are therefore a key element in the control of electrolytes and acid–base
balance in the body. Sodium as NaCl and NaHCO3 is conserved, whereas
potassium is eliminated and ‘fixed’ acid is excreted in the form of
ammonia and phosphate ions in the urine.
Table 14.1 Water balance and factors which disturb
the balance
Sources for the
input of water
Litres Sources of output Litres
Water content in food 1.0 Urine osmotic load 0.7
Food metabolism 0.5 Urine from choice
drinking
0.8
Drinking minimum 0.5 Lungs and airways 0.4
Drinking by choice 1.0 Skin insensible loss 1.0
Faeces 0.1
Total 3.0 Total 3.0
Factors disturbing balance Composition and route
Hyperventilation/fever Loss of pure H2O – diffusion
through skin
Sweating H2O + Na+
, Cl−
– sweat glands
and ducts
Air conditioning (dry air) 0.5–1 L/day pure H2O –
diffusion into lungs
Diarrhoea – cholera 20 L in 48 h Na+
, Cl−
, HCO3
–
,
K+
– small bowel/colon
Lactation – milk Isotonic salts – milk secretion,
breasts
Clinical box 14.1 Clinical consequences of renal failure
The consequences of renal failure are related to kidney functions other
than fluid balance and excretion, which include:
• Hypertension – the kidneys secrete the enzyme renin in response to
impaired renal perfusion. Renin activates angiotensin-converting
enzyme (ACE) to convert angiotensin I to angiotensin II, which is a
powerful systemic vasoconstrictor and stimulates aldosterone secretion
to promote sodium and water retention (see later and Ch. 4). Chronic
disruption of the renin–angiotensin–aldosterone system in renal failure
leads to hypertension. Pharmacological treatment with ACE inhibitors is
used in the management of hypertension (see later). Before the advent
of effective hypotensive drugs, nephrectomy was performed to prevent
renal hypertension.
• Cardiovascular disease – is the major cause of death in renal failure
patients. Ischaemic heart disease is common and often a combination
of arteriosclerosis and atherosclerosis. Incidence of cardiac arrhythmias
and sudden cardiac death is increased in chronic kidney disease (CKD).
• Anaemia – renal interstitial cells secrete erythropoietin, which
stimulates red cell production (see Ch. 12). Destruction of renal tissue
in CKD results in iron and erythropoietin deficiency.
• Vitamin D deficiency – the distal convoluted tubules secrete the
enzyme 1α-hydroxylase. Naturally occurring vitamin D needs to be
hydroxylated to an active metabolite in the liver, then further converted
by 1α-hydroxylase to produce the metabolically active
1,25-dihydroxychlolecalciferol (vitamin D3). Chronic renal failure thus
leads to disorders of bone (renal osteodystrophy), calcium metabolism
and secondary hyperparathyroidism (see Chs 10 and 16).
• Hypoproteinaemia – the persistent and chronic urinary protein loss in
chronic renal failure leads to hypoproteinaemia, which can lead to
impaired protein binding with consequent adverse reactions from
therapeutic agents (see Ch. 4), wasting and malnutrition (see Ch. 16).
• Other metabolic complications – e.g. defective excretion of urate leads
to gout; defective insulin excretion may lead to hypoglycaemia in
insulin-dependent diabetics.
• Other endocrine disorders – may arise owing to defective protein
binding of hormones consequent to hypoproteinaemia (e.g. thyroid
hormone), or impairment of hormone action and excretion (e.g.
hyperprolactinaemia leading to gynaecomastia in men, growth
retardation secondary to complex defects of growth hormone secretion
and action in uraemic children).
• Neurological complications – severe, persistent uraemia depresses
cerebral function and may lead to convulsions (see also Ch. 3).

Anatomy of the kidney 645 14
Renal pyramids
In longitudinal section, the kidney is divided into a number of conical
structures, the renal pyramids (see Fig. 14.2). The gross structure also
reflects the highly organised microstructure with linear feature, the
medullary rays, arranged into the inner and outer stripes. These are
related to the capillary networks and to the straight tubular elements
of the loop of Henle, the vasa recta and the collecting ducts (see
later). The tip of each pyramid forms a papilla which is enclosed in
a funnel-shaped extension of the renal pelvis, the calyx. It is these
structures which collect the urine draining from the collecting ducts
passing through renal papilla at the apex, into a minor calyx (usually
9–12), then into a major calyx (3–4) before passing through the
renal pelvis into the ureters via the pelviureteric junction. The walls
of calyces, renal pelvis and ureters are lined with smooth muscle,
which produces peristaltic waves to carry urine down the ureter
and into the bladder.
The nephron
The functional unit of the kidney is the nephron, of which there are
some 800000 to 1.5 million in each kidney. Each nephron consists of
the renal corpuscle, where the primary urine is first formed, and the
renal tubule, a highly coiled tube where the primary urine is modified.
A simplified overall structure of the nephron is shown in Fig. 14.3.
The renal corpuscle (renal glomerulus)
The renal corpuscle, the filter in the kidney sited in the cortex,
consists of the glomerulus, which is a knot of capillaries attached to
the mesangium, surrounded by the Bowman capsule where fluid is
forced out of the plasma into Bowman space to form the glomerular
filtrate. The Bowman capsule, also known as the glomerular capsule,
elongates to become the renal tubule. It has an inner layer formed
by visceral epithelial cells (podocytes), which, at the vascular pole,
is reflected to form the outer layer (parietal epithelial cells).
ANATOMY OF THE KIDNEY
Gross structure
The adult kidneys are two ‘bean’-shaped structures weighing
approximately 150 g each, lying on either side of the vertebral column
(at approximately the level of T12–L3) in the midline, but outside the
peritoneum in the abdominal cavity (retroperitoneal). The concave
aspect of each kidney faces medially (towards the vertebral column).
Each kidney normally measures 10–12 cm in length, 5–7 cm in width
and 2–3 cm in thickness.
The kidneys are surrounded by three layers of tissue:
• Renal fascia (Gerota fascia) – a thin, outer layer of fibrous
connective tissue that surrounds each kidney (and the
attached adrenal gland).
• Adipose capsule – a middle layer of fat tissue that cushions
the kidneys.
• Renal capsule – an inner, thick, fibrous membrane. The
thickness of the capsule is necessary to withstand the high
tissue pressure of 10 mmHg generated within the tissue ECF
by the filtration process.
The inside of the kidney has three distinct regions:
• Outer cortex borders the convex side and lies immediately
under the capsule. It contains the renal corpuscles and
tubules (apart from the ‘hairpin’ loop of Henle), blood vessels
and the cortical collecting ducts (see later). The renal filtration
processes take place in the cortex.
• Inner medulla (Fig. 14.2) which is deep to the cortex, contains
10–20 striated, cone-shaped regions called renal pyramids.
This alternates with an unstriated region called renal columns.
• Renal sinus which lies adjacent to medulla and opens to the
hilum (an opening in the medial aspect of the kidney) that
allows passage of the renal artery and vein, nerve supply and
ureters (see Fig. 14.2).
0
0
120 ml/min
Dietary
protein
Creatinine clearance GFR (ml/min)
Blood
urea
(mmol/L)
30
30
60 90
High
Normal
Low
10
20
20
0
0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
100 120 140 160 180
40 60 80
Plasma
creatinine
(mg/dL)
A B
Fig. 14.1 (A) The relationship between blood urea concentration and creatinine clearance showing the effect of high, normal and low protein
intakes. (B) Relationship between true glomerular filtration rate (GFR) (as measured by inulin clearance) and plasma creatinine concentration in
171 patients with glomerular disease. The open circles joined by the solid red line represent the relationship that would exist if creatinine were
excreted solely by glomerular filtration; the dashed line represents the upper limit of ‘normal’ for plasma creatinine concentration of 1.4 mg/dL.
In patients (dark dots), variations in GFR between 129 and 60 mL/min were often associated with a plasma creatinine concentration that
remained within the normal range due to increased creatinine excretion, which becomes saturated at a plasma concentration above
1.5–2 mg/dL; as a result, plasma creatinine concentration rises as expected with further reductions in GFR. Redrawn with permission from
Richards P, Truniger B 1983 Understanding water electrolytes and acid base balance. William Heinemann, London.

14
medulla. The PCT is lined by cuboidal cells having fine densely
packed microvilli (brush border) on the luminal side (urine side).
Each cell is joined to the others around it, close to the luminal
boundary, by an occluding band of tight junctions. The base of
each cell (blood side) is inwardly convoluted in many folds which
interdigitate with the cells around it. These structures enormously
expand the surface of the cell for exchange processes. The cells
are also densely filled with mitochondria, which are always present
in cells that are metabolically active and use energy generated from
glucose and oxygen.
Loop of Henle
After the PCT, the nephron then descends from the cortex towards the
medulla via the hairpin loop of Henle. There are three types of loop:
• Loops from juxtaglomerular nephrons which are very long and
extend all the way down to the renal pyramids (medulla).
• Loops from cortical nephrons which are short and only reach
the cortex/medulla border. Approximately 80% of nephrons
have short loops.
• A few intermediate loops between the above types.
The functional reasons for the differences in the length of the loops
are not fully understood but desert animals that produce a highly
concentrated urine have the highest proportion of the long loops. The
loop of Henle consists of several cell types; the bulk of this structure
is the thin descending and thin ascending loops. The cells of this
region are sparse in number, and are narrow, with few infoldings on
either face and few mitochondria. The loop of Henle is amazingly
long, the length being approximately 1000 times the diameter, and
if Fig. 14.3 was drawn to scale, it would be as high as a 20-storey
building! After the thin ascending loop, the next section undergoes a
major change in structure, becoming the thick ascending loop. The
cells in this section are thick, complex and rich both in mitochondria
and cellular inclusions, which reflects their active transport functions.
Distal convoluted tubule
Fluid now leaves the loop of Henle and enters the DCT, which is in
the renal cortex. Here, 10%–15% of ions and fluid of the filtrate are
recovered. Tubules from five to six nephrons then merge to form the
larger CD, which re-enters the renal medulla. Up to this point the
fluid recovery is a fixed proportion of that which has been filtered,
and is said to be constitutive.
Collecting ducts
The CDs are derived from a different embryological origin than the
rest of the nephron, and are divided into a cortical section (cortical
collecting duct (CCD)) and a medullary section (medullary collecting
duct (MCD)). In these ducts the fluid recovery can be varied either
to produce a dilute or a concentrated urine under the influence of
the antidiuretic hormone (ADH), also called vasopressin (see later).
Renal vasculature
Each kidney is supplied by a large artery from the descending aorta,
and together they receive approximately 20% of the cardiac output
(1.2 L/min). After circulating through the medulla and cortex, blood
from renal capillaries is collected in renal venules and leaves the
kidney via the renal vein to join the inferior vena cava. The kidneys
also have a prominent lymphatic drainage.
The renal arteries enter the kidney on the medial surface of
each kidney via the hilum, through which the renal artery enters
and the veins and lymphatics exit; here also the renal nerves enter
and leave the kidney.
The renal tubule
The renal tubule is the reabsorptive part of the renal system. It is
a highly convoluted structure, varying in size throughout its length,
consisting of:
• Proximal convoluted tubule (PCT)
• Loop of Henle
• Distal convoluted tubule (DCT)
• Collecting ducts (CDs).
Although originating in the renal cortex, the renal tubule descends
into the medulla as the hairpin loop of Henle (see later), which
doubles back so that the DCT returns to the cortex, ending next to
the glomerulus of the same nephron.
Proximal convoluted tubule
The fluid formed by the glomerular capillaries flows from Bowman
space along the nephron into the highly coiled structure of the PCT.
The PCT is grossly divided into pars convoluta (initial convoluted
portion) and pars recta (straight portion) that descends into the
Clinical box 14.2 Renal failure
Renal failure occurs when glomerular filtration is compromised from a
variety of causes, but may also be the consequence of renal tubular
function:
• Pre-renal – due to depressed renal vascular perfusion so that the
hydrostatic filtration forces are reduced. Causes can be divided into:
– True volume depletion, e.g. hypotension, dehydration, vomiting,
diarrhoea, haemorrhage (gastrointestinal blood loss), shock
– Decrease in ‘effective’ circulating blood volume, e.g. heart failure,
liver failure, NSAIDs and ACE inhibitors.
• Renal – often called intrinsic renal disease and is due to disease of the
nephron, the glomeruli and or microvasculature, or the tubules, e.g.
microvascular disease as in diabetes mellitus (see Ch. 3), nephrotoxic
drugs, acute tubular necrosis.
– Renovascular
– Macrovascular – renal artery stenosis, renal vein thrombosis
– Microvascular – small vessel disease, e.g. diabetes mellitus,
vasculitis.
– Renal parenchymal
– Glomerulonephritis – nephritic syndrome, rapidly progressive
glomerulonephritis, nephrotic syndrome
– Tubulointerstitial disease – ATN, tubulointerstitial nephritis.
• Post-renal – due to obstruction anywhere in the outflow system: the
renal pyramid (calyces, pelvis), ureters, down to the bladder neck, or
recurrent ascending infections (e.g. pyelonephritis).
Renal failure may be acute or chronic:
• Acute kidney injury is the sudden deterioration of renal function,
which is usually reversible over time. When severe, the consequent
fluid and biochemical disturbances may be life-threatening and
constitute a medical emergency. Management of acute renal failure is
aimed to correct the fluid and biochemical imbalance during the time
needed for renal function to recover. Dietary controls of electrolyte,
nitrogen and water intake (see Ch. 16), pharmacological interventions
(see Ch. 4) and dialysis to remove toxic products of metabolism and
excess fluid may be necessary.
• Chronic kidney disease is a long-standing and progressive
impairment of renal excretory function, which may be insidious in onset
and should be diagnosed after at least 3 months of persistent renal
failure. The biochemical abnormalities may be undetected for long
periods. Causes of chronic renal failure may be congenital (see later)
and include glomerular or vascular disease. Treatment is aimed at
controlling the biochemical and fluid imbalances (including chronic
dialysis), and at the cause, e.g. tight glycaemic control in diabetes
mellitus, and to manage complications. Renal transplantation may
ultimately be needed.

the peritubular capillaries, which envelop both the PCT and DCT, or
descending as looped capillaries into the medulla of the kidney as
the vasa recta around the loop of Henle (see Fig. 14.4).
Blood flowing through the glomerular capillaries is under high
pressure, whereas the tubular capillaries and vasa recta are under
low pressure.
Glomerular filtration barrier
Filtration of the blood entering the glomerulus at the afferent arteriole
relies on the permeability of the glomerular filtration barrier, which
is formed inside out by (Fig. 14.5):
• Capillary endothelial cells with round to oval fenestrations
(holes or pores) measuring 50–100 nm.
• Glomerular basement membrane (GBM) consisting of a fibrillar
network of matrix proteins, rather like an irregular fishing net,
but with holes of a fairly consistent size. Each of these ‘holes’
Renal microvasculature
On entering the kidney, the renal artery divides to form interlobar
vessels, which supply each pyramid. These then subdivide to form
arcuate arteries and finally interlobular arteries supplying the grape-like
glomerular capillaries (Fig. 14.4), where the renal filtrate is formed.
The arterial supply enters the start of the nephron at the
blind-ended dilation, the Bowman capsule, and divides into a knot
of capillaries, the glomerulus. The glomerular capillaries are unusual
in that they have an arteriole at the start of the capillary bed, the
afferent arteriole, and a second arteriole, the efferent arteriole, at
the end of the glomerulus, where the capillaries combine to emerge
from the Bowman capsule.
Peritubular capillaries
The glomerular capillaries reunite into an efferent arteriole which
then divides again to form a second capillary bed, becoming either
Cortex
Renal artery
Renal vein
Arcuate
Interlobular
Arteries
Interlobar
Area of ureter prone
to narrowing and
collection of stones
Longitudinal muscle
Circular muscle
Urothelium
Medullary
pyramid
Pelviureteric
junction
Calyx
Capsule
Pelvis
Vesicoureteric junction
Trigone (on floor of bladder)
External urethral sphincter
Urethra
Abdominal pressure
Ureter
Brim of pelvis
Detrusor muscle
Fig. 14.2 The major components of the urinary tract and bladder. Note the pelviureteric junction, the brim of the pelvis and the
vesicoureteric junction, which are sites where renal stones can lodge and impede urine flow, so causing back pressure and renal damage.

14
Proximal convoluted
tubule
Juxtamedullary nephron
Interlobular
artery and vein
Afferent arteriole
Arcuate
artery and vein
Collecting duct
Interlobar
vein
Interlobar
artery
Vasa recta
Distal convoluted
tubule
Collecting duct
Papillary duct
Thick ascending
loop of Henle
Thin ascending
loop of Henle
Thin descending
loop of Henle
Medulla
Outer
zone
Inner
stripe
Outer
stripe
Inner
zone
Cortex
Fig. 14.3 Structure of the nephron. Primary urine formed within the glomerulus is modified during its passage along the kidney tubules
before entering the collecting duct from where it goes to the bladder for excretion. The zones of the kidney are shown on the left-hand side
with the major blood vessels that supply the kidney. The nephron shown is the juxtaglomerular nephron, consisting of the proximal convoluted
tubule (PCT), which dips deep into the medulla as the thin descending loop of Henle, then bends acutely as the thin ascending loop of Henle
and then becomes the thick ascending loop. The thick ascending loop of Henle emerges into the cortex to form the distal convoluted tubule
(DCT). The DCTs merge to form the collecting duct, which again descends into the medulla and forms the urine. The changing morphology of
the tubule walls reflects the differences in permeability and function. The macula densa, a densely packed group of specialised cells lining the
DCT, is at the top of the thick ascending loop of Henle, a key site for the control of sodium balance. Some nephrons only penetrate into the
outer medulla, the cortical nephrons. It is thought the nephrons with the longest loops of Henle are responsible for forming the most
concentrated urine.

enabling them to withstand the large filtration pressures which
are needed to form the urinary filtrate.
Filtration through the glomerular capillary wall occurs along an
extracellular pathway including the endothelial pores, the GBM and
the slit diaphragm. Thus, formed filtrate enters Bowman space and
then pass through tubules. The main challenge for the glomerular
capillaries is to combine selective leakiness with stability.
Nerve supply to the renal tract
The kidney is supplied via the renal plexus and the course is along
the renal arteries to reach each kidney:
• Sympathetic nervous system triggers vasoconstriction in the
kidney and reduces renal blood flow. This travels through
T10–T11 levels of the spinal cord.
• Parasympathetic nerve supply is through the renal branches of
the vagus nerve (cranial nerve X). The function of this is not
yet clear.
Nerve supply of the ureters is from the following sources:
• Renal plexus
• Aortic plexus
• Superior hypogastric plexus
• Inferior hypogastric plexus
• Testicular (or ovarian) plexus.
Nerve supply to the bladder is described in detail on pages 678–679.
Nerve supply to the sphincters controlling urethral orifice is from
has negative charges on the surface of the matrix, so
molecules with a similar charge would be repelled by these
charges. In health, this prevents negatively charged molecules
from being filtered out of the blood (see later). Matrix proteins
consist of type IV collagen (α3, 4 and 5 chains), laminin,
fibronectin, entactin, other negatively charged glycoproteins
and sulphated glycosaminoglycans, such as heparin sulphate.
• Podocytes have foot processes, which are finger-like
projections of the capillary epithelium that interdigitate with
each other, leaving between them filtration slits, which are
bridged by an extracellular structure, the slit diaphragm. The
foot processes enclose and strengthen the vessels, so
Collecting duct
Loop of Henle
Renal vein
Renal artery
(branch)
Efferent
arteriole
Glomerulus
Bowman
space
Proximal
tubule
Peritubular
capillaries
Distal
tubule
Bowman
capsule
Afferent
arteriole
Vasa recta
Fig. 14.4 Renal vasculature. The blood supply originates from the renal artery (red) and leaves via the renal vein (blue). Blood passes
through two capillary beds, the glomerular capillaries followed by the vasa recta.
Bowman capsule
Lamina densa Basement
membrane
Lamina rara
Lamina rara
Endothelial cell
Fenestra
Epithelial foot process
Slit membrane
Capillary lumen
Fig. 14.5 Glomerular capillary wall. The structure of the
glomerular capillary wall, which is the filtration pathway.

14
and partly from the Wolffian duct. At approximately the fifth or sixth
week of gestation, the Wolffian duct develops a diverticulum, the
ureteric bud, which eventually becomes the renal pelvis and calyces
(proximal and distal convoluted tubules, loop of Henle, collecting
tubules), and the ureters. The ureteric bud invades the cell mass of
the intermediate mesoderm, when cells from the mesoderm migrate
over the ureteric bud and differentiate to eventually form the excretory
part of the kidneys, the nephrons (the renal cortex, glomeruli). The
metanephros migrates upwards to the lumbar region to take up
the lumbar position of the adult kidney. The ureters elongate as
the metanephros ascends.
Permanent kidney
The ureteric buds bifurcate until the 32nd week of gestation producing
1–3 million CDs (Fig. 14.6). At the tip of each is a metanephric tissue
cap (metanephric blastema, containing cells capable of asexual
division and differentiation; see Fig. 14.6B) which forms the nephric
vesicle (see Fig. 14.6C). This eventually forms the Bowman capsule
and the rest of the nephron. As the vesicle elongates, a capillary
complex forms near one end and invaginates into the tubule to form
the Bowman capsule and glomerulus (see Fig. 14.6D–F).
Between the sixth and ninth week, the kidneys ascend to a
lumbar site just between the adrenal glands (Fig. 14.7). By the 10th
week, the metanephros has evolved into the cortex and medulla, and
each ‘tree’ of CDs drains into a minor calyx and converges to form
the renal papilla. Urine produced by the foetus is excreted into the
amniotic fluid but kidney function is not necessary until after birth.
Congenital renal agenesis
Congenital renal agenesis leads to the absence of one (unilateral renal
agenesis) or both (bilateral renal agenesis) kidneys at birth. Bilateral
renal agenesis is rare but incompatible with life. While in utero, the
absence of foetal kidneys leads to a deficiency in amniotic fluid
production (oligohydramnios or anhydramnios). Without amniotic
fluid to cushion the foetus, the foetal facial and other features become
‘squashed’. The combination of absent kidneys, oligohydramnios and
characteristic features is sometimes referred to as Potter syndrome
(also called Potter sequence, oligohydramnios sequence). Unilateral
renal agenesis is more common but not life-threatening as long as
the single kidney remains healthy.
Polycystic kidney disease
Polycystic kidney disease is characterised by multiple renal cysts
(Clinical box 14.4). The autosomal dominant form of polycystic kidney
disease (ADPKD) is a hereditary disorder presenting in adulthood,
with associated other organ abnormalities (e.g. liver cysts). Autosomal
recessive polycystic kidney disease is rare, thought to be due to
gene mutation and is fatal in early childhood.
RENAL FUNCTION
In healthy individuals, the kidneys filter 180 L (125 mL/min) of fluid
in 24 hours, excreting 1.5–2 L as urine (see earlier). They are also
involved in the retention of essential nutrients such as protein and
glucose; water, acid–base and electrolyte balance; and hormone
secretion, as well as the excretion of waste products of metabolism.
The complex processes concerned are:
• Filtration
• Reabsorption, which may be passive or selective
• Secretion.
pudendal nerve, pelvic splanchnic nerves and inferior hypogastric
plexus.
DEVELOPMENT OF THE KIDNEY
In humans, the embryonic kidneys originate from the intermediate
mesoderm (see Ch. 10). The reproductive organs and adrenal cortex
also develop from the intermediate mesoderm. The tissues that are
destined to become permanent kidneys are preceded by embryonic
structures, most of which degenerate and atrophy before birth. Clinical
box 14.3 describes some congenital abnormalities of the kidneys
and urinary tract. There are three stages in the development of
these embryonic structures:
• Pronephros
• Mesonephros
• Metanephros.
Pronephros
Cells that develop into the pronephros originate in the intermediate
mesoderm. Structures known as the cervical nephrostomes, at the
level of the fifth cervical to the third thoracic segments, grow as
evaginations from the segments to fuse and extend in a caudal
direction (downwards) to form a series of ducts, the pronephric
ducts (or nephric ducts). Within the ducts, glomeruli develop.
The pronephric ducts and glomeruli make up the pronephros. The
Wolffian duct forms below the pronephric duct. The pronephros is not
functional, and rapidly degenerates and disappears at an early stage.
Mesonephros
The mesonephros originates in the cell mass on the medial side of
the Wolffian duct (from approximately the sixth thoracic to the third
lumbar segment), developing into a series of tubules. One end of the
tubules dilates and is invaginated by capillaries to form glomeruli.
The mesonephros is functional until the fifth gestational week, but
atrophies rapidly from the sixth week onwards.
Metanephros
The metanephros is destined to become the permanent kidney.
It arises partly from the caudal end of the intermediate mesoderm
Clinical box 14.3 Congenital abnormalities of the kidneys
and urinary tract
Congenital malformations of the kidneys and urinary tract (CAKUT) are
relatively common. Many are asymptomatic and only detected during
investigative (e.g. excretion urogram, ultrasound examination) or
therapeutic procedures (e.g. laparotomy). Some conditions, however, lead
to serious complications, such as progressive renal failure, and require
surgical interventions or even renal transplantation. The aetiology of the
anomalies is generally unknown, but genetic mutation and chromosomal
anomalies have been proposed. The congenital defects include:
• Defect in embryonic development owing to abnormal interaction
between the ureteric bud and metanephric blastema, which may lead
to agenesis (failure to develop), hypo- or dysplasia of the kidneys,
vesicoureteric reflux (VUR) (see later, Clinical box 14.14) and
congenital malformation of the ureters (ectopic or double ureters)
among others.
• Hereditary autosomal dominant or autosomal recessive polycystic
kidney disease.
• Embryological errors with one kidney failing to ascend (ectopic kidney)
or the two kidneys fusing to form a horseshoe kidney, which is still
functional and is only incidentally detected (see Fig. 14.7E).

Renal function 651 14
capillaries, most probably through the gaps between the endothelial
cells and through the fenestrae (regions of thinning of the wall) in
the capillary wall (see Fig. 14.5). The fluid then passes between the
epithelial podocytes, and between these structures lies the basement
membrane. This is the filter bed of the kidney which holds back
plasma proteins from passing into the nephron (see earlier).
From measurements of the permeability of molecules of different
sizes, all molecules of less than 12000 molecular weight (MW 12000)
are filtered into the nephron. This implies that all electrolytes, sugars,
amino acids, vitamins etc., pass easily into the Bowman capsule
Different parts of the nephron perform different functions. Fig. 14.8 is a
simplified diagrammatic representation of how the nephron functions.
See also Renal Filtration Made Easy online (www.studentconsult.com).
Glomerular filtration and the production of
primary urine
Urine is formed by the capillary hydrostatic pressure (HP) forcing
the water and salts of plasma through the wall of the glomerular
Collecting ducts
Collecting
ducts
Metanephric
tissue cap
Nephric
vesicle Glomerulus
Bowman
capsule
Loop
of
Henle
Distal
convoluted
tubule
Proximal
convoluted
tubule
A B C D E F
Fig. 14.6 Development of the renal collecting system and nephrons. (A) The ureteric buds continue to bifurcate until the 32nd week,
producing 1–3 million collecting ducts (B–F). The tip of each collecting duct induces the development of a metanephric tissue cap, which
differentiates into a renal vesicle. This vesicle ultimately forms a Bowman capsule and the proximal and distal convoluted tubules and loop of
Henle. Functional nephric units (of the type shown in (E)) first appear in distal regions of the metanephros at 10 weeks.
Dorsal aorta Renal artery
Ureter Ureter
Sixth week Normal Pelvic kidney Horseshoe
kidney
A B C D E
Fig. 14.7 Normal and abnormal ascent of the kidneys from the pelvis. (A–C) The metanephroi normally ascend from the sacral region of
their definitive lumbar position between the sixth and ninth week. (D) Infrequently, a kidney may fail to ascend, resulting in a pelvic kidney.
(E) If the inferior poles of the metanephroi make contact and fuse before ascent, the resulting horseshoe kidney catches under the inferior
mesenteric artery.

14
and then must be recovered by the rest of the nephron, back into
the plasma.
Pore size and macromolecules
If it is assumed that the ‘holes’ (pores) in the basement membrane
are tiny cylinders in the wall of approximately 1.4 nm in diameter,
as the size of the molecule approaches the diameter of the pore,
it will have less and less chance of being filtered. The size of a
molecule is usually judged by its MW, but this can be misleading
because some molecules are spherical (globular), whereas others
are long and thin. This latter group may get through into filtrate in
small amounts by passing ‘end on’ through the pores, although
from their MW it could be assumed that they are far too large; this
effect may explain why a small quantity of even the largest proteins
do get filtered into the urine, although there may also be a small
population of large pores.
However, the most critical factor that affects the filtration of a
macromolecule is whether it has a surface charge. Haemoglobin
Clinical box 14.4 Polycystic kidney disease
The pattern of inheritance for polycystic kidney disease is autosomal
dominant (ADPKD), which means that each offspring has a 50% chance of
inheriting the responsible mutation and, hence, the disease. ADPKD is a
genetically heterogeneous condition that involves at least two genes. PKD1
is located on 16p13.3 and accounts for most ADPKD cases (85%). PKD2
is located on 4q21-q22 and accounts for 15% of ADPKD cases. ADPKD
presents earlier in life. ADPKD1 is more severe than ADPKD2. The mean
age of end-stage renal disease for patients with ADPKD1 and ADPKD2 is
53 years and 74 years, respectively.
Clinical features are usually loin pain, haematuria, urinary tract
infections, renal stones, hypertension and progressive renal failure.
Approximately 20%–25% have polycystic liver, 10%–15% have mitral
valve prolapse and 5%–50% have berry aneurysms. Differentiating
features from other causes of multicystic disease is that ADPKD patients
have bigger kidney size/volume and there is usually a strong family
history.
Management involves analgesics, good control of BP and proteinuria
and prompt treatment of urinary tract infections.
Collecting
duct
Renal blood flow (25%
of cardiac output)
Renin from afferent arterioles
Juxtaglomerular apparatus
Glomerulus
Secretion
Toxic metabolites
Filtrate: G, AA,
anions, cations,
proteins <20000,
urea
Proximal
convoluted tubule
Thick
ascending
limb
Loop of Henle
Thin
descending
limb
Urea Urine
Vasa recta
Urine concentration and dilution
Counter-current hypothesis
Thin
ascending
limb
Distal
convoluted
tubule
H2O
Na+
Cl–
Na+
Cl–
Na+
Urea
Aldosterone
Reabsorption:
Na+, Cl–
, K+,
hydrogen ion
exchange, H2O
Reabsorption:
Water
Vasopressin
Reabsorption:
G, AA, Na+, Cl–
,
K+
, HCO3
–
Peritubular
circulation
Medulla
Cortex
Medulla
Cortex
80% 20%
Fig. 14.8 Diagrammatic representation of major transport sites in the nephron. Apart from macromolecules, the glomerular filtrate
contains glucose, amino acids, electrolytes such as Na+
, K+
, Cl−
, urea, bicarbonate and water. The PCT is the major site for reabsorption:
99% of the glucose is reabsorbed into the peritubular circulation, as well as essential nutrients and electrolytes. Bicarbonate reabsorption at
the PCT affects renal acid–base homeostasis. Toxic metabolites, cations and anions are also secreted by the PCT. The loop of Henle is the
major site for urine concentration according to the counter-current hypothesis. Further NaCl and water reabsorption takes place in the DCT
and CT, controlled by vasopressin and aldosterone. AA, amino acid; CT, collecting tubule; DCT, distal convoluted tubule; G, glucose; HCO3
–
,
bicarbonate; PCT, proximal convoluted tubule.

• It is the prime site for both the recovery of bicarbonate
and the generation of new bicarbonate depending on the
arterial pCO2
• It secretes a number of organic acids and bases, as well as a
wide variety of toxic and fat-soluble molecules into the urine.
This latter function means that the level of these compounds is
higher in the urine than in the blood capillaries (see later). Urinary
organic acids and bases, as well as toxic and fat-soluble molecules,
can be in excess of endogenous molecules, from administered
drugs or dietary sources. These functions involve a wide range of
different types of transport and a large number of different carrier
molecules (Fig. 14.9). Most of these processes require energy. The
renal metabolic processes are aerobic and consume large amounts
of oxygen, almost equal to cardiac muscle.
Tight junctions
Each epithelial cell of the PCT is joined to those surrounding it by an
occluding band of tight junctions close to the apical, or urine, side
of the cells (rather like the plastic holding a ‘six-pack’ of soft drink
cans); these junctions can vary in their ‘tightness’ or permeability.
In the PCT, they are ‘moderately leaky’, so, although they slow
the rate of passage of small molecules between cells, they do not
permit steep gradients to be established between the lumen and
the blood across the whole epithelium. Any concentration gradients
established between the cells on the blood side of the PCT by the
transport processes across the cell wall will osmotically draw fluid
and some ions through these ‘leaky’ tight junctions. This process
helps to recover water, salts and other small molecules back into
the blood by a relatively low-energy-cost process. This recovery of
water is mainly aided by a member of cellular water channels called
aquaporins (AQPs). Aquaporin 1 (AQP1) is localised in the apical
and basolateral region of the PCT epithelial cell membrane (see
Fig. 14.9A). AQP1 is not regulated by vasopressin, whereas AQP2,
located in the apical plasma membrane and intracellular vesicles of
CD principal cells, is regulated by vasopressin. The high permeability
of the PCT enables a vast volume of fluid to be recovered at low
energy cost. The PCT only uses approximately 5% of the total
energy consumption of the kidney.
The sodium pump
The ‘power house’ which drives most of the processes in the kidney
is the sodium pump (sodium–potassium pump, Na+
/K+
-ATPase pump),
located in the basolateral membrane of the tubular epithelial cells.
All cells in the body have the ability to pump sodium from inside the
cell across the cell membrane into the ECF (see Ch. 1). The pump
requires energy in the form of adenosine triphosphate (ATP), which
is generated from oxygen and glucose. The pump must also have
K+
on the outside of the cell, and it usually pumps 3Na+
out of the
cell for every 2K+
transferred in the opposite direction. Transport
of sodium in PCT by this pump is an example of primary active
transport (uphill against electrochemical gradient).
The walls of the epithelial cells of the PCT are polarised, which
is to say they have functionally different properties on the luminal
(urine) side compared with the blood side of the cell (see Fig. 14.9B).
The sodium pumps are only found on the blood side of the cell, as
tight junctions between the epithelial cells maintain the differential
distribution of membrane proteins between apical and basal
membranes, and this difference enables the cells to transport ions
and non-electrolytes from the urinary filtrate back into the blood.
A rise in intracellular Na+
concentration increases sodium pump
activity, to ‘pump’ Na+
ions out of the cell into the ECF. The pumping
(MW 67000) escapes into the urine, whereas albumin (MW 62000),
although smaller, is not filtered. This is related to the fact that although
both molecules are globular proteins, albumin has a negative surface
charge, so is held back by the repulsion of the charges on the
fibrillar matrix of the basement membrane, whereas haemoglobin
is not charged, so it can pass through relatively freely.
In disease states the surface charge on the fibrillar matrix can
be disturbed and albumin now appears in the urine (albuminuria),
which is a useful early warning sign of kidney injury.
Filtration forces
The HP at the afferent arterioles as they enter the glomerulus is
approximately 50 mmHg, which is approximately 15 mmHg higher
than most other systemic capillaries. The capillary HP only falls by
5 mmHg along the length of the glomerular capillary to 45 mmHg
in the efferent arterioles. This large HP and high permeability of the
capillary walls causes a large fraction of fluid and small molecules to
be filtered into the Bowman capsule of the nephron. This ‘outward’
force is, however, balanced by the opposing pull of the plasma
proteins which, being too large to pass through the wall, exert an
osmotic force in the opposite direction to the HP force. This is the
colloid osmotic pressure (COP) or oncotic pressure of the plasma
proteins and has a value of approximately 25 mmHg at the start
of the glomerular capillaries. The COP gradually rises along the
length of the capillary, as water and salts move out of the blood,
so increasing the effective concentration of the plasma proteins. By
approximately one-third along the length of the glomerular capillary,
the COP has risen to approximately 35 mmHg.
In addition, the movement of fluid into the Bowman capsule
surrounding the capillaries causes a rise in HP of approximately
10 mmHg in the tubular pressure within this space because the
exit into the rest of the nephron is narrow. These two pressures
balance the HP so only approximately 20% of the volume of the
blood is filtered into the nephron, as shown in Fig. 14.8. Note that in
other systemic capillaries, the pressure in the ECF is usually slightly
negative (−0.5 mmHg).
The HP of the blood draining from the glomerulus is 45 mmHg,
as opposed to 12 mmHg in muscle capillaries. This high pressure
is needed to drive the blood through the second capillary bed of
the peritubular capillaries or through the vasa recta (see Fig. 14.4).
The COP of the peritubular blood is also elevated to 30–35 mmHg,
which also helps to draw fluid back into the peritubular capillaries.
Proteins
Proteins are mostly held back by the basement membrane. However,
a small percentage is filtered and has to be recovered by the cells
of the nephron as the filtrate passes down the renal tubule. This
recovery is by the process of receptor-mediated endocytosis so the
eventual loss of protein into the urine is small, usually approximately
50–80 mg/24 h.
Functions of the proximal
convoluted tubule
The first segment of the tubular portion of the nephron, the PCT,
has four main functions:
• It recovers some 70% of glomerular filtrate with respect to the
filtered water and electrolytes
• It reabsorbs most of the filtered sugars, amino acids,
nucleosides, other small non-electrolytes and low-molecular-
weight proteins (e.g. retinol-binding proteins, α and β
microglobulins)

14
H+
H+
H+
H+
H+
K+
channels
Facilitated carriers
‘Uphill’
‘Downhill’
ATPase
Na+
channels
Na+
pump
K+
K+
K+
Na+
/K+
-ATPase (Na+
pump) Na+
and HCO3
– recovery
Na+
Na+ Na+
Na+
Na+
Na+
Na+
Dicarboxylate
Dicarboxylate
Na+
H+
+ HCO3
–
H+
H2CO3
H2CO3
H2CO3
H2CO3
Na+
Na+
Na+
, K+
, Cl–
3HCO3
–
HCO3
–
HCO3
–
H+
HCO3
–
HCO3
–, sugars,
amino acids
Amino acid
(SGLT)
Amino acid
Sugar
GLUT series
Carbonic anhydrase
Sugar
Glomerular filtrate
Cl–
PAH–
A– PAH–
Cl–
Aquaporin 1
Basolateral
face
Early proximal
convoluted tubule
Late proximal
convoluted tubule
Secretion of
organic acids
Middle proximal
convoluted tubule
Na+
-dependent
uptake of
sugars/amino acids
Peritubular
capillary
Aquaporin 1
Renal
tubule
Leaky tight
junctions
Carbonic anhydrase
Leaky tight
junctions
CO2 + H2O
CO2 + H2O
CO2
CO2
H2O
H2O, Cl–
H2O, Cl–
Cl–
H2O
Cl–
H2O
H2O
H2O
B
C
D
E
A
Fig. 14.9 Functions of the proximal convoluted tubule (PCT). (A) The glomerular capillaries filter all small ions, sugars and amino acids
into the tubule at a rate related to their plasma concentrations and the GFR. (B) Filtered Na+
is recovered in exchange for H+
ions and by
ATPase-dependent H+
transport. (C) In the middle PCT, sugars and amino acids are recovered by a Na+
-dependent uptake into the cells of
the PCT, then moved into the blood by facilitated downhill carriers, such as the GLUT series. (D) In the late PCT, Na+
is recovered by Na+
channels. (E) The transport pathway for organic anion secretion. See text for further details. GLUT, glucose transporter; PAH, para-
aminohippuric acid; SGLT, sodium-coupled glucose transporter.

Some of the H+
ions are fed into the Na+
/H+
antiport process
and thus help to recover Na+
ions. The Na+
and the HCO3
–
are
extruded into the blood on the basolateral side of the cell by the
Na+
/K+
-ATPase and by a Na HCO
+ −
3 3 carrier (see Fig. 14.9B). These
processes recover the filtered HCO3
−
and approximately 30% of
the filtered Na+
water will osmotically accompany the process, so
aiding the fluid and ionic balance. Inhibition of carbonic anhydrase
activity thus promotes the excretion of Na+
and water (see also
Ch. 4). Acetazolamide is a carbonic anhydrase inhibitor.
Water
As ions are moved into the ECF on the blood side of the proximal
tubular epithelium, both between cells via the ‘leaky’ tight junctions
and into the basal infoldings, osmotic forces are generated which
draw water through the cell and across the tight junctions (see
Fig. 14.9). The passage of water through the lipid bilayer of the cell
membranes has been something of a puzzle. The PCT recovers
some 67% of 180 L of the glomerular filtrate, which is approximately
120 L of fluid being recovered over 24 hours. Although the tight
junctions between the cells can be classified as moderately ‘leaky’,
the total surface area offered by this paracellular route between the
cells would be inadequate to explain this vast movement of water.
In addition, because water molecules are partly polar and have a
negative charge, it is difficult to envisage that this molecule could
pass through a lipid bilayer.
Aquaporins
A chance finding from work on the protein content of the red cell
membrane identified a special class of proteins – the AQPs. The AQPs
are membrane-spanning proteins with the ability to form a specific
channel for water through the cell membranes. Approximately 10
classes of aquaporins have been identified, with AQP1 being most
prevalent on both sides of the cells of the PCT, which explains the
unexpected high water permeability of this tissue (see Fig. 14.9). These
molecules allow the osmotic gradient created by the movement of
various electrolytes and non-electrolytes to exert a much greater force
than could be predicted, and permit a relatively low expenditure of
energy for the vast movement of fluid. The location of other AQPs,
especially AQP2, which can be added to the luminal side of the CD
cells under the influence of ADH, will be discussed later.
Peritubular capillaries
The PCT and the DCT are enveloped in a dense capillary network,
the peritubular capillaries (see Fig. 14.4). The recovery of fluid into
these capillaries is further aided by the raised COP of 30–35 mmHg
of the blood draining from the glomerulus. This also draws water,
salts and other molecules into the blood by the Starling mechanism
so that by the time this blood passes into the veins, it has a normal
COP of 25 mmHg.
Sugars, amino acids and other small
organic molecules
Sugars, amino acids and other small molecules are recovered from the
glomerular filtrate by sodium-dependent carriers found on the luminal
side of the PCT cell wall (see Fig. 14.9C). Each of these carriers has a
special site for the binding of Na+
and a site for a specific molecular
species. There are several carriers for sugars (Na+
-coupled glucose
transporter (SGLT)), five for amino acids, others for ions and many
nutrients, each of which are specific for their own molecule. Once
both sites are occupied, the carrier undergoes transformation and
the Na+
and the other molecule on the carrier are now transferred
of sodium out of the cell, and a gradient in the opposite direction for
K+
, creates a potential energy gradient across the cell wall that can
be used to recover many substances from the glomerular filtrate.
Carrier proteins
In the membranes of all epithelial cells are a number of carrier proteins
which can move ions across the cell walls on either the lumen or
the blood side of the cell. These carriers use the potential energy
of the gradients of Na+
or K+
ions set up by the sodium pump to
move ions either both in the same direction or one goes ‘out’ and
the other comes ‘in’. This arrangement maintains the balance of
positive and negative charges across the cell wall, i.e.
• A positive ion and negative ion go out together (symport or
co-transport) or
• A positive ion goes ‘out’ in exchange for a positive ion coming
‘in’ (antiport or countertransport).
The arrangement of these carriers is also different on the two sides
of the cell and often certain ions, such as K+
, are recirculated, being
carried into the cell by one carrier and then passing back out again
either via an ion selective channel or on another carrier. The overall
effect of these carriers is to recover most of the filtered ions, as
well as sugars and amino acids, from the tubular fluid back to the
blood (see Fig. 14.9B).
Ion channels
There are also membrane-spanning proteins which form ion channels
that are selective for a specific ion which will move through a pathway
formed by the transmembrane loops of protein. Ions move under
the influence of the concentration gradient through these channels
across the cell wall. Some ion channels can be in an ‘open’ state,
which permits the ion to pass through, or a ‘closed’ state when the
flow is impeded. These changes in opened or closed state, called
‘gating’, can be brought about by variation in the membrane potential
or by ligands (chemical factors such as acetylcholine (ACh), cyclic
nucleotides or G proteins) (see Ch. 4; see also Fig. 14.9B).
Recovery of bicarbonate by the PCT
Bicarbonate (HCO3
–
) is filtered at the same concentration as the
blood, i.e. 24–26 mM, which represents some 4000 mM/24 h. The
first segment of the PCT has cells which exchange Na+
for H+
ions
using the Na+
gradient to ‘power’ the process. This is an antiport
process by which there is a balance in charge and is a major
component in the recovery of filtered Na+
(see Fig. 14.9B). There is
also an H+
-ATPase–dependent process in this section which secretes
the H+
ions into the tubule, but it is only a small part of the process
and reduces the pH by the end of the PCT to 6.7.
The H+
produced by these two processes reacts with the filtered
HCO3
–
ions to form carbonic acid (H2CO3), which immediately
dissociates non-enzymically to form CO2 and H2O (see also Ch.
3). The CO2, being lipid soluble, crosses the lumen side of the cell
membrane where the enzyme carbonic anhydrase is present, both
bound to the cell wall and in the cytoplasm. In the cell, carbonic
anhydrase catalyses the formation of H2CO3 from CO2 and H2O,
speeding up the reaction many-fold, so that H2CO3 rapidly forms
inside the cell, which again dissociates to form H+
ions and HCO3
–
ions
(see Fig. 14.9B).
CO H O H CO H HCO
2 2 2 3 3
+ +
+ −

Most of the bicarbonate is thus reabsorbed, and the H+
ions are
excreted in the urine. This is an important process in the renal control
of acid–base balance (see later and also Chs 1 and 3).

14
In this region, there are also Na+
channels which allow Na+
to
enter the cell and be recovered into the blood by the Na+
/K+
-ATPase.
This would produce a large potential difference, but Cl−
ions pass
through the leaky tight junctions into the intracellular spaces and
balance the Na+
ion charge. Water accompanies these processes,
so water and salt are recovered (see Fig. 14.9).
Secretion of organic anions and cations
Renal tubules can secrete a wide variety of toxic metabolites, both
ingested in the diet and produced as by-products of metabolism,
including drugs. These are often organic lipid-soluble anions and
cations that can cross the cell membrane into the cell. These
metabolites could accumulate in the cytoplasm, requiring a specific
system of transport to eliminate the molecules from the circulation.
Organic anion transport
Organic anions are mostly weak aromatic and aliphatic organic
acids, with pKs generally of less than 7. The transporter systems
to eliminate organic anions have a wide substrate specificity. At the
pH of blood (7.4), these molecules are anions, whereas in the acid
pH of the urine, they become undissociated and lipid soluble. The
renal tubules are able to secrete these compounds into the lumen
so the urinary concentration of these molecules is higher than in
the plasma. This is a basis for measuring renal plasma flow by the
clearance method described later. Although this secretory mechanism
is an advantage for the elimination of unwanted molecules, the
broad specificity of the process means that many drug molecules
will also be excreted. For example, this was a major problem with
penicillin when the bulk of the administered dose was lost into the
urine. Probenecid was found to competitively inhibit the secretion of
penicillin, so that administration of probenecid together with penicillin
maintained the plasma level of the antibiotic (see Ch. 4). Probenecid
inhibits organic anion transporters.
By the use of coloured organic acids, the site of secretion
was identified as the second S2 segment of proximal tubules. The
mechanism of PCT anion secretion is shown in Fig. 14.9E and some
examples of typical compounds are given in Table 14.2.
The SLC22A gene family codes for organic anion transporter
(OAT) proteins. The OAT family plays the central role in renal organic
anion transport. OAT1, OAT3, OAT4 and URAT1 are expressed in
the proximal tubular cells of the kidneys. OAT1 and OAT3 mediate
uptake of a wide range of relatively small and hydrophilic organic
anions from plasma. URAT1 transports those organic anions from the
cytoplasm of the proximal tubular cells into the lumen of the nephron.
Other known substrates of OAT1 include para-aminohippurate (PAH),
into the cell. This process is termed co-transport and although it
does not use energy directly, it does again use the steep gradient
for sodium across the cell wall which has been generated by the
Na+
pump on the opposite side of the cell to ‘power’ the entry of
the non-electrolyte ‘up’ their concentration gradient (see Fig. 14.9C).
This is secondary active transport (see also Chs 2 and 4).
The Na+
-dependent SGLT co-transport carriers will move their
sugar molecules against a concentration gradient. In the first part
of the PCT, there are SGLT2 carriers, which have a low affinity for
glucose, so they will work when there is a high sugar content in the
lumen. In the later PCT segment, where the concentration of sugar
is low, SGLT1 carriers, which have a high affinity for glucose, will
move the sugar against a steep concentration gradient to recover
molecules from the filtrate back into the blood.
As these processes depend on a finite number of carriers in the
cell wall, a sudden large excess of a particular molecule present in
the blood will increase the amount filtered into the tubule and cause
all the sites to become occupied. When this occurs, the process is
said to be saturated; the molecules are not fully recovered by the
PCT, and will appear in the urine. This condition is seen in diabetes
mellitus when glucose appears in the urine (glycosuria), leading to
an osmotic diuresis (see also Ch. 3).
Facilitated carriers
Once inside the PCT cell wall, there are other carriers on the blood
side for sugars and amino acids called facilitated carriers. This is a
type of secondary active transport (see Chs 2 and 3). For sugars,
these are the GLUT series, with other series for amino acids, ions
and other nutrients. These types of carrier move the non-electrolytes
only down their concentration gradient into the ECF and then by
diffusion into the blood. This type of carrier can also work in the
opposite direction and carry sugars, amino acids and other molecules
from the blood into the cell when the concentration gradient is
reversed (see Fig. 14.9C).
Sodium and chloride
The initial recovery of Na+
is coupled to the Na+
/H+
antiporter which
in turn is dependent on HCO3
–
in the tubule to generate the H+
ions.
The first third of the PCT recovers most of the HCO3
–
ions, so that
when its concentration in the tubular fluid falls, the recovery of Na+
slows. However, to overcome this problem, the next section of the
tubule has a Cl HCO
− −
3 coupled exchange process, so here the
HCO3
–
ions are returned to the tubular fluid to help recover Cl−
ions.
Now, the H+
/Na+
antiport has more HCO3
–
to react with to help the
recovery of more Na+
ions, as well as the Cl−
(see Fig. 14.9D).
Table 14.2 Representative compounds secreted by the renal organic anion and cation transport systems
Anions Cations
Endogenous compounds Drugs Endogenous compounds Drugs
Amino acids
Benzoate
Bile salts
Cyclic AMP
Long-chain fatty acids
Hippurate
Hydroxybenzoates
Hydroxyindoleacetic acid
Oxalate
Prostaglandins
Urate
Acetazolamide
Cephalothin
Chlorothiazide
Ethacrynic acid
Furosemide
Indometacin
Penicillin G
Probenecid
Saccharin
Salicylate
Acetylcholine
Epinephrine (adrenaline)
Choline
Creatinine
Dopamine
Histamine
5-Hydroxytryptamine
Norepinephrine (noradrenaline)
N-Methylnicotinamide
Serotonin
Thiamine
Amiloride
Amprolium
Atropine
Cimetidine
Hexamethonium
Mecamylamine
Morphine
Neostigmine
Paraquat
Quinine
Tetra-ethylammonium

Nephrotoxicity
Some drugs can damage the cells of the nephron as they accumulate
within the cytoplasm and this nephrotoxicity is related to their uptake
in the tubule cells by these processes and the lower ability of the cells
to transport these drugs into the urine. Neonates are protected from
this damage as their uptake transport system is poorly developed
at this stage.
Organic cation transport
Many organic cations in the blood are excreted by the kidney where
a series of organic cation transporters (OCT1–3) are expressed. These
are electrogenic organic cation transporters with a broad specificity,
which suggests they are involved in the first step of secretion of the
compounds, moving the molecules across the basolateral membrane.
The exit across the brush border is accompanied by an organic cation/
H+
antiporter acting down the lumen/cell H+
gradient established
by Na+
/H+
exchange. Table 14.2 gives some examples of these
compounds (Clinical box 14.5). However, the detailed mechanism
of their transport has not been well characterised and work is still in
progress, although the structure of OAT and OCT has been identified.
Renal function tests
The symptoms of renal failure can masquerade under an amazing
variety of clinical conditions, so it is essential to be able to screen
patients using simple low-cost techniques before proceeding to
more complex and expensive diagnostic tests.
Blood and urine tests
In routine blood tests, raised levels of urea and creatinine are the
first signs of possible renal problems, which can be confirmed by
testing the urine, where increased levels of protein and tubular debris
after centrifugation can often be found. Measurement of the urinary
volume over 24 hours and the ability to form concentrated urine, when
water intake is restricted, can also be used and will identify both
problems within the kidney and of the water control mechanisms.
Relative density of urine
This can be measured by a number of methods.
Osmolality
Osmolality of urine depends on the number of particles present
and can be measured directly by the depression of freezing point
with an osmometer. It is significantly increased in glycosuria but
not influenced by temperature or protein.
Specific gravity
A more simple guide is to measure the specific gravity using a
hydrometer, which compares the specific gravity of the test fluid
with the specific gravity of pure water:
Specific gravity density of test fluid density of water
=
In pure water, the float will sink to a level of 1.000 on the hydrometer.
With increasing density of the test solution, the scale on the
dicarboxylates, prostaglandins, cyclic nucleotides, urate, folate,
diuretics, angiotensin-converting-enzyme (ACE) inhibitors, antiviral
agents, β-lactam antibiotics, antineoplastics, mycotoxins, sulphate
conjugates, glucuronide conjugates, cysteine conjugates, ochratoxin
A, non-steroidal anti-inflammatory drugs (NSAIDs) and uraemic toxins.
Para-aminohippuric acid
Hippurate is the prime organic anion secreted by the kidney and
approximately 1 g/day is excreted in the urine. PAH is an amide
derivative of the amino acid glycine and para-aminobenzoic acid.
It is a model substrate for this process and on the basolateral side
of the cell there is a two-stage process (see Fig. 14.9E). The first
step is the entry of dicarboxylates (α-ketoglutarate and glutarate)
co-transported with sodium. The ubiquitous Na+
pump maintains
the low Na+
in the cell, which enables this co-transport to proceed.
Then the intracellular dicarboxylate exchanges with an organic anion,
in this case PAH, which moves into the cell on the apical (luminal)
side of the cell. The PAH is then exported into the lumen on the
basolateral side in exchange for another anion, such as chloride,
urate or hydroxyl ions, so the PCT can concentrate PAH to a much
higher level than in plasma (200–300 times).
In plasma (pH 7.4), PAH with a pK of 3.8 is 99% ionised, whereas
in urine with a pH of 4.5, 83% is ionised. The non-ionised fraction
can diffuse through the lipid cell membrane, so making the urine
more acidic and increasing the secretion of PAH into the urine.
This leads to a complete clearance of PAH on a single passage
through the kidney.
In contrast, the excretion of some molecules, such as probenecid,
phenobarbital and salicylic acid, can be increased by urinary
alkalisation (see Ch. 4). This mechanism is a balance between the
pKa, the partition coefficient (Kp) and the pH, so that the excretion of
some drugs, such as barbital and urate, are not increased by urinary
alkalisation. PAH has been found to enhance the rate of excretion of
water, Na+
, K+
and HPO2
−
and this is seen in patients receiving massive
doses of carbenicillin. This also occurs in starvation where there are
increased organic acids derived from fat metabolism (see Ch. 3).
PAH is useful for the measurement of renal plasma flow (RPF)
because it is secreted primarily by the renal tubules; only 20%–30%
is filtered by the glomerulus. PAH is completely filtered from plasma
in the nephron and not reabsorbed by the tubules, in a manner
identical to inulin. The clearance of PAH is reflective only of RPF
to portions of the kidney that deal with urine formation, and thus
underestimates actual RPF by approximately 10%.
PAH and drug dosage
When the GFR falls to 10% or less of normal, hippurate accumulates
in the blood and competes for the binding of several drugs, such as
salicylate, phenytoin, sulfonamides and furosemide. There will be
an increased level of the unbound drug in the plasma with a greater
therapeutic effect for a given dose. In contrast, when such patients
are dialysed, the hippurate is removed so the protein binding now
increases and the therapeutic effect of some drugs will be decreased
and the dose must be adjusted to allow for this effect.
Efflux transporters and drugs
Efflux transporters are active transport systems that extrude drugs
out of cells (see Ch. 4). They require energy to function. These
efflux transporters have a broad range of specificity so can handle
many molecules. The transport proteins can also be induced or
upregulated, thereby accounting for the failure of some drugs to
continue to act with repeated doses. This effect explains why some
anti-cancer agents fail to work after the initial positive response, and
may contribute to bacterial multidrug resistance.
Clinical box 14.5 Furosemide
Furosemide is bound to plasma proteins and is not filtered so only passes
into the tubule by these secretion processes. Indometacin, aspirin and
probenecid compete with this step, so reduce the diuretic action of this
drug, although they do displace it from the protein binding which
increases entry into the tubule by filtration (see Ch. 4).

14
Proteinuria
Physiologic proteinuria does not exceed 150 mg/24 h for adults
and 140 mg/m2
in children. A urine dipstick is highly sensitive in
detecting albumin (limit approximately 0.2 g/L). A dipstick allows
rough quantification of urine from 0 to ++++. A urine dipstick does
not identify globulin fraction of protein and can be negative in Bence
Jones proteinuria (free immunoglobulin light chains in urine).
Protein quantification is expressed as g/L or g/24 h. Twenty-four-
hour urine collections are time consuming and practically difficult;
hence an alternative measure, the protein:creatinine ratio (PCR) on
a random urine sample, has now been validated, widely accepted
and used. A first or early morning urine sample is more accurate
(Clinical box 14.6).
Proteinuria may be increased by a factor of 2–3 times by strenuous
exercise or fever. Other causes of transient proteinuria include urinary
tract infection, vaginal mucus, orthostatic proteinuria (occurs after
patient has been upright for some time and is not found in early
morning urine – this condition is uncommon in patients over 30
years old) and pregnancy. Causes of persistent proteinuria include:
• Primary renal disease – this may be glomerular (e.g.
glomerulonephritis) or tubular
• Secondary renal disease – diabetes mellitus, hypertension,
connective tissue diseases, vasculitis, amyloidosis, myeloma,
congestive cardiac failure.
Renal handling of molecules
Simple estimates of renal function can be derived from changes in
the way that the kidney handles molecules. The kidney can handle
molecules in three ways:
• First, a molecule can be simply filtered and then passed
unchanged into the urine (Fig. 14.10A)
• Second, it can be filtered then reabsorbed as it passes
through the PCT, so the final concentration in the urine is less
than in plasma (see Fig. 14.10B)
• Finally, a molecule can be filtered and then more can be
added to the urine by secretion in the PCT, making the
concentration in urine higher than in plasma (see Fig. 14.10C).
These mechanisms can be studied by the use of a technique called
clearance. Water being abstracted from the tubule will alter the
concentration in the urine but its effect will depend on the transport
of each molecule. Even molecules which are only filtered will be
concentrated in the urine by this process.
Renal clearance
The clearance of a molecule is defined as ‘volume of plasma cleared
of that molecule per minute’. Because no molecule is fully cleared
hydrometer will float to a higher level, which is related to the ionic
content. Plasma has a specific gravity of 1.010 (285 mOsm). Urine
can vary from a specific gravity of 1.035 (1400 mOsm), the most
concentrated and dark, down to 1.005 (50 mOsm), the most dilute
and pale. Note, however, because the density of fluids varies with
temperature and hot fluids are less dense, it is essential to allow
the urine to cool to the calibrated temperature of the hydrometer.
In hot environments, it is necessary to ensure that the hydrometer
used is calibrated to the range of climatic temperature.
Although not frequently performed, measurement of the specific
gravity of a urine specimen can give an indication of the efficiency
of the renal control of fluid balance mechanisms (see later). If the
specific gravity is 1.035, glycosuria should be considered; when
it is 1.040, this indicates the presence of extrinsic osmotic agents
(e.g. contrast)
Refractometry
This is based on measurement of refractory index, which depends
on the size and weight of solutes and correlates well with osmolality.
Dry chemistry
Dry chemistry is incorporated into dipsticks and detects the presence
of cations and protons by colour change.
Analysing urine
The history of urinalysis can be traced back to ancient Egypt, where
polyuria and haematuria were mentioned in medical papyri, and, by
400 BC, Hippocrates had observed the changes to the colour and
odour of urine and its relation to disease. Healthy urine should be
clear and a straw colour. Other colours can indicate the presence
of drugs, blood haemoglobin or bilirubin. The odour of urine can
reflect chemical conditions: a fruity odour or acetone in diabetes
mellitus; a musty odour indicates hepatic disease; and ingestion
of various dietary constituents, such as garlic, gives other odours.
The various penicillins are excreted via the kidney and can impart
a strong odour to the urine. By the end of the 18th century, the
chemistry of urinalysis had progressed to various spot tests and
then to test papers, which identify specific constituents present in
the urine. Table 14.3 sets out the range of tests commonly in use
and their purposes.
Specialised spectrophotometers can be used to quantify the
concentration of various constituents in urine.
Table 14.3 Urine tests and purposes
Range of tests Uses
Specific gravity To monitor drugs in athletes
pH 4.8–7.4 Acid–base disturbances
Leucocytes Inflammatory disease of the kidney
Nitrite Presence of bacteria
Protein (albumin) Renal disease
Glucose Diabetes mellitus renal threshold 8.3–10 mM
Ketones Increased fat degradation, gastrointestinal
infection in diabetes mellitus
Urobilinogen Liver disease or increased haemolysis
Bilirubin Liver damage, hepatitis, cirrhosis
Blood Renal and post-renal bleeding
Clinical box 14.6 Interpretation of urine protein to urine
creatinine ratio
Child under age 2 years
Normal ratio 0.5
Adults and children over age 2 years
Normal ratio 2 mg/mmol correlates with 0.2 g protein/day (i.e. 2 ×
10 mg protein/day)
Nephrotic range 3.5 (correlates with 3.5 g protein/day)
Interpretation of urine albumin to creatinine ratio (ACR)
Microalbuminuria: ACR of 2.5–30 mg/mmol (men) and 3.5 to 30 mg/
mmol (women)
Macroalbuminuria: ACR of 30 mg/mmol (this is approximately equivalent
to PCR 50 mg/mmol, or a urinary protein excretion 0.5 g/24 h).

as a bolus. Because this molecule is filtered, the level in the blood
will rise to a peak value then fall with time, as shown in Fig. 14.11A.
The urine is collected for a set period and the concentration of
‘inulin’ in the urine and the volume formed in mL/min (UinV) can be
easily determined. The problem, however, remains to find a value of
plasma which reflects the average concentration for the period (Pin).
Various methods have been used to obtain a mean of this value of
plasma concentration, including infusing a dilute ‘inulin’ solution to
balance the renal loss as shown by the dotted line in Fig. 14.11A, or
calculating the area under the curve, but errors in this value have
a large effect on the calculation of Cin.
Note that whatever level of ‘inulin’ appears in the blood, the
same level is filtered into the urine, so the relationship becomes a
straight line with a slope of 45 degrees. Fig. 14.11B shows that the
clearance (Cin) of this molecule is independent of the blood level.
Values of ‘inulin’ clearance are in the range of 125 ± 30 mL/min
for normal male subjects. This is the value taken as ‘normal’ GFR.
Again, note that the range of Cin in normal subjects is quite large,
i.e. ± 30 of the population mean value of 125, and depends on body
size, age and sex. Females have a lower value than males with a
mean of approximately 90 mL/min being taken as normal. Infants
do not achieve adult GFR until they are approximately 4 years old
and cannot fully concentrate their urine until the kidney has matured.
Renal function begins to decrease with increasing age (after the age
of approximately 65–70 years).
Creatinine clearance
Creatinine is a breakdown product of muscle metabolism (creatine
phosphate) and is usually produced at a constant rate by the body
(depending on the muscle mass), so has a constant level in the blood.
(Note: creatinine is a di-amino acid and must not be confused with
creatine.) This molecule was thought to be a good marker for GFR
because it is endogenous, i.e. occurs naturally in the circulation,
and the plasma concentration (Pcr) is relatively constant. Serum
by the kidney, it is more a concept than a reality. It is a simple
way of quantifying the handling by the nephron of various types
of molecules. The most useful renal function which can be derived
from a clearance measurement is the GFR.
If the renal excretion (Ux × V), i.e. the concentration of a molecule
in mM in the urine (Ux) multiplied by the volume of urine formed
per minute (V), is measured and divided by the concentration of the
molecule in plasma (Px), we can gain some idea of how the nephron
is handling the molecule. This is termed the clearance of a molecule.
The clearance of molecule x is expressed as:
C U V P
x x x
= ×
( )
where:
Ux = the concentration in the urine in mM
Px = the concentration in plasma in mM
V = the volume of urine formed per min, i.e. mL/min.
The unit of clearance is mL/min.
Clearance of molecules that are only filtered
If a molecule is filtered and then passes unchanged into the urine,
the clearance of such a molecule is an index of the effective GFR of
all the nephrons. The concentration of such a molecule will be raised
in the urine, as it will remain trapped in the tubule after filtration,
where some 99% of water and other constituents of the filtrate are
mostly recovered as they pass along the tubule.
‘Inulin’ clearance as an index of GFR
In the past, ‘inulin’ (a plant starch) of MW 5200, was used for testing
renal clearance as a molecule that is filtered and then passed
unchanged into the urine. ‘Inulin’ is now no longer available and
polyfructans are used instead. Inulin clearance, however, is still a
benchmark against which all other methods are judged, and the term
‘inulin clearance’ is still used. To perform a clearance test with ‘inulin’
(Cin), the bladder is first emptied and the ‘inulin’ injected intravenously
Filtration only
Reabsorption of
water and salts
A
Filtration plus
secretion
C
Filtration plus
reabsorption
B
Fig. 14.10 Renal handling of molecules. (A) Molecules can be filtered only and not reabsorbed or secreted, but will still have an increased
concentration in the urine due to the fact that fluid is recovered along the nephron. (B) Molecules that are filtered and reabsorbed will have a
very low concentration in the urine. (C) Molecules that are filtered and secreted will have an elevated concentration in the urine and very low
levels in the blood draining from the nephron.

14
Urea clearance
Urea is also a natural product, but it is reabsorbed and recirculated
in the kidney so it gives values three-fifths of GFR; urea clearance,
Cu, is approximately 80 mL/min. The ratio of Ccr to Cu can be used to
reduce variation. Cu does, however, vary with water intake, so if the
water intake is low even more is reabsorbed and the value of Cu falls.
Current methods for measuring renal
clearance (half-life)
Fig. 14.11A shows that the level of ‘inulin’ in plasma when injected
as a bolus decreases with time as it is filtered through the kidney.
If the kidney is damaged and GFR is depressed, the rate of ‘inulin’
filtration with time will be less, and the blood level will fall more
slowly (hatched line in Fig. 14.11A). This fact can then be used as
an indication of renal function. An easily measured molecule, such
as 51
Cr-EDTA (ethylene diamine tetra-acetic acid, MW 300) is given
as a bolus and then the blood level followed for a period by taking
serial blood samples. EDTA is a molecule which strongly binds to
chromium (Cr). 51
Cr is an isotope which emits gamma rays and is
easy to count. Initially the counts in plasma samples will rapidly rise
to a maximum. Then decrease over a period. The time can then be
taken for the isotope level to fall to half of the maximum, which is the
half-life (t1/2) for healthy subjects (see Fig. 14.11A). With the progressive
deterioration of renal function the t1/2 gradually increases, indicating
loss of filtration capacity, and reflects the number of nephrons which
are still functional. This method is quick and cheap and has largely
replaced other clearance methods. It has limited clinical use apart from
use in estimation of GFR in a potential kidney donor. It can be used
in certain groups of renal failure patients with unreliable estimated
GFR, e.g. amputees and those with extremes of body weight.
Clearance of molecules that are filtered
and reabsorbed
Clearance of molecules that are filtered and reabsorbed is not used
as a test, but gives an idea of one of the most important functions of
the kidney (see Fig. 14.10A). Molecules such as glucose have a very
low clearance (0.2 mL/min) because they are actively reabsorbed. The
normal plasma level is 4–5 mM and only tiny amounts are found in
the urine of normal subjects; however, as the blood level of glucose
increases a point is reached – the renal threshold – when glucose
appears in the urine at the same rate as ‘inulin’, etc. This is the result
of the saturation of all the carrier sites; i.e. there is a limited number
of sites for uptake and, if there is a large excess of glucose in the
blood, they all become occupied and now the molecule passes
through the PCT, as if it was only filtered. As can be seen from
Fig. 14.12A, once the threshold is reached the behaviour of glucose
parallels that of a molecule which is only filtered, such as creatinine.
The threshold is not a sharp point but has a ‘splay’ as different
nephrons have a slightly different value for threshold. The threshold
is approximately 8–10 mM in a healthy subject. After a meal with a
high sugar content, this value is exceeded for a short while, which
explains why a small amount of glucose is found in the urine of healthy
people. The displacement of the glucose response, compared to
that of a molecule that is only filtered, is expressed as the tubular
maximum, Tm, and represents the total capacity of the kidney to
reabsorb glucose. With diabetes mellitus, glucose in the urine is
common due to the lack of insulin and high levels of glucose in the
plasma, but as the disease progresses, microvascular complications
lead to renal damage and a much elevated threshold for glucose.
Now, little glucose appears in urine, although the plasma levels may
be 20 mM or greater (normal 4–5 mM). This is why urine testing for
glucose in diabetes mellitus is currently no longer used and has
creatinine is affected by the level of GFR and by factors independent
of GFR, including age, gender, race, body size, diet, certain drugs
and laboratory analytical methods. This makes it a poor marker of
true renal function.
Creatinine clearance, Ccr, gives values close to ‘inulin’, i.e. 125 mL/
min, although there is a small component of secretion. However,
the error caused by the raised value of urinary creatinine, Ucr, is
balanced by a plasma chromogen which raises the value of Pcr, so
the errors cancel.
Serum creatinine levels may vary from one laboratory to another,
depending on the method used to measure. It is usually 60–80 µmol/L
in males (higher muscle mass) and 40–60 µmol/L in females (lesser
muscle mass). It is simple to measure and is elevated only in renal
failure. Creatinine is mostly filtered but is secreted by proximal
tubules as well.
Maximum
Time (minutes)
Blood level (mg)
Inulin or
creatinine
Urine
excretion
(mg/min)
Renal
failure
‘Inulin’
level
in
blood
IV bolus
t 1
2
/
t 1
2
/
Ideal level if given IV infusion
0
0
5
10
2 4 6 8 10
A
B
Fig. 14.11 Inulin clearance. (A) Molecules that are filtered only,
such as ‘inulin’, can be re-used as an index of GFR. If ‘inulin’ is
given as a bolus into the plasma, the level rises rapidly to a
maximum, then ‘falls’ off with time as it is filtered. In renal failure, the
rate of ‘fall’ is much reduced and by measuring the time to reach a
value that was half the maximum, an index of renal function can be
derived from the fall off in plasma level. To get a true reading,
plasma level ‘inulin’ would have to be infused at a rate to match the
filtered loss; as this is not known, this is difficult to achieve. (B) As
the urine excretion matches the blood level, it indicates that this
molecule is filtered only. IV, intravenous.

Use of clearance methods to assess renal function
RBF is approximately 1.2–1.4 L/min, i.e. one-fifth of cardiac output.
Thus we can then, by relatively simple methods, obtain the effective
GFR and RBF using clearance techniques. The ratio of GFR to RBF
is called the filtration fraction (FF) and is approximately 0.10–0.15;
i.e. 20% of the plasma passing through the kidney is filtered into
the nephron.
FF GFR RBF in PAH
= = C C
With the large number of patients with possible renal failure, it is
essential to take a detailed history and to be able to screen patients
using blood tests and simple low-cost techniques before proceeding
to those which are more complicated and expensive.
Advanced clinical tests
If signs of renal failure are detected on simple testing, a variety of
diagnostic tests can then be used to identify the site of the renal
dysfunction, e.g. obstruction, by imaging, ultrasound, nuclear medical
imaging, computed tomography scans or the gamma camera.
Renal control of fluid balance
The mechanisms which balance fluid intake with fluid loss are more
precise than those for acid–base and electrolyte balance. The control
of these processes resides in an osmoreceptive complex located in
the hypothalamus (Fig. 14.13A) and comprises the subfornical organ,
the organum vasculosum of the lamina terminalis and the median
pre-optic nucleus, all of which input onto the magnocellular neurons
of the supraoptic (SO) and paraventricular nuclei (PVN). The SO and
PVN neurons can act both as osmoreceptors and also synthesise
two peptide hormones – vasopressin and the reproductive hormone
oxytocin.
Vasopressin
Vasopressin (or ADH) is a nonapeptide (nine amino acids) that has
two cysteine residues in positions 1 and 6, linked by a disulphide
bridge (Fig. 14.13B). It has a short half-life of 15–20 minutes. ADHs
evolved very early in evolution and are found in most animal species.
In mammals, vasopressin is released from the posterior pituitary
in response to a small rise in the osmotic pressure of the plasma
usually caused by an increased rate of water loss. There is an
inverse relationship between the plasma vasopressin level and the
osmolarity of the urine (Fig. 14.13C). Note, however, that although
the volume and concentration of urine vary, the net loss of solute
does not, and is maintained constant for a given period. There is
thus a mechanism by which the water balance is separated from
that of solute.
Water intake is regulated to maintain a physiological serum
osmolality of 285–290 mOsm/kg. Normally, the level of vasopressin
in the plasma is in the range 2–4 pg/mL and is rapidly increased as
the plasma osmolarity changes. Osmotic threshold for vasopressin
release is 280–290 mOsm/kg. Thirst plays an important role in water
balance and only a 2%–3% change in plasma osmolarity can produce
a strong desire to drink water. This precise matching of the plasma
vasopressin level to osmolarity is the central mechanism of water
homeostasis (Fig. 14.14A, B). The normal response to a fall in water
intake is a rise in plasma osmolarity, and within minutes, an increase
in the plasma vasopressin level.
Once vasopressin has been synthesised by neurons of the SO
and PVN, it is then attached to the transport protein neurophysin
as granules, which are then rapidly transported within 30 minutes
been replaced by measuring the glucose level in blood with various
reagent strips which give an accurate colour change depending on
the level of glucose in the blood. This colour is measured by various
meters which now can respond in approximately 10 seconds or less.
Clearance of molecules that are filtered
and secreted
Some molecules are both filtered and secreted, such as organic
acids and bases, and molecules that are lipid soluble or are toxic
and have been converted into glucuronides by the liver (see Ch. 4).
With these compounds, more appears in the urine than in the blood
as they are secreted into the tubule. As with sugars, this process
saturates because there is a finite number of carriers. The process
has both a threshold and Tm. The values for clearance of molecules
such as PAH are in the region of 650–700 mL/min. Because these
compounds are both filtered and secreted, the amount remaining in
the blood leaving the nephron is very low and can give an indication
of the RPF, i.e. the clearance of PAH, CPAH = RPF. Because the PAH
is only present in the plasma, the renal blood flow (RBF) can then
be calculated by correction with the haematocrit (Hct), i.e.
RBF Hct
PAH
= −
C 1
0
0
2.5
7.5
0
5
5 15
Tm
Tm
Threshold
Splay
10
0 1 2 3 4
Filtration only
Filtration
only
Filtration plus
secretion
Filtration
plus
reabsorption
Urine
excretion
(mM/min)
Urine
excretion
(mM/min)
Blood level of glucose (mM)
Blood level of PAH (mM)
10
15
20
5
5
10
A
B
Fig. 14.12 Clearance of molecules that are filtered and
reabsorbed, such as glucose. (A) Initially no glucose appears in
the urine, as it is reabsorbed; however, once the plasma level
exceeds the renal threshold, glucose is filtered into the urine. This
point is related to the availability of carriers to recover the filtered
glucose, which eventually becomes saturated. Different nephrons
vary in their saturation level so there is a splay in the threshold level.
Once the threshold is exceeded, glucose is just filtered and the
line is parallel to that of molecules which are only filtered. The
displacement of this line gives an index of the tubular maximum, Tm,
for the recovery of glucose. (B) For molecules which are filtered and
secreted, the level in the urine is higher than in the plasma. This
process will also saturate in most cases. Molecules such as
para-aminohippuric acid (PAH) are virtually cleared from the plasma
by these processes.

14
is steep, and in addition the gradient, can be altered by the fluid
volume of the ECF, which will increase or decrease the sensitivity
of the response (see Fig. 14.13). Vasopressin can also be released in
response to a fall in blood pressure, but the change in blood pressure
must be of a much larger magnitude than that of osmolarity.
to the posterior pituitary, down microtubules in the axons of the
neurohypophyseal tract; here it is stored prior to release.
Bursts of action potentials in these axons of the neurohypophyseal
tract, in response to a tiny rise in osmotic pressure, cause the release of
vasopressin into the bloodstream. However, the slope of this response
Cerebellum
Pituitary
Paraventricular
neurons
Osmoreceptors
Baroreceptor
input
Vasomotor centre
(medulla oblongata)
Vagus and
glossopharyngeal
nerves
Total solute excretion
Urine osmolarity
Urine flow rate
Min
Max
Max
0 Plasma VP
A
B
C
Supraoptic
neurons
Optic
chiasm
Anterior lobe Posterior lobe
VP
S S
Cys - Tyr - Phe - Gln - Asn - Cys - Pro - Arg - Gly(NH2)
Fig. 14.13 Vasopressin secretion. (A) Anatomy of the hypothalamus and pituitary gland (mid-sagittal section) depicting the pathways of
vasopressin (VP) secretion. Also shown are pathways involved in regulating VP secretion. Afferent fibres from the baroreceptors are carried in
the vagus and glossopharyngeal nerves. The vasomotor centre includes the solitary tract nucleus. The closed box illustrates an expanded
view of the hypothalamus and pituitary gland. (B) The amino acid sequence of vasopressin. (C) Relationship between plasma VP levels and
urine osmolarity, urine flow rate and total solute excretion.

0
Normal
260 270 280 290 300 310
Plasma osmolarity (mOsm/kg H2O)
Max
Plasma
VP
10% increase in
volume/pressure
10% decrease in
volume/pressure
A
0
260 270 280 290 300 310
Plasma osmolarity (mOsm/kg H2O)
Tubular
lumen
Capillary
COOH
ATP
AMP
Cyclic
PKA
Inactive
PKA
Active
Adenylate
cyclase
Protein
phosphorylation
Vesicles with inactive
water channels
Active water
channels
Fusion of
vesicles with
apical cell
membrane
VP
Max
Plasma
VP
(pg/mL)
Plasma
VP
(pg/mL)
0
–30 –20 –10 0 10 20
% Change in blood volume or pressure
Max
B
C
Fig. 14.14 Action of vasopressin. Interaction between osmotic and haemodynamic stimuli for vasopressin (VP) secretion. With decreased
blood volume and pressure, the osmotic set point is shifted to lower plasma osmolarity values and the slope is increased. An increase in
blood volume and pressure has the opposite effect. (A) Changes in VP secretion in response to plasma osmolarity variation. (B) Plasma VP
levels in relation to plasma osmolarity and changes in blood volume or pressure. (C) Cellular action of VP.

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.-14 - The renal system.pdf