RENAL SYSTEM

RENAL SYSTEM
Kidneys
- function as filters, removing
metabolic products and toxins
from the body and excreting
them through urine
- play a key hemostatic role by
regulating bodys fluid status,
electrolite balance, acid-base
balance
- produce hormons involved in
erythropoesis, calcium
metabolism, and the regulation
of blood pressure and blood
flow

RENAL SYSTEM
The kidneys
-Are paired, bean-shaped organs
- lie on the posterior wall of the
abdomen behind the peritoneum on
either side of the vertebral column.
- In an adult human, each kidney
weighs between 115 and 170 g and is
approximately 11 cm long, 6 cm wide,
and 3 cm thick.
- Each kidney is covered by a fibrous,
almost nondistensible capsule
- In the middle of their concave surface
there is a slit in the capsule, the hilus,
the port of entry for the renal artery
and nerves and site of exit for the
renal veins, the limphatics and the
ureter.

RENAL SYSTEM
A cut section through the
kidney reveals
- the cortex , an outer
granular region with
glomeruli and a large
number of convoluted
tubules, and
- the medulla, darker
inner region consisting of
parallel arrangements of
tubules and small
vessels. It lacks glomeruli

RENAL SYSTEM
The medulla in the human
kidney is divided into conical
masses called renal pyramids
(8-18).
The base of each pyramid faces
the corticomedullary border, and
the apex terminates in a papilla,
which lies within a minor calyx.
Minor calyces collect urine
from each papilla. The numerous
minor calyces expand into two
or three open-ended pouches,
the major calyces.
The major calyces feed into
the pelvis.
The pelvis represents the
upper, expanded region of the
ureter, which carries urine from
the pelvis to the urinary bladder.
The walls of the calyces, pelvis,

RENAL SYSTEM
Blood flow to the two kidneys is
equivalent to about 25% (1.25 L/min) of
the cardiac output in resting individuals.
About 90% of the blood entering the
kidneys perfuses superficial glomeruli and
renal cortex; only 10% perfuses
juxtamedullary glomeruli and medulla
The renal artery branches progressively to
form the interlobar artery, the arcuate
artery, the interlobular artery, and the
afferent arteriole, which leads into the
glomerular capillaries (i.e., glomerulus).
The glomerular capillaries come together
to form the efferent arteriole, which leads
into a second capillary network, the
peritubular capillaries, which supply blood
to the nephron or vasa recta which provide
blood for tubules located in the medulla.

RENAL SYSTEM
The vessels of the
venous system run
parallel to the arterial
vessels and
progressively form the
interlobular vein,
arcuate vein, interlobar
vein, and renal vein,
which courses beside
the ureter.
Lymph vessels drain the
interstitial fluid of the
cortex ( they are absent
in the renal medulla)
and leave the kidney
following arteries
towards the hillus

RENAL SYSTEM
Ultrastructure of the
Nephron
The functional unit of the
kidneys is the nephron.
Each human kidney contains
approximately 1.2 million
nephrons, hollow tubes
composed of a single cell
layer.
The nephron consists of
- renal corpuscle,
- proximal tubule,
- loop of Henle,
- distal tubule, and
- collecting duct system.

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The renal corpuscle components:
A.Vascular elements
B.The mesangium
C. The Bowman capsule and space
A.The vascular elements form the
glomerulus, a network of capillaries
supplied by the afferent arteriole and
drained by the efferent arteriole. It is
surrounded by Bowmans capsule.
The capillaries are coverd by
podocytes, epithelial cells that form
the visceral layer of Bowmans
capsule
The space between the visceral and
parietal layer of Bowman s capsule
joins the proximal tubule
Endothelial cells of glomerular
capillaries lie on a basement
membrane that is surrounded by
podocytes

RENAL SYSTEM
Vascular elements
The glomerular filtration barrier consists of:
- endothelial cells of glomerular capilaries,
- basement membrane
- the layer of epithelial podocytes
1.Endothelial cells
-almost completely surrounded by glomerular
basement membrane
-contain large fenestration (70nm holes) with no
restriction to the movement of water and small
solutes, including proteins and other large
molecules; they serve only to limit the filtration
of cellular elements.
-filtration occurs at the peripheral portion of the
capillary wall, which is covered with basement
membrane and podocytes
- There is a small region towards the center of the
glomerulus where endothelial cells come into
direct contact with smooth-muscle-like

RENAL SYSTEM
2.Basement membrane
-separates endothelial layer
from epithelial layer in all
parts of the glomerulus
- has three layers: lamina rara
interna, lamina densa, lamina
rara externa
- has important contribution to
the permeability
characteristics, restricting
intermediate to large sized
solutes
-it is a site of strongly anionic
charges (sialic and
dicarboxilic aminoacids
residues and function
primarily as a charge-

RENAL SYSTEM
3.Podocytes
-Have foot processes that
interdigitate and cover the
basement membrane
-Foot proceses are separated
through filtration slits which are
connected by a thin diaphragmatic
structure with pores ranging 4-14
nm, composed of several proteins ,
nephrin, podocin, alfa-actinin, CD2AP with key role in podocyte
function.
-Filtration slits function primarily as
a size selective filter keeping the
proteins and macromolecules that
cross the basement membrane
from entering Bowmans space
-Glycoproteins with negative
charges cover podocytes, filtration

RENAL SYSTEM
B. Contractile mesangial cells
- Form a network of support for the glomerular
capillary loops
- Posess properties of smooth muscle cells
- Is continuous with the smooth muscle cells of
afferent and efferent arteriole
- Secrete the extracellular matrix
- Exibit fagocytic activity
- Secrete prostaglandins and citokines
- Regulate blood flow by altering the capillary
surface area(influence filtration rate)

Juxtaglomerular apparatus (JGA)

-Part of the complex mechanism that regulate renal
blood flow, filtration rate, modulates Na + balance
and systemic blood pressure
- includes: extraglomerular matrix, macula densa,
granular cells
Macula densa=region of specialised epithelial cells of
the thick ascending limb where it contacts its
glomerulus
Granular cells, specialized smooth muscle cells in the
wall of afferent arteriole which produce, stores and
regulate renine release

BM, basement membrane; BS,

Bowman's space; EA, efferent
arteriole; EN, endothelial cell; FP,
foot processes of the podocyte; M,
mesangial cells between
capillaries; P, podocyte cell body
(visceral cell layer); PE, parietal
epithelium; PT, proximal tubule

RENAL SYSTEM
Tubule segment of the
nephron:
- Proximal convoluted tubule
- Proximal straight tubule
- Thin descending limb of loop of
Henle
- Thin ascending limb of loop of
Henle
- Thick ascending limb of loop of
Henle
- Distal convoluted tubule
- Connecting tubule
- Initial collecting tubule
- Cortical collecting tubule
- Outer medullary collecting duct
- Inner medullary collecting duct

RENAL SYSTEM
Each nephron segment cells are uniquely suited to perform specific
transport functions.
Proximal tubule cells
-extensively amplified apical membrane (the urine side of the cell)
called the brush border,
- highly invaginated basolateral membrane (the blood side of the cell)
with many mitochondria.
the descending and ascending thin limbs of Henle's loop
- poorly developed apical and basolateral surfaces and few
mitochondria.
The cells of the thick ascending limb and the distal tubule
- abundant mitochondria and extensive infoldings of the basolateral
membrane.
The collecting duct has two cell types: principal and intercalated.
Principal cells- moderately invaginated basolateral membrane, contain
few mitochondria, play an important role in reabsorption of NaCl and
secretion of K+
Intercalated cells,-high density of mitochondria, play an important role
in regulating acid-base balance. One population secretes H+ (i.e.,

RENAL SYSTEM
All cells in the nephron, except intercalated cells, have
in their apical plasma membrane a single nonmotile
primary cilium that protrudes into the tubule fluid
Primary cilia are
- mechanosensors ( they sense changes in the rate of
flow of tubule fluid) and
- chemosensors (they sense or respond to compounds
in the surrounding fluid),
- they initiate Ca++ dependent signaling pathways,
including those that control kidney cell function,
proliferation, differentiation, and apoptosis (i.e.,
programmed cell death).

RENAL SYSTEM
Kidneys are also endocrine organs:
- granular cells of JGA produce Renine
- Proximal tubule cells convert circulatig 25-hydroxivitamin
D to the active metabolite 1,25-dihydroxivitamin D
(controls calciu and phosphorus metabolism)
- Fibroblast-like cells in the interstitium of the cortex and
outer medulla secrete erythropoetin in response to a fall
in local tissue PO2
- Tubule cells secrete angiotensine, bradykinin. cAMP, ATP
- Kidney release prostaglandins and several kinines acting
as local control circulation hormons

RENAL SYSTEM
Urine formation consists of three
general processes:
- Glomerular filtration
- Reabsorbtion of the substance from the
tubular fluid back into blood
- Secretion of some substance from blood
into the tubule fluid

RENAL SYSTEM
Glomerular filtration is a passive movement of plasma ultrafiltrate from the
glomerular capilaries into Bowmans space which is contigous with the lumen of
proximal tubule.
plasma ultrafiltrate is devoided of cellular elements (red and white blood cells
and platelets) and essentially protein free; it has the same concentration of salts
and organic molecules, as plasma.
Molecules filtration depend on their sizes and electrical charge:
- neutral molecules with radius < 20 are filtered freely(water, glucose, sucrose,
creatinine, and urea)
- molecules between 20 and 42 are filtered to various degrees
- molecules larger than 42 are not filtered
- for any given molecular radius, cationic molecules are more readily filtered
than anionic molecules, explained by the presence of negatively charged
glycoproteins on the surface of all components of the glomerular filtration
barrier.
- because most plasma proteins are negatively charged, the negative charge on
the filtration barrier restricts the filtration of proteins that have a molecular
radius of 20 to 42 or greater.

molecules must travel through several barriers to move from the capillary
lumen to Bowman's space (fenestrated epithelium basement

RENAL SYSTEM
Glomerular filtration dynamic is governed by
pressures:
- glomerular capillary hydrostatic pressure (HPGC)
forcing fluid out of the capillary,
- glomerular capillary oncotic pressure (GC)
attracting fluid into the glomerular capillary,
- Bowman's space hydrostatic pressure (HPBS)
opposing capillary hydrostatic pressure, and
- Bowman's space oncotic pressure (BS) attracting
fluid into Bowman's space (typically there is negligible
protein in the Bowman's space, so BS is not significant).
Net filtration pressure = (HPGC HPBS) GC

RENAL SYSTEM
additional points concerning Starling forces and this pressure change are
also important.
- HPGC decreases slightly along the length of the capillary because of the
resistance to flow along the length of the capillary.
- GC increases along the length of the glomerular capillary. Because
water is filtered and protein is retained in the glomerular capillary, the
protein concentration in the capillary rises, and GC increases.
- the glomerular capillaries are different from other capillaries (which
have significantly reduced pressures at the distal end of the capillary),
because the efferent arteriole (at the other end of the glomerulus) can
constrict and maintain pressure in the glomerular capillary.
- there is very little reduction in HPGC through the capillary, and filtration
can be maintained along its entire length.
- afferent and efferent arteriolar resistance can be controlled by neural
influences, circulating hormones (angiotensin II), myogenic regulation,
and tubuloglomerular feedback signals, allowing control of glomerular
filtration by both intrarenal and extrarenal mechanisms .

RENAL SYSTEM
Glomerular filtration rate (GFR)
GFR is the amount of plasma (without protein and cells) that is
filtered across all of the glomeruli in the kidneys, per unit time.
GFR is equal to the sum of the filtration rates of all functioning
nephrons, an index of kidneys function
In a normal adult, GFR is 100 to 125 mL/min, with men having
higher GFR than women.
Many factors contribute to the regulation of GFR, which can be
maintained at a fairly constant rate, despite fluctuations in mean
arterial blood pressure (MAP) from 80 to 180 mm Hg
Maintaining normal GFR is critical for eliminating excess fluid and
electrolytes from the blood and maintaining overall homeostasis.
Significant alteration of any of the parameters in the equation
above can affect GFR.

RENAL SYSTEM
GFR is proportional to the sum of the Starling forces that exist across the
capillaries [(HPGC HPBS )-(GC-BS)] multiplied by the ultrafiltration
coeficient Kf
Kf represents the intrinsic permeability of the glomerular capillary and
the glomerular surface area available for filtration; Kf is approx 100
times greater in glomerular capilaries compared to systemic capillaries;
HPGC is aprox twice HP in systemic capillaries i
GFR can be altered by changing Kf or any of the Starling forces;
Alteration in HPGC can be induced through:
1. changes in afferent arteriolar resistance (resistance =>HP GC, GFR;
resistance =>HPGC, GFR )
2. changes in efferent arteriolar resistance (resistance =>HPGC,
GFR ; resistance =>HPGC, GFR; )
3. changes in renal arteriolar pressure transiently change HP GC.

RENAL SYSTEM

RENAL SYSTEM
Renal plasma flow (RBF)
- determins indirectly the GFR
- delivers substrates for excretion in urine
- delivers O2, nutrients, hormons to the nephron cells, returns CO2 and reabsorbed fluid and
solutes to general circulation
- modifies the rate of solute and water reabsorbtion by the proximal tubule
- participates in the concentration and dilution of urine

Whole blood enters the renal arteries but only plasma is filtered at the glomerular capilaries.
Renal blood flow (RBF) is approx. 1 l/min
Renal plasma flow (RPF)= RBF x (1-Ht)
RPF = 1l/min x 0.6 = 600 ml/min
Not all the plasma presented to the capillaries is filtered.
The filtration fraction FF is the proportion of RPF that becomes glomerular filtrate:
FF = GFR/RPF
In the normal adult
FF = (125 ml/min: 600 ml/min) x 100 = ~ 20%
The unfiltered plasma (approx. 80%) exits the efferent arteriole to the peritubular capilaries

RENAL SYSTEM
Renal clearance is the volume of plasma cleared
of a substance per unit time
The renal clearance can be used to measure GFR,
RBF, RPF, and determine weather a substance is
reabsorbed or secreted along the nephron .
The clearance equation incorporates the urine and
plasma concentrations of the substance, and the
urine flow rate and is usually reported in mL/min
or L/day:
U = urine concentration of the
cleared substance
P = plasma concentration of the
cleared substance
V = urine flow

RENAL SYSTEM
Any substance that meets the following criteria can serve as an
appropriate marker for the measurement of GFR.
1.Be freely filtered across the glomerulus into Bowman's space
2.Must be neither reabsorbed nor secreted by the renal tubules
3.must be neither metabolized nor produced by the kidney
4. Must be physiologicaly inert (not toxic, not to alter the GFR
These criteria are met by inulin, a polyfructose. To measure
inulin clearance it is infused intravenously, and when stable
plasma level is achived, timed urine collection are made. C
inulin= GFR. Infusing inulin is not rutinely used becouse of
the invasive nature of the procedure. Instead the renal
clearance of endogenous substance creatinine is used
Creatinine, a byproduct of skeletal muscle creatine metabolism,
can be used to measure GFR
Creatinine is freely filtered across the glomerulus into
Bowman's space, and to a first approximation, it is not
reabsorbed, secreted, or metabolized by the cells of the
nephron .(there is 10% secretion into the renal tubules from
the peritubular capilaries
Accordingly, the amount of creatinine excreted in urine per
minute equals the amount of creatinine filtered at the
glomerulus each minute
NV=125ml/min for a body surface area of 1.73 m2

RENAL SYSTEM
Regulation of the GFR occurs by changes in blood flow to the
glomeruli via:
a)intrinsic feedback systems,
b) Hormones and vasoactive substances, and
c) renal sympathetic nerves.
a)Intrinsic systems include:
1.myogenic mechanism and
2. tubuloglomerular feedback
These systems allow minute-to-minute regulation of GFR over a
wide range of systemic blood pressures (MAP 80 to 180 mm Hg).
The kidney is unique in that the glomerular capillaries have
arterioles on either end of the capillary network. Constriction of
the afferent or efferent arterioles can elicit immediate effects on
the HPGC, controlling GFR

RENAL SYSTEM
a)intrinsic feedback systems
1.myogenic mechanism, (tendency to contract when
stretched)
- makes the renal arteries and arterioles respond
directly to increases in systemic blood pressure by
constricting, thereby maintaining constant
filtration pressure in the glomerular capillaries.
- Increase in vessel diameter opens strech
activated, nonselective cation channels in vascular
smooth muscle, depolarizing the cell and leading
to an influx of Ca2+ that stimulate contraction

RENAL SYSTEM
a)intrinsic feedback systems
2.Tubuloglomerular feedback (TGF), is a regulatory mechanism that
involves the macula densa of the juxtaglomerular apparatus..
- As juxtaglomerular apparatus functionally associates the distal tubule
to the afferent arteriole, the tubular flow past the macula densa can
control afferent arteriolar resistance.
- If distal tubule flow or tubular fluid sodium concentration decrease,
afferent arteriolar resistance decreases which increases GFR
- if distal tubular flow or osmolarity is high, TGF will increase afferent
arteriolar resistance, decreasing GFR.
- Macula densa does not sense flow per se, but the higher luminal [Na +]
or [Cl-] resulting from high flow; there is an activation of nonselective
cation channels allowing Ca 2+to enter macula densa cells. The
increase Intracellular Ca2+ concentration causes macula densa cells to
release paracrine agents (adenosine, tromboxane, ATP) that may
trigger contraction of nearby vascular smooth muscle cells

RENAL SYSTEM

RENAL SYSTEM
b) Hormones and vasoactive substances
The renin-angiotensin-aldosterone system (RAAS)
- activated in response to low renal vascular flow. Renal vascular baroreceptors
stimulate renin secretion by the juxtaglomerular cells at the ends of the afferent
arterioles. This, in addition to the modulation of renin secretion by the macula
densa, will activate the RAAS . The renin will act locally and through the systemic
circulation to produce angiotensin II, and thus control GFR.
Angiotensin II
- is produced systemically and locally within the kidneys

- exerts both direct and indirect effects on the GFR.

- It is a vasoconstrictor, and in the kidneys, it acts directly on the renal arteries,
and to a greater extent at the afferent and efferent arterioles, increasing
resistance, reducing HPGC, and decreasing GFR;
- angiotensin II actually has greater effect on the efferent arteriole than afferent
arteriole. At the same time, it can constrict glomerular mesangial cells, reducing
Kf, and thus, GFR.

RENAL SYSTEM
b) Hormones and vasoactive substances
Endothelin
- secreted by endothelial cells of the renal vessels, mesangial cells, and
distal tubular cells in response to angiotensin II, bradykinin, epinephrine,
and endothelial shear stress.
- causes profound vasoconstriction of the afferent and efferent arterioles
and decreases GFR and RBF.
- this potent vasoconstrictor may not influence GFR and RBF in resting
subjects,
- production of endothelin is elevated in a number of glomerular disease
states
Adenosine
- produced within the kidneys
- causes vasoconstriction of the afferent arteriole, thereby reducing GFR
and RBF.
- adenosine may play a role in tubuloglomerular feedback.

RENAL SYSTEM
b) Hormones and vasoactive substances
Atrial natriuretic peptide (ANP)
- is released from the right cardiac atrial myocytes in response to stretch (at high blood volume).
- dilates the afferent arteriole, and constricts the efferent arteriole, increasing HP gc, and thus, GFR.
- The enhanced flow increases sodium and water excretion, reducing blood volume.

Intrarenal prostaglandins (PGE2 and prostacyclin [PGI2])

- Prostaglandins do not play a major role in regulating RBF in healthy, resting people
- Synthesis of prostaglandins is stimulated by dehydration and stress (e.g., surgery, anesthesia),
angiotensin II, and sympathetic nerves. during pathophysiological conditions such as hemorrhage.
Prostaglandins are produced locally within the kidneys, and they increase RBF without changing
GFR.
- Prostaglandins increase RBF by dampening the vasoconstrictor effects of sympathetic nerves
and angiotensin II. This effect is important because it prevents severe and potentially harmful
vasoconstriction and renal ischemia.
- are vasodilators and serve to counteract primarily angiotensin II-mediated vasoconstriction,
acting at the level of the arterioles and glomerular mesangial cells.
- Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin will block prostaglandin synthesis
and restrict the compensatory renal vasodilation. Thus, administration of these drugs during renal
ischemia and hemorrhagic shock is contraindicated because by blocking the production of
prostaglandins, they decrease RBF and increase renal ischemia.
Prostaglandins play an increasingly important role in maintaining RBF and GFR as individuals age.
Accordingly, NSAIDs can significantly reduce RBF and GFR in the elderly.

RENAL SYSTEM
b) Hormones and vasoactive substances
NO, an endothelium-derived relaxing factor
- important vasodilator under basal conditions; Increased production of NO causes
dilation of the afferent and efferent arterioles in the kidneys. Whereas increased
levels of NO decrease total peripheral resistance, inhibition of NO production
increases total peripheral resistance.
- it counteracts the vasoconstriction produced by angiotensin II and catecholamines.
The factors stimulating NO production:
- blood flow increase with greater shear force acting on endothelial cells in the
arterioles
- vasoactive hormones, including acetylcholine, histamine, bradykinin, and ATP,
facilitate the release of NO from endothelial cells.
Adenosine Triphosphate
Cells release ATP into the renal interstitial fluid.
ATP has dual effects on GFR and RBF.
Under some conditions, ATP constricts the afferent arteriole, reduces RBF and GFR,
and may play a role in tubuloglomerular feedback.
ATP may stimulate NO production and increase GFR and RBF.

RENAL SYSTEM
c) Innervation of the kidneys
Sympathetic nerve fibers
- originate in the celiac plexus,
- lie adiacent to the smooth muscle cells of the branches
of the renal artery and the afferent and efferent
arteriole
- Innervate the renin producing granular cells of afferent
arteriole;
- Innervate also proximal tubule, loop of Henle, distal
tubule, collecting duct;
- Release norepinephrine and dopamine
There is no parasympathetic innervation

RENAL SYSTEM
Major effects of simpathetic stimulation:
- vasoconstriction
- Strongly enhance Na+ reabsorbtion of proximal tubule cells
- stimulate renine secretion because the dense accumulation of fibers near
the granular cells of JGA
- A few myelinated fibers conduct baroreceptor and chemoreceptor
impulses that originate in the kidney
Sympathetic nerves and catecholamine secretion (NE and Epi) are
stimulated in response to reductions in systemic blood pressure and
cause vasoconstriction of the renal arteries and arterioles.
At tonic levels of sympathetic nerve activity, the intrarenal systems will
counteract this effect, to ensure the kidney vasculature remains dilated,
preserving GFR.
During high sympathetic nerve activity (hemorrhage, strenuous exercise),
sympathetic nerve activity overrides the intrarenal regulatory
mechanisms and reduces renal blood flow and GFR

RENAL SYSTEM