URINE FORMATION

Block VIII Module 1

February 25, 2010
Dr. A. Villaflor
Group 2

THE KIDNEY o Filtered fluid is processed to

- Regulate the composition and volume
of the plasma water.
- Determines the composition and
volume of the extracellular fluid
compartment.
- Influence the intracellular fluid
compartment by continuous exchange
of water and solutes across all cell
membranes.
- Endocrine gland producing
erythropoietin
- Regulation of BP: Renin-Angiotensin-
Aldosterone System (RAAS): regulates
blood volume and amount of salt in
the body
Renal Blood supply
- 21% of the cardiac output (1200
mL/min)
- renal a --> interlobar a --> arcuate a
--> interlobular (radial) a --> afferent
arterioles --> glomerular capillaries
--> efferent arterioles --> peritubular
capillaries --> interlobular v -->
arcuate v --> interlobar v --> renal v
The Nephron
- Functional unit
- 1 million per kidney
- Cannot regenerate
- Physiologic loss of 10% per ten years
after age 40
- The nephron
1. Glomerulus
o tuft of capillaries
o Lined by epithelial cells
o Enclosed by Bowman’s capsule
o Filtering structure
2. Tubules
o Several segments
form urine
o Proximal, descending limb, loop
of Henle, ascending thin,
ascending thick, macula densa,
early distal, late distal,
connecting tubule, cortical
collecting, medullary collecting,
large collecting ducts
- Regional differences:
o Cortical (peritubular capillaries
surround the entire tubular
system)
o Juxtamedullary nephrons (vasa
recta form the long efferent
arterioles)
URINE FORMATION
- Glomerular filtration
- Tubular reabsorption
- Tubular secretion
Mathematical expression:
Urinary excretion rate
= filtration rate – reabsorption rate +
secretion rate
Glomerular filtration
- Filtered fluid (glomerular filtrate is
protein-free with no cellular elements)
- GFR is about 20% f the renal plasma
flow
- Determined by balance of hydrostatic
and colloid osmotic pressures, AND
capillary filtration coefficient (Kf)
(permeability and filtering surface
area)
Glomerular capillary membrane
- Endothelium of the capillary
- Basement membrane
 - Podocytes – foot-like processes
(epithelial cell layer) have gaps called
slit pores
- Primary point for restriction to plasma
proteins is the basement membrane
Filterability
- Charge selective – negative
substances are filtered less
o Albumin can’t pass through
- Size selective – bigger substances
filters less
o Water, Na+, and glucose are
filtered well
GFR = Kf X net filtration pressure
Net filtration pressure = sum of
hydrostatic and colloid osmotic forces that
either favour or oppose filtration across
the glomerular capillaries
Kf = hydraulic conductivity and surface
area of the glomerular capillaries
(thickness of the membrane and the
Forces Favoring Filtration
- Glomerular hydrostatic pressure (HPg)
= 60 mmHg
- Bowman’s capsule colloid osmotic
pressure (OPb)
Forces Opposing Filtration
- Bowman’s capsule hydrostatic
pressure (HPb) = 18 mmHg
- Glomerular capillary colloid osmotic
pressure (OPg) = 32 mmHg
Net filtration pressure = HPg – HPb –
OPg + OPb
= (60 – 18 – 32) mmHg
= +10 mmHg
GFR = Kf X (HPg – HPb – OPg + OPb)
Increased GFR
- Increased glomerular capillary
filtration coefficient
- Increased glomerular capillary
hydrostatic pressure
HPg – determined by
1. Arterial pressure
2. Afferent arteriolar resistance
3. Efferent arteriolar resistance
Increased glomerular hydrostatic pressure
- Increases arterial pressure
- Dilatation of afferent arterioles
- Constriction of efferent arterioles (not
less than 3-fold increase in resistance)
Decreased GFR
- Increased Bowman’s capsule
hydrostatic pressure (obstruction to
the urinary tract)
- Increased glomerular capillary colloid
osmotic pressure
1. Arterial plasma colloid osmotic
pressure
2. Fraction of plasma filtered by
glomerular capillaries (filtration
fraction)
Decreased glomerular hydrostatic pressure
- Decreased arterial blood pressure
- Afferent arteriole constriction
- More that 3-fold increase in efferent
arteriolar constriction or resistance
Increased capillary colloid pressure
- Increased filtration fraction
1. Increase GFR
2. Reduce renal plasma flow
RENAL BLOOD FLOW (RBF)
- 1200 mL/ min
- 21% of the cardiac output
- RBF = renal artery pressure – renal
vein pressure / total renal vascular
resistance
Renal artery pressure = systemic pressure
Renal vein pressure = 3 to 4 mmHg
Total renal vascular resistance =
interlobar, afferent and efferent arterioles
Renal vascular resistance controlled by:
- Sympathetics
- Hormones
- Local internal renal control
mechanisms
 Arteriolar
resistance
Control
Increased afferent
Decreased
afferent
Increased efferent
Decreased
efferent
Physiologic control of GFR and RBF
- Decrease GFR
1. Sympathetic activation
2. Norepinephrine/epinephrine
3. Endothelin
- Increase GFR
1. Endothelial-derived nitric oxide
2. Prostaglandins
Angiotensin – prevents drop in
GFR
AUTOREGULATION OF GFR AND RENAL
BLOOD FLOW
Intrinsic feedback mechanisms
aimed to keep RBF and GFR in
constant levels
- Maintain oxygen delivery
- Maintain nutrient supply
- Remove waste products of metabolism
- Allow precise control of renal excretion
of water and solutes – prevent extreme
changes in renal excretion
Glomerulotubular balance
- Tubules increase reabsorption rate
in response in GFR
Tubuloglomerular feedback
- Ensure relatively constant NaCl
delivery to the distal tubules and
Net ultrafiltration
Renal blood flow
pressure
helps prevent spurious fluctuation
in renal excretion
1. Afferent arteriolar feedback
mechanism
2. Efferent arteriolar feedback
mechanism
- Uses the juxtaglomerular complex
– macula densa cells (initial distal
tubule) and the juxtaglomerular
cells (walls of the afferent and
efferent arterioles
Drop in NaCl delivery to the distal tubule
---
Signal to the macula densa
1. Afferent arteriolar dilatation –
increase GFR
2. Increase renin release from the
juxtaglomerular cells – angiotensin
cascade – increase GFR
Myogenic Autoregulation of RBF and GFR
- Ability of individual blood vessels to
resist stretching during increased
arterial pressure
High protein intake increases RBF and
GFR
High blood glucose increases RBF and
GFR
 Physiologic and pharmacologic factors with effects on glomerular
hemodynamics

Afferent Efferent
Renal blood Ultrafiltration
arteriolar arteriolar Kf GFR
flow pressure
resistance resistance
Renal
sympathetic
nerves

Epinephrine
Adenosine
?

Cyclosporine
NSAIDs ?

Angiotensin II

Endothelin-1

High protein
diet

Nitric Oxide ? ?
Atrial
natriuretric
peptide (ANP)
Prostaglandins
E2/I2
?
Calcium
channel
?
blockers
ACE inhibitor /
angiotensin ?
receptor
blockers
= glomerular filtration – tubular secretion
+ tubular reabsorption
Glomerular filtrate flow

Proximal tubule  loop of Henle  distal

convoluted tubule  collecting tubules 
collecting ducts  URINE

Final urine composition Amount Amount Amount % of

Filtered reabsorb Excreted Filtered
- Tubular reabsorption (most ed load
Reabsorb
substances, glucose, urea, Na+) ed
Glucose
180 180 0 100
- Tubular secretion (K+, H+) (g/day)
Bicarbon
ate
4,320 4,318 2 >99.9
(mEq/day
)
Sodium
Urine Excretory rate (mEq/day 25,560 25,410 150 99.4
)
Chloride
(mEq/day 19,440 19,260 180 99.1
)
Urea
46.8 23.4 23.4 50
(g/day)
Creatinin
1.8 0 50 0
e (g/day)

Tubular reabsorption
- Quantitatively large
o Small change in GFR and
tubular reabsorption can
potentially cause a large
urinary excretion of that
substance
o Not true in reality, GFR and
reabsorption is closely
coordinated to prevent large
fluctuations in urinary
excretion
- Highly selective
o Tubular segments control
the rate of reabsorption of
each substance
independently, for precise
control of the composition of
the body fluids
Transport mechanisms
- Transcellular
- Paracellular
- Ultrafiltration (bulk-flow) –
hydrostatic and colloid osmotic
forces
- Passive
o Osmosis
o Diffusion, facilitated diffusion
- Active transport
o Primary
o Secondary (co-transport,
counter transport)

Solute and water transport in the loop of
Henle
- Descending part of the thin
segment – highly permeable to
water, moderately permeable to
solutes, simple diffusion occurs
- Thin ascending limb of the loop –
less reabsorptive function
- Thick ascending limb of the loop –
high metabolic activity, highly
reabsorptive function,
impermeable to water
Distal tubule
- Juxtaglomerular complex – first
part of the distal tubule, provides
feedback control of GFR and blood
flow
- Avid reabsorption of sodium,
potassium, and chloride
- Impermeable to water and urea
- Diluting segment
Late distal tubule and cortical collecting
tubule
- Principal cells
o Sodium reabsorption and
potassium secretion
 K+ enters the cell
because of the
sodium-potassium
ATPase
 High intracellular K+
allows diffusion into
the luminal fluid
- Intercalated cells
o Secrete hydrogen and
reabsorbed bicarbonate
H2O + CO2  H2 CO3  HCO3 + H+
Absorbed secreted
 capillary hydrostatic
pressure --- decrease
reabsorption rate
o High resistance of the
Medullary collecting duct afferent and efferent
- Final site for urine processing arterioles decreases
- Permeability to water is controlled capillary hydrostatic
by ADH pressure --- increase
- Permeable to urea reabsorption rate
- Secretes H+ against a large
concentration gradient – role in 4. Renal interstitial hydrostatic and
acid-base regulation colloid osmotic pressure
o Increase renal interstitial
The relative degree of reabsorption of fluid hydrostatic pressure
solute versus the reabsorption of water in decreases interstitial fluid
a tubular segment, determines the colloid osmotic pressure,
concentration of that solute in the tubular decreases net reabsorption
fluid
Hormone Site of Action Effects
Regulation of tubular reabsorption  NaCl, H2O
Distal tubule/
Aldosterone reabsorption,
Collecting duct
1. Glomerulotubular balance K+ secretion
o Most basic controlling
mechanism for tubular  NaCl, H2O
Angiotensin Proximal tubule reabsorption,
reabsorption  H+ secretion
o Intrinsic ability of the tubules
to increase reabsorption rate
Antidiuretic Distal tubule/ H2O
in response to increased hormone Collecting duct reabsorption
tubular load
o Occur independently of
Atrial
hormones natriuretic
Distal tubule/ NaCl
o Prevent overloading of the Collecting duct reabsorption
peptide
distal segments when GFR Proximal
increases PO42-
tubules, thick
Parathyroid reabsorption
ascending loop
hormone Ca++
2. Colloid osmotic pressure of the of Henle/
Distal tubules reabsorption
plasma
o Systemic plasma colloid
osmotic pressure increase Sympathetic Nervous System
peritubular capillary colloid - Activation constricts the afferent
osmotic pressure increases and efferent arterioles, GFR
reabsorption decreased
o Higher filtration fraction - Activation increases sodium
reabsorption in the proximal
means greater fraction of
tubule, the ThAL
plasma filtered, increases
- Increases renin release and
plasma protein and thus
angiotensin II formation - increase
increases capillary
tubular reabsorption
reabsorption rate

3. Peritubular capillary and renal

interstitial fluid physical forces REGULATION OF ECF OSMOLARITY AND
o High arterial pressure SODIUM CONCENTRATION
increases peritubular
Osmolarity
 - Total concentration of solutes in
the ECF
- Amount of solutes divided by the
volume of ECF
- Regulated by ECF water
Total body water
- Controlled by fluid intake
o Regulated by factors that
control thirst
- Renal excretion of water
o Controlled by factors that
influence GFR and tubular
reabsorption
Renal ways of excreting water
- Excess body water – urine
osmolarity can reach to 50 mOsm/L
(dilute)
- Body water deficit – urine
osmolarity can go as high as 1200
to 1400 mOsm/L (concentrated)
- Excretion of a dilute or
oncentration urine made without
major changes in the excretion of
solute (Na+ or K+)
Antidiuretic hormone (ADH)
- Vasopressin
- Secreted by the posterior pituitary
gland
- Alters renal excretion of water
independently of the rate of solute
excretion
- Allows more water reabsorption on
the distal and collecting tubules
and decreases the urine output
Diluting the urine
- Glomerular filtrate osmolarity is
about the same as plasma (300
mOsm/L)
- Proximal tubule – water and solutes
are in equal proportions
reabsorbed
- Descending limb of the loop of
Henle – water reabsorbed by
osmosis making the tubular fluid
hypertonic (until it equilibrates with
the surrounding interstitial fluid of
the renal medulla) – about 4x the
original glomerular filtrate
osmolarity
- Ascending limb of the loop of
Henle – both the thin and the thick
segments, ACTIVE reabsorption of
Na+, K+, and Cl- while impermeable
to water. Tubular fluid becomes
dilute as it ascends the loop,
(hypoosmotic). Osmolarity can be
as low as 100 mOsm/L – 1/3 that of
plasma, until the early distal
convoluted tubule
- Hypoosmolarity of the fluid in this
segment is independent of the
presence of ADH
SUMMARY:
- Results from the continuous
reabsorption of solutes and failure
of water reabsorption from the
distal tubules
- Fluid leaving the ascending limb of
the loop and early distal tubule is
ALWAYS DILUTE REGARDLESS OF
THE LEVEL OF ADH
- Large amounts of dilute urine is
excreted, if ADH is absent, making
the distal tubules which are
continually reabsorbing solutes to
be impermeable to water
Concentrating the urine
Requirements:
1. High levels of ADH
2. High osmolarity of the renal
medullary interstitium – provides
the osmotic gradient needed for
water reabsorption in the presence
ofADH
Medullary interstitium surrounding the
collecting ducts are NORMALLY
HYPEROSMOTIC
The presence of ADH in high levels move
water from the collecting tubules to the
interstitium
Water is reabsorbed back into the blood
by the VASA NRECTA --- minimal
amounts of concentrated urine
Creation of a hyperosmotic renal
medullary interstitium
- Operation of the
COUNTERCURRENT mechanism
 - Special anatomical arrangement of
the loops of Henle and vasa recta
(specialised peritubular capillaries)
--- 25% of human nephrons are
JUXTAGLOMERULAR – loops of
Henle and vasa recta extending
deep into the medulla, before
returning back to the cortex
- Role of the collecting ducts
Countercurrent mechanism
1. Interstitial fluids osmolarity in all
parts of the body – 300 mOsm/L.
the same as the plasma
2. Interstitial fluid osmolarity of the
renal medullary area – 1200 to
1400 mOsm/L
3. It has accumulated large amounts
of solutes in greater excess of
water
Role of Urea
- Urea contributes about 40% (500
mOsm/L) of the renal medullary
interstitium osmolarity
- Passively reabsorbed from the
inner medullary collecting ducts
- Reabsorption: as water flows into
the ascending limb, into the distal
and cortical collecting duct – zero
urea absorption due ti
impermeability of these tubules;
with ADH, and consequent water
reabsorption to the interstitium,
urea concentration inside the
tubules increases. As the fluid
reach the inner medullary
collecting duct, (permeable to ure),
urea now diffuses into the
interstitium. ADH increases the
permeability of this segment to
urea.
STEPS…
1. Plasma flowing form the
descending limb of the vasa recta
becomes hyperosmotic
a. Water diffusion out of the
blood
b. Solute diffusion from the
renal interstitium into the
blood
2. In the ascending limb of the vasa
recta, solutes diffuse back into the
interstitium and water diffuses
back into the vasa recta.
The ‘U’ shape capillary prevents
the loss of solutes from the
interstitium.
COUNTER CURRENT EXCHANGER
The vasa recta does not create the
medullary hyperosmolarity, but preserves
it by the diffusion of fluid and solutes into
and out of the medullary interstitium and
the blood.
Though it minimizes solute loss
from the interstitium, it maintains its
absorptive capacity through bulk flow due
to the colloid osmotic and hydrostatic
pressures that favour reabsorption in
these capillaries.
THIN ASCENDING LOOP
- Impermeable to water
- More permeable to NaCl
- Some passive diffusion of NaCl in
to the interstitium
- The tubular fluid becomes more
dilute as it flows to the thick
segment
- Urea from the medullary
interstitium (from the inner
medullary collecting duct) diffuses
back into this segment
THICK ASCENDING LOOP
- Impermeable to water
- Active transport of electrolytes
- Tubular fluid becomes dilute
ADH
- Supraoptic and paraventricular
nuclei of hypothalamus 
synthesis
- Posterior pituitary  storage
- Calcium entry in the nerve endings
increase to affect membrane
permeability when hypothalamic
nuclei are stimulated  ADH
release
- AV3V – anteroventral region of the
3rd ventricle (subfonical organ and
the organum vasculosum of the
lamina terminalis)
- Osmoreceptors – neuronal cells
excited by changes in ECF
osmolarity.
-