Erythropoiesis

Red Blood cell ( RBC) production is a tightly regulated

process. Basal RBC production is roughly 10RBCs/hr or even
more in the events of anaemia/hypoxia. The kidney is a major
organ involved in this process and is responsible for the
monitoring of the RBC levels and increasing RBC output
through the production of erythropoetin.

 Mature RBCs are produced from erythroid

progenitor cells which in turn are derived
from the fetal liver
Erythroid burst-forming units ( BFU-E)
divides to produce erythroid colonyforming units(CFU-E)
Further differentiation leads to production
of proerythroblasts, reticulocytes and
ultimately mature RBCs (2/52)

 Maturation of the BFU-E and CFU-E

depend on the growth factor
erythropoietin ( EPO)
90% of EPO is produced by the
kidney and 10% is from the liver
Kidney derived EPO is produced by a
subpopulation of interstitial
fibroblasts and possibly proximal
tubular cells in response to
decreased oxygen tension

 Growth factors eg interleukin-3, GM-CSF,

stem cell factor, activin, insulin-like
growth factor(IGF-I) act synergistically
with EPO to reduce apoptosis and those
promote proliferation of erythroid cells
EPO receptors have been demostrated in
the brain, retina, heart, sketetal muscle,
kidneys and endothelial cells and hence
EPO has an effect outside the bone
marrow

 In the kidney treatment with high

dose EPO has been shown to reduce
ischemia-reperfusion injury in animal
models, due to decreased apoptosis.

Regulations of EPO production and

erythropoiesis
Production of EPO and hence
erythropoiesis is closely associated
with circulating Oxygen.
Under hypoxic conditions, the alpha
subunit of the regulatory protein
hypoxia-inducible factor-1 (HIF-1 is
exposed
Binding of HIF-1 alpha with HIF-1
beta, hepatic nuclear factor-4 ( HNF4) and p300 turns on erythropoietin

 Once the hypoxia has been corrected, HIF1 alpha is ubiquinated and rapidly
degraded by proteosome and thus
shutting down erythropoietin production
Erythropoiesis is decreased in chronic
inflammation. Apoptosis of erythroid
progenitor cells occurs in the presence of
the tumor associated antigen RCAS1,
which is also produced by macrophages
under inflammatory conditions

 In renal cell Ca, erythropoesis is enhanced

due to a mutation in the von Hippel-Lindau
( VHL) gene, as a result there are constituvely
increased levels of HIF-1 and polycythemia
Erythropoiesis is decreased in chronic renal
failure due to decreased EPO levels as a
result of reduction in the number of functional
EPO-producing cells within the kidney thus
anemia is common in the later stages of the
disease.

 Recombinant human erythropoietin

(rHuEPO) has been shown to an
effective treatment for this type of
anemia
rHuEPO can be used in malignancy
induced anemia as it is highly
associated with venous
thromboembolism and high mortality.

Bone Mineral Regulations

Normal regulation of bone
mineralization through maintenance
of serum calcium and phosphorus
levels is achieved through the
actions of vitamin D and parathyroid
hormone (PTH)
The actions of both hormones are
exerted largely by the kidney

Vitamin D regulation
The major source of vitamin D is through
dermal synthesis of the precursor compound
cholecalciferol ( vitamin D3) or through
dietary intake of vitamin D3 fortified foods.
Vitamin D3 has minimal biological activity
and requires two hydroxylations to become
active.
First occurs in the liver through the action of
25-hydroxylase to form 25hydroxycalciferol(calcidiol)

 The calcidiol molecule is bound to vitamin

D binding protein and transported to the
kidney, where it is filtered and reabsorbed
by renal tubular cells where the 2 nd
hydroxylation occurs.
Tubular cells contain both 1a hydroxylase
and 24a-hydroxylase, hydroxylation
produces either inactive 24,25dihydroxycholecalciferol or 1,25dihydroxycholecalciferol ( calcitriol)

 Calcitriol production is regulated by calcidiol

levels as well as the 1a-hydroxylase levels.
These are in turn determined by PTH and
plasma phosphate levels( increased enzyme
activity) and calcitriol levels ( decreased
enzyme activity)
Unregulated calcitriol synthesis can occur in
macrophages in granulomatous conditions
eg TB and sarcoidosis and in prostate
epithelial and cancer cells.

Vitamin D activity
Through a single intracellular vitamin D
receptor calcitriol regulate gene transcription
Its primary function is the maintenance of
serum calcium and phosphurus levels.
Its 4 main target organs are the
Intestines( increases intestinal absorption of
calcium and to a lesser extend phosphorus)
The bones ( regulates osteoblast activity and in
combination with PTH allows for osteclast
activation and bone resorption)

 The kidney ( increases reabsorption of

calcium)
Parathyroid gland( suppresses PTH
release)
Recent evidence suggests that both
calcidiol and calcitriol may also function
as antiproliferative agents. Prostate
epithelial and cancer cells also
demostrate VDR and vitamin D may
suppress the growth of these cells
especially in combination with androgens

Parathyroid hormone
regulations
Synthesis, secretion and degradation of
PTH are influenced directly by serum
calcium levels through calcium sensing
receptors located on parathyroid cells.
During hypocalcemia, PTH synthesis and
secretion is increased while degradation is
decreased.
Hyperphosphatemia also directly stimulate
PTH release primarily in advanced renal
insufficient.

Parathyroid hormone
activity
PTH exerts its activity through
PTH/PTHrP receptors which are
localised in the kidneys and bones
Its effect on bone metabolism
depends upon its administration, if
its given
continuously stimulates bone resorption
and increases calcium and phosphorus
levels.
Intermittently leads to increased bone
formation and mineral density

Effects of PTH on the kidney

It increases active calcium
reabsorption at the distal tubule level
It decreases phosphate reabsorption
in the proximal convoluted tubule
through its action on the sodium
phosphorus cotransporter
It stimulates calcitriol production by
increasing 1a-dehydroxylase and
decreasing 24a-dehydroxylase level

Renal tubular function

Each section of the tubule is specialized to
facilitate absorption and secretion of certain
substances through a variety of transport
mechanism
Glucose reabsorption is driven by passive Na+
reabsorption. In the early (S1 and S2) PCT this
occurs through a high-capacity, low affinity
Na/glucose transporter called SGLT-2
In the later (S3) segment of PCT reabsorption
occurs through a low capacity, high affinity
2Na/glucose transporter called SGLT-1

 Intracellular glucose is then transported

out of the cell through the basolateral
membrane by the facilitative transporter
GLUT-2.
Under normal plasma glucose levels, all
filtered glucose is reabsorbed
However if plasma levels exceed 200mg%,
then the filtered load will exceed the
reabsorptive threshold and urinary glucose
will be detected.