Medical Physiology

560

Renal Physiology
Part One
 Overview of the Renal System

Learning Objectives

1. Describe the major body fluid compartments and give typical volumes.
2. Outline the role of the renal system in control of body fluid composition and in the
balance between fluid and electrolyte ingestion and excretion.
3. Indicate the site of release of renin, erythropoietin and vitamin D3 by the kidney and, in
each case, summarize the stimuli for secretion and the major functions.
4. Describe in sequence the tubular segments through which ultrafiltrate flows from
Bowmans capsule to the ureter. Identify the cortical/medullary location of each renal
tubule segment.
5. Compare and contrast the structure and function of cortical and juxtamedullary
nephrons.
6. Describe in sequence the blood vessels through which blood flows when passing from
the renal artery to the renal vein, including the glomerular blood vessels, peritubular
capillaries and vasa recta.
7. Explain the functional significance for glomerular filtration of having arterioles at either
end of the glomerular capillary network.
8. Explain the functional significance of having post-filtration blood entering the peritubular
capillary network in terms of glomerulo-tubular balance (GTB).
9. List the anatomical elements of the juxtaglomerular apparatus (JGA) and know its major
functions are renin secretion and Tubulo-glomerular feedback (TGF).
10. Compare and contrast characteristics of renal oxygen consumption with other organs.

Renal Physiology 1
 Overview

Introduction
Most lay people correctly identify the kidneys as excretory organs. Whilst it is true that kidneys
excrete metabolic waste products such as urea, uric acid, creatinine and creatine, as well as many
foreign substances, this view of the kidney is too narrow. Given the wide range of intake of
substances in the diet, the kidney must respond by varying the rates of excretion of many
substances to achieve balance, thereby ensuring that constancy of the internal environment is
maintained.

Urine formation starts with glomerular filtration of plasma at an exceedingly high rate (150-200
liters per day!). Typically about 99% of glomerular filtrate is reabsorbed during passage along the
renal tubules. For this to occur the luminal lining of the nephrons consist of different specialized
epithelia. The rate of reabsorption is highest proximally and reduces distally. The distal tubule
and collecting duct generally receive a fairly constant fraction of the filtrate (about 10%). These
sites are subject to the most precise hormonal regulation to maintain water and sodium balance.
This basic model of filtration-reabsorption holds for many substances, though for others such as
potassium and H+ (acid/base regulation) and some organic molecules, reabsorption and secretion
across the nephron epithelia is important.

Endocrine and Synthetic Functions Of The Kidney

As an organ of regulation, the kidney is a target for several hormones including, for example,
anti-diuretic hormone and aldosterone. In addition, the kidney acts as an endocrine organ by
producing and releasing hormones that act on other organs or tissues.

Erythropoietin (EPO)
EPO is a glycoprotein hormone, which controls the rate of formation of red blood cells from
stem cells in the bone marrow. The stimulus for EPO secretion is reduced local PO2 in the
kidney (not systemic arterial oxygen tension) . About 80% of EPO is produced in the kidney and
most of the rest comes from the liver. The site of production of renal EPO is fibroblasts in the
renal interstitium. The mechanism coupling low PO2 to EPO secretion involves increased local
production of prostaglandins within the renal cortex during hypoxia, which in turn activates EPO
synthesis. Patients with renal failure usually have insufficient EPO and develop anemia.

Renin
Renin is an enzyme. It is synthesized and stored in granules within juxtaglomerular cells lining the
afferent arteriole. It is released in response to a fall in effective circulating volume. Release of
renin initiates a cascade of events resulting in production of the hormones angiotensin II and
aldosterone.

Renal Physiology 2
 Overview

Vitamin D3
Vitamin D3 is a steroid derived from precursors that are either ingested or produced from the
action of UV light on the skin. The active form of vitamin D3 is 1,25-dihydroxycholecalciferol,
also known as calcitrol. It is produced by a series of metabolic steps in the liver and kidneys. 25-
hydroxylated D3 arrives from the liver and undergoes final activation in the kidney involving
hydroxylation at the 1- position by the mitochondrial enzyme 1 -hydroxylase, located in the
proximal tubule. This process is stimulated by parathyroid hormone, the secretion of which is
directly coupled to a fall in serum free calcium concentration. The main physiological action of
calcitrol is to increase intestinal absorption of dietary calcium, though it also reduces renal
calcium excretion.

The kidney produces several paracrine signaling molecules that regulate aspects of glomerular
filtration or tubular transport. These include local angiotensin II, prostaglandins, dopamine, nitric
oxide and purines such as adenosine. These will be mentioned at appropriate times in later
lectures.

Functional Anatomy

Anatomy Review: The kidneys are bean-shaped retroperitoneal organs, situated one each side of
the vertebral column. Each kidney is typically 12 cm long and weighs about 150g. On the medial
surface at around the level of the first lumbar vertebra is the renal hilus, through which the renal
artery and vein, nerves, lymphatics and the renal pelvis pass. When bisected from pole to pole in
the coronal plane, the cut surface of the kidney shows a pale outer region, the cortex, and a
darker inner region, the medulla, which is further divided into several conical areas called renal
pyramids. The apex of each pyramid tapers towards the renal pelvis, forming the renal papillae.
Striations called medullary rays are visible on renal pyramids, which are due to straight tubular
(collecting ducts and loops of Henle) and vascular (vasa recta) elements in these regions. The
renal pelvis has a funnel shaped upper end and is continuous with the ureter below, which runs a
course of about 30cm to the bladder. [Note: for USMLE I you should know the nature of the
transitional epithelium lining the lower urinary tract and also the functional innervation of the
ureters and bladder. These were dealt with in anatomy and we will focus on the physiology of the
upper urinary tract only.]

Renal Physiology 3
 Overview

The Nephron

The nephron is the functional unit of the

kidney. Young adults have between 500-800
thousand nephrons per kidney. The number
of functioning nephrons gradually decreases
with age and is 300-700 thousand per kidney
by 80 years.

Q: What is the advantage of having many

thousands of small nephrons rather than a
few larger tubules?

Histology Review: Each nephron consists of

an expanded proximal end called the
Bowmans capsule, which is invaginated by a tuft of capillaries called the glomerulus. The
glomerulus is the site of primary urine formation by filtration of plasma. The Bowmans capsule
is continuous with a long narrow nephron tubule, which is the site of modification of the primary
filtrate by reabsorption and secretion. The proximal tubule is the first part of the renal tubule
and consists of a convoluted part and straight part, which is continuous with the loop of Henle.
Epithelial cells lining the proximal tubule have an apical microvillous brush border membrane.
This increases their surface area, particularly in the convoluted part, and reflects the high rates of
transport seen in this segment. A narrowing of the renal tubule as it descends from the cortex
towards the medulla, marks the transition to the loop of Henle, which is lined in its first two
parts by flat squamous cells. The thin descending limbs descend variable distances into the
medulla (see nephron types below). The loop of Henle is U-shaped and the thin ascending limb
turns, rising back towards the cortex. The cells of the thin limbs are structurally similar, but have
important functional differences, which will be discussed later in the section on urine
concentration and dilution. In the region of the outer medulla, the cells lining the nephron
become cuboidal once more in the thick ascending limb of Henles loop. The next short segment,
the macula densa, is closely associated with the glomerulus and is part of an important regulatory
structure, the juxtaglomerular apparatus (see below). The cuboidal cell morphology continues
into the next segment, the distal tubule. In the renal cortex, distal tubules from around six
nephrons converge to join a collecting duct. As the collecting ducts descend through the renal
medulla towards the papilla, they converge to form large Ducts of Bellini, which deliver final
urine into the renal calyces. The nephron and collecting ducts are embryologically distinct and the
collecting duct should not, strictly speaking, be labeled as part of the nephron. Functionally
however, the cells of the late distal tubule and cortical collecting duct are the same. There are two
cell types; about two-thirds are Principal cells and are involved with sodium and water balance.
Interspersed between the Principal cells are intercalated cells, which are involved with acid-base
balance.

Renal Physiology 4
 Overview

Cortical and Juxtamedullary Nephrons

There are two distinct populations of nephrons, which differ in some aspects both structurally
and functionally. About 85% are cortical nephrons, with glomeruli in the outer cortex and short
loops of Henle, which may only just enter the renal medulla. The other 15% of nephrons are
known as juxtamedullary nephrons (JM). These nephrons have a larger filtration rate than cortical
nephrons and have glomeruli located at the cortico-medullary boundary. Although the proximal
and distal tubules are still located in the cortex, they have long loops of Henle, which may extend
all the way to the tip of the renal papilla. JM nephrons and their associated vasa recta capillaries
are responsible for urine concentration. Species that are able to concentrate their urine the most
have a higher proportion of JM nephrons and also longer loops of Henle. JM nephrons reabsorb
a higher proportion of the glomerular filtrate than cortical nephrons. Thus they are said to be
salt conserving nephrons. In states where effective circulating volume is reduced, the
proportion of blood received by JM nephrons is increased, helping to conserve ECF volume.

Renal Physiology 5
 Overview

Renal Blood Flow

Renal Vascular Anatomy

Histology Review: Almost all of the blood entering the kidney does so via the renal artery.
Reflecting the embryological development of the kidneys as a multilobed structure, the arterial
system divides into lobar branches within the kidney. Interlobar branches run between the renal
pyramids and branch at the corticomedullary junction as arcuate arteries. There is limited
anastomosis within the kidney and infarcts are frequently associated with a particular lobe.
Arcuate vessels give off small interlobular arteries passing vertically into the renal cortex. The
interlobular vessels give origin to the afferent arterioles, which supply the glomerular capillaries
and are the most important vessels from the point of view of physiological regulation of
glomerular filtration. The glomerular capillaries form elaborate loops, which converge to form a
second arteriole called the efferent arteriole. The efferent arteriole then gives rise to a second
capillary bed surrounding the nephrons, known as peritubular capillaries. The vasa recta are
specialized branches derived from the peritubular capillaries, which descend in parallel with long
loops of Henle, deep into the renal medulla and papilla. Peritubular capillaries eventually
recombine to form venules and blood is returned to the renal vein via interlobular, arcuate,
interlobar and lobar veins in sequence.

Renal blood flow is about one fifth of the cardiac output, which is remarkable considering that
the kidneys comprise only about 1-2% of the body weight. The reason for having high blood
flow is to supply the demands of glomerular filtration. The filtration units of the kidney are
located in the renal cortex. This means that all blood entering the kidney passes through the
glomeruli and peritubular capillaries of the renal cortex. Less than 10% of the renal blood flow
follows a course through the renal medulla via the vasa recta and only about 1% reaches the renal
papilla. Blood flow declines along the corticomedullary axis, so that the inner renal medulla and
papilla is always on the verge of ischemia. The reason for low blood flow in these areas relates to
preserving the medullary hypertonicity that is needed for the urine concentration mechanism.

Renal Physiology 6
 Overview

Determinants of Renal Blood Flow

Blood is forced through the

Renal Vascular Resistance Is Relatively Low kidney by the hydraulic
pressure, developed by the
Vascular Resistance is Controlled At Afferent heart, against resistances
located in the renal vasculature.
And Efferent Arterioles Almost all the resistance to
blood flow is located in the
100

Efferent arteriole
afferent and efferent arterioles

Peritubular capillary
(i.e. the pressure drop from
75 renal artery to vein occurs at
Pressure (mmHg)

these sites). Alterations in

Afferent arteriole

Intrarenal vein
50 systemic blood pressure
Renal artery

Renal vein
Glomerular

generally cause changes in

capillary

25 blood flow in the same

direction (increased perfusion
0 pressure = increased blood
flow), whilst altered vascular
resistance usually leads to changes in blood flow in the opposite direction (increased renal
vascular resistance = reduced blood flow). In the kidney these relations hold, but are blunted by
autoregulation acting to stabilize renal blood flow and glomerular filtration. The renal arterioles
are key sites for regulating renal blood flow and glomerular filtration. The tone of renal arterioles
is carefully controlled by a fine balance of vasoconstrictors (renal sympathetic nerves, circulating
angiotensin II and locally released mediators such as adenosine) and vasodilators (especially
locally released prostaglandins and nitric oxide).

Renal Physiology 7
 Overview

The Juxtaglomerular Apparatus

The ascending limb of Henles loop, as it re-enters the cortex to become the distal tubule passes
very close to the Bowmans capsule of its own nephron. A short specialized segment, the macula
densa, comes into contact with the afferent and efferent arteriole. At this point the cells of the
afferent arteriole are specialized granular (juxtaglomerular) cells with secretory vesicles containing
renin. This close association of vascular and tubular elements from the same nephron occurs in
all nephrons and is known as the juxtaglomerular apparatus. The apparatus has two major related
roles, first feedback regulation of glomerular filtration rate and second the release of renin in
relation to the body fluid volume status.

Structure/Function Correlates In The Renal Vasculature

Renal Physiology 8
 Overview

Two Arterioles In Series Reduces Pressure

De
Drop Across The Glomerular Capillary
sig
ne Glomerular capillary

df
or
40

30
fi ltra
Pressure (mmHg)

20
tio
10 n!
Skeletal muscle capillary

Normalizing Distal Tubular Fluid Delivery:

Glomerulo-Tubular Balance
Blood flow Peritubular capillary
oncotic pressure

Glomerular
Filtration

Reabsorption

Distal Nephron Fluid Delivery Normalized

Q: What is the significance of having arterioles capable of independent activity at each end of the
glomerular capillary?

Q: What is the significance of having two capillary beds (glomerular and peritubular) in series?

Renal Physiology 9
 Overview

Renal Oxygen Consumption

The kidneys have a very high demand for oxygen, due to the metabolic load placed on nephron
epithelial cells to recover most of the filtered solute load. A unique property of renal oxygen
demand is its dependence on blood flow. This relationship arises because a rise in blood flow is
associated with more glomerular filtration and therefore a greater metabolic demand for nephron
epithelia to recover more solutes. The high blood flow in kidney in relation to tissue mass also
gives rise to the observation that the kidney has the lowest arterio-venous difference in oxygen
concentration of any organ. This is often wrongly taken to mean that renal oxygen consumption
is low. In fact renal tissue has among the highest oxygen demands per gram of tissue. This
becomes clinically apparent in pre-renal acute renal failure (ARF). States of acutely lowered
effective circulating volume, including hemorrhage, dehydration, shock etc can lead to a rapid
accumulation of urea and creatinine in serum, reflecting loss of renal function. ARF carries a high
mortality because relatively short periods of ischemia cause injury to the highly metabolically
active renal cells.

Summary of important actions associated with solute and fluid movements

in the kidney

Representative Nephron
Glomerular
Afferent capillaries Efferent
arteriole arteriole

Renal artery

Filtration

Peritubular
capillaries
Reabsorption

Secretion

Renal vein
Excretion

Renal Physiology 10
 Glomerular Filtration

Glomerular Filtration

Learning objectives.

1. Give normal values for renal blood flow, effective renal plasma flow, glomerular filtration
rate and filtration fraction.
2. Identify the filtration barriers, if any, that impede the filtration of water, sodium, inulin,
albumin and red blood cells.
3. Given the capillary and Bowmans capsule hydrostatic and oncotic pressures, calculate the
net filtration pressure at the glomerular capillaries. Predict the effect on glomerular
filtration rate caused by changes in any of these driving forces.
4. Predict the changes in net filtration force that occur as blood travels along the glomerular
capillary, and colloid osmotic pressure rises.
5. Explain how changes in plasma flow rate affect glomerular filtration rate.
6. Define the filtration coefficient, Kf, at the glomerular capillary and explain its role in
determining glomerular filtration rate.
7. Describe the relative resistances of the afferent and efferent arterioles and the effects of
selective changes in each on renal blood flow and glomerular filtration.
8. Define autoregulation of renal blood flow and glomerular filtration. Describe the
myogenic and tubuloglomerular feedback mechanisms
9. Outline the effects on renal blood flow and glomerular filtration if renal sympathetic
nerve activity increases or if the renin-angiotensin system is activated.

Renal Physiology 11
 Glomerular Filtration

Introduction

A typical glomerular filtration rate is about 180 liters per day! Filtration rate is large to allow
excretion of multiple solutes present at low concentration in plasma, while avoiding the need for
numerous active transport mechanisms in the nephron. Since the kidneys receive a large fraction
of the cardiac output to serve glomerular filtration, they are excellent sensors within the vascular
system.

Glomerular filtration
Afferent arteriole Efferent arteriole
Glomerular capillaries

Bowmans space no protein

all other molecules

and ions at ~same
concentration as
plasma

Structure And Properties Of The Filtration Barrier

What is allowed through the Water and small solutes are freely
glomerular filter? filtered. Larger solutes are restricted by
the structures between the glomerular
1.0
capillary lumen and Bowmans space.
Molecular size and Molecular size is a major determinant
Inulin
shape are
concentration ratio

(~5000) of filterability. Substances with a

determinants of molecular weight of up to around 10
Filtrate/plasma

filterability
0.5 kDa are passed freely. As molecular
weight increases from 10 to 70 kDa
there is a roughly linear decline in the
Hemoglobin (68000) 8nm amount filtered.
0.0 Albumin (~69000)
0 35 70
Molecular weight (thousands)

Renal Physiology 12
 Glomerular Filtration

Albumin is on the limit of filterability on the basis of its size alone. It is essential that albumin is
not lost in the urine, since plasma albumin contributes most to plasma oncotic pressure. Loss of
albumin in urine (proteinuria) when it occurs in large amounts is called nephrotic syndrome
and is associated with systemic edema why?

Another determinant of filtration is the

What is allowed through the electrical charge on a macromolecule.
glomerular filter? In the case of proteins at the
physiological pH of extracellular fluid
+Ve charged
of 7.4, they carry a net negative charge.
Electrical charge
Negatively charged macromolecules are
neutral of macromolecules
also determines repelled by the glomerular filter.
Filtration

their filterability
-Ve
charged

Effective molecular radius

Filtration barrier
Neutral
molecule Anion Anion

Glomerulonephritis: loss of negative charge on glomerular membranes

proteinuria

Renal Physiology 13
 Glomerular Filtration

The barrier structures within the glomerulus are the capillary endothelium, the basement
membrane and the filtration slits between foot processes of podocytes. Endothelial cells have
large fenestrations and the only things excluded here are blood cells. The glomerular basement
membrane consists of a fiber meshwork that has pores with an average diameter of about 7nm,
offering significant resistance to sieving of macromolecules. However, podocyte filtration slits are
the key barrier to filtration of macromolecules. A transmembrane potein called nephrin bridges
the gap between foot processes, acting as the most important functional barrier.

linical Correlate: Changes in the filtration properties of the barrier in disease states often leads to
the appearance of protein in the urine, which is an important clinical finding. The current leading
cause of chronic renal failure in the US is diabetic nephropathy. This disease is characterized by
progressive loss of nephrons and accounts presently for almost half of the approximately 100,000
patients per year with chronic renal failure. An early indication of diabetic renal damage is the
appearance of small quantities of albumin in the urine (microalbuminuria). Several other renal
diseases are characterized by glomerular damage and proteinuria and testing urine for protein is a
routine screening procedure.

Renal Physiology 14
 Glomerular Filtration

Determinants of Glomerular Filtration Rate

Net ultrafiltration pressure (PUF) is

Determinants of glomerular
filtration
GFR = PUF KF
GFR = glomerular filtration rate
PUF = net ultrafiltration pressure
Kf = ultrafiltration coefficient
Kf can be regulated to alter GFR
glomerular filtration rate.
determined by the balance of Starlings
forces. The ultrafiltration coefficient, Kf,
relates PUF to glomerular filtration rate.
Kf is the product of permeability and
surface area. Kf can be regulated by
mesangial cells. These cells are located in
the central part of the glomerular tuft,
holding the glomerular structure in
position. Mesangial cells are contractile
and are able to respond to a variety of
hormones and paracrine agents.
Contraction of mesangial cells is thought
to reduce the filtration surface area and
is thus a mechanism for regulating

The slide illustrates the balance of

Forces for glomerular filtration Starlings forces at the afferent and
Hydrostatic (P) and Oncotic ( )
efferent ends of a glomerular capillary.
afferent efferent The hydrostatic pressure difference
across the capillary wall is one
determinant of the net ultrafiltration
PGC GC pressure. The hydrostatic pressure
PBS inside the glomerular capillary (PGC) is
influenced by arterial pressure and by
Afferent end Efferent end the resistances of the afferent and
45 mmHg PGC 44 mmHg
0 mmHg 0 mmHg
efferent arterioles.
BS
-10 mmHg PBS -10 mmHg
-25 mmHg -34 mmHg
10 mmHg
GC
PUF 0 mmHg
The high rate of plasma filtration
results in a significant hydrostatic
pressure inside Bowmans space of
about 10 mmHg. PBS is driving pressure for fluid flow along the nephron. Note in the slide that
PBS has a negative sign so that all the pressures can be added to obtain a net ultrafiltration
pressure. The gradient of oncotic pressure is another determinant of PUF. In the normal
glomerulus, there is virtually no protein entering Bowmans space, so that the tubular oncotic
pressure BS is zero. The oncotic pressure inside the glomerular capillary GC opposes filtration
and so again has a negative sign on the above slide. At the afferent end of the capillary the
balance of Starlings forces results in a positive net ultrafiltration pressure. However, GC
increases along the capillary as a function of filtration, such that at the efferent end of the
glomerular capillary PUF is reduced and may even be zero.

Renal Physiology 15
 Glomerular Filtration

The graph shows the changes in

Dynamics of glomerular filtration Starlings forces as blood passes along
Area to net the glomerular capillary. Hydrostatic
ultrafiltration
Filtration equilibrium pressures in the capillary and
pressure
50 50 Bowmans space remain almost
constant. Note that PGC at the efferent
40 Hydrostatic pressure in 40
glomerular capillary
end must be lower than at the afferent
Pressure (mmHg)

end in order to have axial blood flow

30 30
Glomerular capillary plasma through the glomerulus. By contrast,
oncotic pressure
20 20 GC increases as a consequence of
glomerular fluid filtration. The curved
10 10
Hydrostatic pressure in Bowmans line in the figure shows one possible
space
0 0 profile for oncotic pressure along the
Length of glomerular capillary capillary. The vertical height (at each
length along the x-axis) between the
top line (PGC) and the GC curve represents the net ultrafiltration pressure (PUF) at that distance
along the glomerular capillary. The shaded area is proportional to the average PUF for the whole
glomerulus. In the example above, GC has increased sufficiently to completely oppose the
hydrostatic pressure gradient and from that point to the efferent arteriole there is no further
filtration. This is known as filtration equilibrium.

Renal Physiology 16
 Glomerular Filtration

Autoregulation of Renal Blood Flow and Glomerular Filtration Rate.

Renal blood flow and glomerular

Glomerular blood flow & filtration filtration rate are fairly constant across
are autoregulated a wide range of mean arterial blood
pressures. This phenomenon is called
1.5 Autoregulatory 150 autoregulation. Total renal vascular
range resistance varies in direct proportion to
renal arterial pressure so that flow
Renal Glomerular
remains roughly constant. This
blood filtration
myogenic mechanism phenomenon continues in denervated
flow tubuloglomerular
rate
(ml/min) kidneys, and so must be due to
(l/min) feedback
intrarenal mechanisms. Control of
0 0 afferent arteriolar resistance is the key
0 90 mmHg 190 process. This occurs by a myogenic
mechanism in the first instance.
Distension of the wall of the afferent
arteriole as flow increases results in contraction of the smooth muscle in the wall of the arteriole.
Vascular resistance thus increases and blood flow is reduced to the normal rate. The myogenic
mechanism is greatly augmented by tubulo-glomerular feedback (TGF)

During autoregulation, as blood pressure increases, so

does vascular resistance
Flow = Pressure
Resistance

Afferent arteriole Efferent arteriole

Arterial
pressure PGC

vasoconstriction

Mechanism?
myogenic
tubuloglomerular feedback

Renal Physiology 17
 Glomerular Filtration

Myogenic mechanism of autoregulation

blood pressure

afferent arteriole stretch

non-specific cation channels open

depolarization

calcium channels open

afferent arteriole contracts

Tubuloglomerular feedback

afferent arteriole

A1 receptor Vasoconstriction

adenosine

ATP macula
densa

Na+
2Cl- +
K

NaCl
macula densa
delivery cell

TGF operates at the single nephron level and involves the macula densa. The macula densa is
able to sense the flow rate of tubular fluid entering the distal tubule. When flow rate increases,
the macula densa signals to the afferent arteriole by releasing adenosine, causing it to contract,

Renal Physiology 18
 Glomerular Filtration

thereby reducing both glomerular plasma flow rate and glomerular capillary hydrostatic pressure.
The resultant fall in GFR reduces flow along that nephron and normalizes flow past the macula
densa, completing the feedback loop.
[Note: we have discussed previously that adenosine tends to be local metabolic factor that causes
vasodilatation. This common effect is mediated via A2 receptors. The afferent arteriole expresses
A1 receptors, which cause vasoconstriction at this site.]

A common misconception is that

Autoregulation does not mean autoregulation is so efficient that
that RPF and GFR never change. GFR never changes. The reality
is that RBF and GFR can be
hemorrhage altered and in some situations
this is part of a physiological
MAP response to stress. Systemic
factors that can regulate RBF and
Arterial baroreceptors Renin-angiotensin
activated system activated GFR include the renal
sympathetic nerves. Most of the
postganglionic nerves release
Renal nerves norepinephrine, which is a
stimulated Renal
arterioles vasoconstrictor in the kidney and
constrict RBF and GFR will reduce RBF and GFR.
fall During hemorrhage activation of
the baroreceptor reflex causes
increased sympathetic tone
causing a fall in RBF and GFR. This is appropriate in a state where retention of ECF volume is
necessary. Other systemic factors include the hormomes epinephrine, vasopressin and
angiotensin II, all of which are vasoconstrictors (and all would be elevated during hemorrhage).

Hormones with renal vasodilator properties include atrial natriuretic peptide and glucocorticoids.
It is worth noting that the paracrine mediators nitric oxide and prostaglandins provide important
balance as vasodilators opposing the action of the endocrine vasoconstrictors.

Renal Physiology 19
 Renal Calculations

Quantifying Renal Function

Learning objectives.

1. Explain the clearance principle and give the renal clearance formula.
2. Using the clearance formula for an appropriate compound, provide estimates of
glomerular filtration rate, renal plasma flow rate (and renal blood flow).
3. Distinguish between the use of inulin and creatinine clearances as measures of glomerular
filtration rate.
4. Given GFR, urine flow rate and the plasma and urine concentrations of a substance,
calculate its filtered load, excretion rate, clearance, net tubular transport rate, fractional
reabsorption and fractional excretion.
5. Interpret information provided by a renal titration curve, including the transport
maximum, renal threshold and splay.
6. Account for the dependency or otherwise of renal clearance on plasma solute
concentration in terms of membrane transporter saturation.

Renal Physiology 20
 Renal Calculations

The Clearance Concept

In a limited sense the function of the kidneys is to clean the extracellular fluids. Renal clearance
expresses the degree to which a substance is removed from the blood and excreted into the urine.
One of the kidneys major functions is to achieve balance between ingestion and excretion of
many substances. Ingestion varies widely and so, therefore, do normal rates of renal excretion. If
we are interested in knowing whether the rate of excretion is appropriate for the composition of
the plasma, renal clearance becomes a key thing to measure.

The definition of renal clearance is given

on the slide. Note that clearance is not the
Renal clearance rate at which a substance appears in the
urine (e.g. mg/min), it is a measure of the
The VOLUME of plasma rendered free of a given volume of plasma cleaned per unit
substance in one minute
time. Clearance methods involve
Calculated as a ratio: measurement of urine flow rate and the
concentrations of a substance in urine and
amount of substance in urine per minute
C= plasma. The clearance of anything can be
concentration of substance in arterial plasma
measured. Use of the clearance concept,
when applied to certain substances, is still
UX V mg/ml ml/min
C= = = ml/min the most practical (and usually the only)
PX mg/ml way to measure glomerular filtration rate
and to assess transport functions in
humans.

Given the following data, calculate the amount of urea that is excreted into the urine each minute
and the volume of blood plasma required to supply this quantity of urea: Plasma urea
concentration = 0.2 mg/ml, urine concentration of urea = 12 mg/ml, urine flow rate = 1ml/min.

Renal Physiology 21
 Renal Calculations

Using Clearance To Estimate Glomerular Filtration Rate

How to measure GFR

Need a substance (a) with special properties: 1. Freely filtered
(concentration in Bowmans space
= concentration in plasma)

2. Not reabsorbed
3. Not secreted

H2O

Amount of a excreted per minute = amount of a filtered per minute

Urine conc. of a x urine flow rate = glomerular filtrate conc. of a x GFR

Ua x V = GFa x GFR GFR = Ua x V

GFa
Pa

Inulin is a polysaccharide with a molecular weight of about 5500. It is normally present in small
amounts in the diet, and must be infused in order to measure clearance. Inulin is small enough to
pass freely through the glomerular filtration barrier, but is neither reabsorbed nor secreted by the
nephron and cannot be metabolized. As such the rate of inulin filtration equals the rate of inulin
excretion and the volume of plasma cleared is equal to the glomerular filtration rate. The slide
shows that, because we can equate the rate at which inulin is filtered (glomerular filtration rate
plasma inulin concentration) and the rate inulin is excreted (urine flow rate urine inulin
concentration), we can rearrange this equation to obtain GFR = UinV/Pin, which is the clearance
of inulin (Cin).

Since inulin must be infused, it is not usually convenient to measure inulin clearance clinically. A
suitable alternative is creatinine. Creatinine is a product of muscle metabolism. The rate of
creatinine production is a function of a patients muscle mass, and so from day to day is quite
constant. Creatinine is not a perfect substance for the measurement of GFR, because it is
partially secreted by the proximal tubule (about 10% of its excretion comes from secretion). As
such creatinine clearance is slightly higher than the true GFR, but is accurate enough for routine
clinical application. Plasma creatinine concentration is in steady state where balance is achieved
due to a constant production rate, matched by the renal excretion rate. In the problem below the
effect of a sudden 50% decrease in GFR is considered.

Renal Physiology 22
 Renal Calculations

A patient has a glomerular filtration rate of 120ml/min and a plasma creatinine concentration of
1 mg/dL. An abrupt change in her renal function occurred, causing glomerular filtration rate to
fall to 60 ml/min over the next week. Draw graphs to show what happens to the rate of urinary
creatinine excretion and plasma creatinine concentration.

2
Pcr UcrV Creatinine
1
mg/dL Pcr production from
muscle
0
1.2 Pcr
UcrV 0.6 UcrV
Filtered creatinine = GFR x Pcr
mg/min GFR
0.0 At steady-state, creatinine excretion
UcrV must equal creatinine production:
120 GFR Pcr proportionately
GFR
60
mL/min
0
0 days 7

Renal Physiology 23
 Renal Calculations

From the solution to the above problem, it will be apparent that plasma creatinine concentration
is a function of GFR. The slide shows that, clinically, you can therefore use plasma creatinine
concentration to estimate GFR.

A normal value (set point) for GFR is 125ml/min/1.73m3 body surface area. Even with this
correction for body surface area, the value for GFR is lower in young children and declines in old
age. The Gault-Cockroft formula is used clinically to estimate GFR in the steady state from a
measurement of plasma creatinine:

GFR(ml / min) [(140 age) Weight (kg )] ( Pcr(mg / dL) 72)

Renal Physiology 24
 Renal Calculations

Using Clearance To Estimate Renal Blood Flow

By now in the course, if I asked you how to determine the blood flow through an organ you
would probably tell me to go and use the Fick Principle (or words to that effect!). Good idea.

Suppose that a substance X is removed from the blood during its passage through the kidney.
Then applying the Fick Principle:

Renal blood flow = (Amount of X excreted per min)/(A-V concentration difference of X)

= (UX V)/(AX-VX)

So, if we could measure X in the urine and both the renal arterial and venous blood, we could
apply the Fick equation directly. This would be technically very difficult and is unnecessary when
substance X is the organic acid para-aminohippuric acid (PAH). As well as being filtered at the
glomerulus, PAH is secreted by the proximal tubule and, so long as the plasma PAH
concentration is low, all the PAH that escapes filtration gets secreted into the nephron. This
means that the concentration of PAH in renal venous blood is zero.

PAH handling by the kidney

At low plasma concentrations:

Volume of plasma cleared

of PAH (= CPAH)
= volume of plasma
entering kidneys
~ 1/5 filtered
= renal plasma flow

enters in remaining 4/5

renal artery secreted

~ none in the
renal vein

all excreted in
the urine

Thus the Fick equation simplifies:

Renal blood flow = UPAHV/APAH.

In practice mixed venous PAH concentration PPAH is used as a close estimate of APAH and the
Fick equation is the same as the clearance equation. By using PAH clearance, we are really

Renal Physiology 25
 Renal Calculations

calculating renal plasma flow rate (RPF), since plasma, not whole blood, is what is being cleared
of PAH.

ERPF = UPAHV/PPAH.

The term effective renal plasma flow rate (ERPF) is often used when the clearance of PAH is
applied to derive renal blood flow, since the measurement relates strictly to plasma flowing to
functional nephron units.

Mass balance equation

Amount of PAH entering kidneys per min

RPF x PPAH
~0 Equal

Amount of PAH leaving kidneys per min

UPAH x V RPF x PPAH = UPAH x V

Urine flow rate = 1 ml/min

UPAH = 65 mg/ml
RPF = UPAH x V
= CPAH !
PPAH
PPAH = 0.1 mg/ml
Renal plasma flow?

RPF = CPAH = 65 mg/ml x 1 ml/min = 650 ml/min

0.1 mg/ml

Q: If CPAH = 650ml/min and the patient has a hematocrit of 45%, what is the rate of renal blood
flow?

Filtration Fraction (FF)

From the forgoing discussion, using a value of GFR of 125 ml/min and ERPF = 700 ml/min,
the fraction of plasma that is filtered is 125/700 (note the units cancel out to give us a ratio) =
18%. FF is typically in the range 15-25%.

Quantifying Tubular Function

Useful data about the transport of a substance by the renal tubule can be obtained by applying a
few simple calculations:

Renal Physiology 26
 Renal Calculations

1. How much of substance Z is filtered per unit time (filtered load)?

Glomerular filtration rate (GFR) Plasma concentration of Z (PZ)

(units = mg/min)

2. How much of substance Z is excreted in the urine per unit time (excretion rate)?

Urine flow rate (V) Urine concentration of Z (UZ)

(units = mg/min)

3. How much of substance Z was reabsorbed (i.e. if filtered load > excretion rate)?
(GFR PZ) - (UZ V)
(units = mg/min)

4. How much of substance Z was secreted (i.e. if excretion rate > filtered load)?
(UZ V) - (GFR PZ) (units = mg/min)

Fractional Reabsorption and Excretion

These terms describe the rate of excretion or reabsorption that is occurring expressed as a
proportion of the rate at which a substance is filtered. It may be expressed as a ratio, or in %
units. So, if we were to say that the fractional reabsorption of sodium in the proximal tubule was
65%, this would mean that 65% of the amount of sodium filtered would be reabsorbed at this
site.

5. What proportion of the filtered load was excreted (fractional excretion)?

FEZ = [ (UZ V) (GFR PZ) ] 100 (units = %)

(this is useful if you wish to assess changes in excretion that are occurring independent of
changes in GFR)

6. What proportion of the filtered load was reabsorbed (fractional reabsorption)?

FRZ = 100 - FEZ (units = %)

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 Renal Calculations

Relationships Between Clearance and Plasma Concentration

Why is it that the clearance of some

The relationship between PX and CX
depends on tubular transport
substances is constant irrespective of plasma
concentration, whilst the clearance of other
700
substances can vary dramatically with their
600
CPAH plasma concentrations? The answer lies in
Clearance (ml/min)

500
the nature of tubular transport of the
400 substance. Take the simplest case first, that
300 of inulin, which is not transported at all by
200 the nephron. Note that the flat line on the
CIN = GFR
100 CGLUC
figure for inulin does not mean that the
0
CUREA excretion rate for inulin is constant. If GFR
Plasma concentration
is constant, then the excretion rate for inulin
rises as a function of the plasma
concentration:

Renal Physiology 28
 Renal Calculations

UinulinV

Pinulin
As plasma concentration rises, the filtered load rises. Since inulin is not reabsorbed or secreted,
the rate of excretion is the same as the filtered load. Since the rate of excretion matches the
change in filtered load, the volume of plasma cleaned per unit time (i.e. clearance) remains
constant.

The profile for glucose is very different. First there is zero clearance over a wide range of plasma
glucose concentrations, indicating that all the filtered glucose is reabsorbed by the tubule. Then a
plasma glucose concentration is reached where some glucose spills over into the urine. This is the
point where the glucose reabsorption mechanism has been saturated. The transport maximum
for glucose has now been exceeded and further increases in the filtered glucose load simply spill
into the urine. This scenario may occur, for instance, in diabetes mellitus.

Q. What are the maximum and minimum possible glucose clearances?

The clearance of PAH also shows dependence on plasma PAH concentration. Again this is due
to the fact that the membrane transporters for PAH are saturable (some antibiotics use these
secretory transporters). At low plasma concentrations, all PAH molecules are excreted, so the
volume of plasma cleared is equal to the volume at which it arrives (i.e. renal plasma flow rate).
Once the transporters are saturated though, some PAH passes through the peritubular capillaries
and into the renal vein. Now the clearance rate falls below RPF. As the plasma PAH
concentration continues to rise, proportionally more and more PAH escapes excretion and the
volume of plasma cleaned falls progressively.

Q. What are the maximum and minimum possible PAH clearances (assume zero PAH
reabsorption)?

Renal Physiology 29
 Renal Calculations

Renal Titration Curves

Renal titration curves show that nephron Renal titration curves provide a way to
transport may be saturable e.g. glucose determine a transport maximum (Tm).
600
filtered excreted They are also the origin of terms like
Glucose transport (mg/min)

splay and renal threshold.

TM ~ 375mg/min
450
The slide shows the relationship between
reabsorbed

300 splay glucose filtration, excretion and

reabsorption and plasma glucose
150
concentration. To draw these curves in
Renal
threshold
practice, we would measure the excretion
rate for a range of plasma glucose
0 200 400 600 800 concentrations and plot the excretion
Plasma glucose concentration (mg/dl) curve. We would calculate the filtered
load as described previously, knowing
GFR and plasma glucose. The rate of glucose reabsorption would then be derived from the
difference between filtration and excretion. The graph has been drawn for a normal GFR of 125
ml/min, which is assumed to remain constant. So, if plasma glucose is 100mg/dL, then the
filtered load will be 125 mg/min etc. Note that until the plasma glucose concentration reaches
about 200 mg/dL, none is excreted. The plasma concentration at which excretion is first
recorded is known as the renal threshold. At this plasma concentration, those nephrons which
are the worst at reabsorbing glucose begin to allow glucose to escape into the urine. As plasma
glucose concentration rises further even those nephrons that reabsorb glucose the best are now
overwhelmed and glucose escapes them too. The existence of a population of values for single
nephron maximal glucose reabsorption rate produces the curving of the lines for overall
excretion and reabsorption rates. This phenomenon, due to nephron heterogeneity, is called
splay. The transport maximum for glucose is about 375 mg/min and can be estimated from the
titration curve, as the level at which the reabsorption curve asymptotes. This level is reached at a
plasma glucose concentration of about 400 mg/dL.

Defects in renal glucose handling, causing glycosuria, can occur as a result of reduced Tm or
increased splay, which may occur in pregnancy. However, the most common abnormality relates
to a rise in plasma glucose concentration associated with diabetes mellitus. Patients may have
plasma glucose levels in excess of 600mg/dL, which clearly exceeds Tm. Clinically, the
observation is glycosuria. The presence of osmotically active glucose molecules within the
nephron lumen causes more water to be retained in the nephron and excreted in the urine. This
phenomenon is called osmotic diuresis and accounts for the polyuria, dehydration and thirst
associated with untreated diabetes mellitus.

Renal Physiology 30