Download Mohammed Mustafa Qonswa Esmail _Review

Review of literature
Gross anatomy of the human kidney
The kidneys are situated posteriorly behind the peritoneum on each
side of the vertebral column and are surrounded by adipose tissue. In fresh
state, the kidneys are reddish brown in colour. Superiorly, they are level
with the upper border of the twelfth thoracic vertebra. Inferiorly, they
reach the level of the third lumbar vertebra. The right kidney is usually
inferior to the left one by about 1.25 cm, due to the relationship of the
right kidney to the
liver. The long axis of each kidney is directed
inferolaterally and the transverse axis posteromedially. Hence the anterior
and posterior surfaces usually described as anterolateral and posteromadial.
The upper pole of the left kidney overlies the eleventh rib, while that of the
right kidney overlies the twelfth rib (Chummy, S.S, 2006).
The hilum of the kidney is a vertical slit like depression at its medial
border. The hilum transmits the renal vessels, nerves and the beginning of
the
ureter.
It
faces
somewhat
forwards
as
well
as
medially
(Cormack,2002). The anterior surface of hilar center is approximately at
the transpyloric plane, about 5cm from the midline and slightly medial to
the tip of the ninth costal cartilage. The posterior surface of the hilar center
lies opposite the lower border of the spinous process of the first lumbar
vertebra. The level of left hilum is slightly higher in position than the right
hilum. The kidneys are about 2.5cm lower in the standing than in the
recumbent position (Snell, 2007.).
-4-
Review of literature
Each kidney has anterior and posterior surfaces. Posteriorly, the
relations of both kidneys are similar, comprising mostly the diaphragm and
quadratus lamborum muscles, with overlap medially on to psoas major
muscle and laterally on to transversus abdominis muscle. The upper part of
posterior surface of the kidney lies on fibers of the diaphragm, which arise
from the medial and lateral arcuate ligaments. The subcostal vein, artery and
nerve,
on
emerging
beneath
the
lateral
arcuate
ligament,
lie
behind the posterior surface of the kidney. Also this surface is related to
iliohypogastric and ilioinguinal nerves as they emerge from the lateral
border of psoas major muscle ( Standring et al., 2008).
The anterior surface of the right kidney has relations that differ from
those structures adjacent to the left one. The anterior surface of the right
kidney shows a small area on its upper pole that is related to the right
suprarenal gland. A large area below this adjoins the hepatic impression of
right lobe of liver and a narrow medial area is related to the 2nd part of the
duodenum. Inferiorly, the anterior surface is in contact laterally with the right
colic flexure and medially with part of the small intestine. The areas related
to the small intestine and almost those in contact with the liver are covered
by peritoneum. While the suprarenal, duodenal and colic areas are devoid of
peritoneum. The anterior surface of the left kidney has a small medial area
on its superior pole, which is occupied by left suprarenal gland. The upper
two-thirds of the lateral half of the anterior surface is related to the spleen. A
central quadrilateral area lies in contact with the body of the pancreas and
splenic vessels. Above this, a small triangular region between the suprarenal
and splenic areas is in contact with the stomach. The lower lateral region is
related to the left colic flexure and the beginning of the descending colon,
-5-
Review of literature
while the lower medial region adjoins the coils of the jejunum. The gastric
area is covered with the peritoneum of the omental bursa, while the splenic
and jejunal areas are covered by the peritoneum of the greater sac. The
suprarenal, pancreatic and colic areas are devoid of peritoneum(Standring
et al.,2008).
Each kidney has superior and inferior poles. The superior pole is
thick rounded, nearer to the midline than the inferior pole .The inferior
pole is smaller and thinner. It lies above the iliac crest by about 2.5cm.
(Zomorrodi et al.,2010)
The kidney possesses a thin, loosely adhering capsule that gives the
fresh organ glistening appearance. All surfaces are usually smooth in adult.
But during fetal life and for the first few months after birth, lobes can be
distinguished at the kidney surface. These demarcations between lobes
become blurred in early childhood and give the kidney surface its uniform
smooth appearance in adult life. (Junqueira and Carneiro.,2005)
The perinephric fat lies outside the renal capsule. At the body
temperature, it is solid in consistency. It is in the shape of an inverted
cone. (Chummy, S.S,2006).
The renal fascia surrounds the perinephric fat. Above, the renal
fascia blends with the fascia under the diaphragm, leaving a separate
compartment for the suprarenal gland. Medially, the fascia blends with the
sheaths of the aorta and inferior vena cava. Laterally, it is continuous with
the transversalis fascia. Only inferiorly, it remains relatively open tracking
around the ureter into the renal pelvis. So, the kidney has in fact, three
-6-
Review of literature
capsules which are arranged from outward, inward as follow, renal fascia,
perinephric fat and the true fibrous capsule (Standring et al., 2008).
Renal nerves are derived from both parts of the autonomic system.
The sympathetic preganalionic cells lie in the lateral horn of the spinal cord
from 12th thoracic to the 1st lumbar segments. They send preganglionic
fibers to thoracic and lumbar splanchnic nerves. The postganglionic fibers are
in the coeliac, renal and superior hypogastric plexus and for the lowest
splanchnic nerve, they reach the renal ganglion in the hilum of the kidney.
They are vasomotor in function. The parasympathetic supply is via the
vagus but it is of uncertain function. (Standring et al.,2008)
The vascular supply of the kidney
The kidney has arterial blood supply by a single renal artery to each
kidney. It is present in about 70% of individuals, (while the other 30%
supplied by accessory renal artery). The renal artery is derived directly
from abdominal aorta. Near the renal hilum, each artery divides into an
anterior and posterior division, with each branch sometimes divides further
to form interlobar arteries located between renal pyramids. There is no
anastomosis between these main branches (Snell,2002) .
Each kidney is supplied by a large branch of aorta called the renal
artery. At the hilum of the kidney, it divides into two branches. Each of
these branches gives rise to a number of segmental arteries. These
arteries are end arteries, as they don't anastomose with each other. They
are distributed to different segments of the kidney. (Standring et al.,
2008)..
-7-
Review of literature
The kidney can be divided into five vascular segments called; apical,
upper anterior, inferior, lower anterior and posterior. Each segment is formed
of three or four medullary pyramids and their associated cortical substance,
which is, called renule. Each one is supplied by segment artery, which is the
primary branch of anterior and posterior divisions of renal artery.
(Junquekira and Carneiro,2005)
Lobar arteries arise from the segmental arteries just before entering
the renal substance. Each lobar artery gives off two or three interlobar
arteries that course toward the cortex on the sides of renal pyramids. At the
junction of the cortex and medulla, the interlobar arteries divide into
arcuate arteries. They form arch over the bases of the medullary
pyramids. The interlobular arteries branch off at right angles and follow a
course perpendicular to the renal capsule between adjacent lobules through
the cortex. The afferent glomerular arterioles arise from interlobular
arteries but a few arise from arcuate and interlobar arteries. The efferent
arterioles
branch
again
to
form
a
peritubular
capillary
network.(Carlson,1999)
The afferent arteriole then branches into a tuft-like grouping of five
to eight capillaries, the glomerular capillaries, which called the glomerulus.
This is not entirely true for the kidney, however, here, blood leaving the
glomerular capillaries flows into the efferent arterioles, and not into venules.
From the efferent arterioles, blood moves into the peri tubular capillaries
(meaning “capillaries around the tubules”) (Drake et al., 2005).
-8-
Review of literature
The venous drainage of the kidney is through the renal vein that drains
directly into the inferior vena Cava. They lie in front of renal arteries and
behind the pancreas. They join the vena cave at right angles, at the level of
the second lumbar vertebra .The lymphatics of the kidney drain to para-aortic
nodes at the level of the second lumbar vertebra. The surface of the upper
pole may drain through the diaphragm into nodes in the posterior medistinum
(Mc Minn,1995 ).
-9-
Review of literature
Histology of the human kidney
The cut surface of the hemisectioned kidney shows an outer dark
brown, granular cortex and an inner lighter medulla. The renal medulla
consists of pale, striated and conical pyramids. Each pyramid shows a
broad base directed peripherally towards the cortex and an apex called the
renal papilla. The latter converges to the renal sinus where it projects into the
minor calyx (Junqueira and Carneiro, 2005 )
The tips of the renal papillae are perforated by 10-25 openings of the
ducts of Bellini (the collecting ducts). The latter form sieve like region is
known as the area cribrosa. A cup likes minor calyx, which joins two or
three neighboring minor calyces to form a major calyx. It surrounds the apex
of the renal papilla. The three or four major calyces are larger subdivisions
that empty into the renal pelvis. The latter represents the continuation of
the proximal portion of the ureter (Stevens and Lowe, 2005).
The portion of the cortex overlying the base of each pyramid is known
vneighboring pyramids from each other. This tissue is termed cortical
columns of Bertin (Gartner and Hiatt, 2001).
Macroscopically, there are types of substances in the renal cortex. The
first is red dot like granules termed renal corpuscles. The second is
convoluted tubules called the cortical labyrinth. Thirdly, structure in the
form of longitudinal striations termed medullary rays, which are cortical
continuations of material located in the renal pyramids. Each medullary ray
-10-
Review of literature
consists of one or more collecting tubules together with the straight portions
of several nephrons. (Cormack, 2002)
Each pyramid with its associated overlying cortex is regarded as a
lobe. In human, the kidney is multilobar or multipyramidal organ, but in rat
and mice, the kidney is unilobar or unipyramidal organ. Each renal lobe is
made up of a number of lobules .A kidney lobule is formed of a main
medullary collecting duct (papillary duct) and all the cortical collecting
ducts and associated nephrons that empty into it. (Lesson et al.,1988)
The uriniferous tubules consist morphologically of four major
subdivisions; the proximal, the intermediate, the distal and the collecting
tubules. Functionally, the uriniferous tubules consist of two distinct
portions; nephron and collecting tubules. The nephron comprises a renal
capsule and a renal tubule. The renal capsule concerned with filtration from
the plasma. The renal tubule is responsible for selective reabsorption from
the glomerular filtrate to form the urine. Collecting tubules carry fluid from
several renal tubules to a terminal papillary duct and then to minor calyx
to form hypertonic urine. (Fawcett and jensh, 2002)
-11-
Review of literature
Fig (A): General organization of the kidney. Right: Parts of a juxtamedullary
nephron and its collecting duct and tubule. (Standring, et al.,2005)
-12-
Review of literature
Histological structure of the nephron
The nephron composed of four successive parts. They are; renal
corpuscle, proximal convoluted tubule, intermediate tubule (previously
known as loop of Henel) and distal convoluted tubule (Bergman et
al.,1996).
Renal corpuscle (Malpighian corpuscle)
The renal corpuscle is an oval to round structure. It is
approximately 150-250 um in diameter. The juxta -medullary corpuscles are
much larger than the cortical ones .The larger extramedullary corpuscles
are the first to differentiate during development (Cormack 2002).
The renal corpuscle is composed of glomerular tuft of capillaries
which is invaginated into Bowman's capsule. The glomerular tuft of
capillaries are derived from afferent arteriole. They are lined by
endothelial cells, resting on glomerular basement membrane and
supported by intraglomerular mesangial cells and matrix (Junqueira and
Carneiro,2005).
Bowman's capsule around the glomerulus is a double walled cup that
has visceral and parietal layers. The parietal layer is composed of simple
squamous epithelium. It is supported by basal lamina and a thin layer of
reticular fibers, (Gartner and Hiatt, 2001).
The visceral layer of Bowman's capsule is composed of epithelial cells
that are highly modified to perform a filtering function. These large cells
called podocytes. They bear numerous long, tentacle like cytoplasmic
extensions known as primary (major) processes. Each primary process
bears many secondary processes, named pedicels. The latter completely
-13-
Review of literature
envelop most of the glomerular capillaries by interdigitating with
pedicles from neighboring major processes of different podocytes. The
pedicles leave 25-nm-spaces-between them known as filtration slits
(Douglas,2000).
The filtration slits are covered by a filtration slit membrane. It is of 5-6
run in thickness. These membranes are considered to be similar to the
diaphragms
closing
pores
in
fenestrated
type
(n)
endothelium
(Miner,1999).
described that, each podocyte has a nucleus that is often infolded and
irregular in outline. The cytoplasm contains a small prominent Golgi
apparatus, a moderate number of cisternal profiles of RER and a abundant
free polyribosomes. (Krause,1996) stated that, podocytes have a welldeveloped cytoskeleton. It is composed of numerous microtubules and
intermediate filaments. They extend through the cell body as well as their
primary and secondary processes. (Junqueira and Carneiro 2005)found
that, actin filaments and heavy myosin have been localized in the bases of
foot processes. A chain of proteins: vinculin, talin and others connect the
actin filaments to fibronectin and laminin in the basement membrane.
The glycocalyx is the main component of the plasma membrane of the
foot processes. It is negatively charged material and composed of a 140
KD sialoglycoproteins, which is termed podocalyxin. It also contains
complement 3b receptor and Heymann's antigen (Fawcett and jensh,2002).
The basal lamina is lying between podocytes and their processes
externally and endothelium internally. It is of about 320 - 340 nm, in thickness
in adult humans .It is thinner in young children and in most of experimental
-14-
Review of literature
animals (Burkitt etal.,2000). The basal lamina shows three zones of varying
electron density. Centrally is the electron dense lamina densa while on each
side, the more electron lucent lamina rara externa and lamina rara interaa are
situated (Cormack,1997).
The middle dense layer of basal lamina is the lamina densa. It is about
100nm in thickness and consists of collagen fibres which acts as a physical
filter and glycosaminoglycans. Both lamina rara externa and densa contains
proteoglycans. They are rich in heparin sulfate that is arranged in regular
lattic network of angular particles (Gartner and Hiatt,2001). The negative
charge of proteoglycans is responsible for electrostatic barrier of the
glomerular filter. (Young etal.,2006).
The glomerular capillaries are lined by thin endothelium that is
perforated by pores of about 70.-90 nm in diameter without pore
diaphragms. The spaces between the glomerular capillaries is loaded with
mesangial cells in an extracellular matrix (Garthner and Hiatt, 2001)
Mesangial cells are also termed as lacis cells and form part of what is
called the juxta-glomerular apparatus (Ross et al., 2003). They are irregular
in shape with many cytoplasmic processes that extend between endothelial
cells, reaching the capillary lumen (Bergman et al.,1996). Their structural
characteristics are similar to those of pericytes in that, they have many
bundles of microfilaments. Intraglomerular mesangial cells are probably
phagocytic and function in resorption of the basal lamina. They also may by
contractile, as they are rich in actin and myosin. in addition, they have
receptors for vasoconstrictors such as angiotensin II and thus reduce blood
flow through the glomerulus. Moreover, they may support the capillaries of
-15-
Review of literature
the glomreulus in regions where the visceral layer of Bowman's capsule
does not come into contact with the capillaries (Herbert and Kirz,1993).
The mesangium is a specialized connective tissue which binds the
loop of glomerular capillaries and fills the spaces between endothelial
surfaces that are not invested by podocytes (Eroschenko,2000).
The juxtaglomerular apparatus
The juxtaglomerular apparatus composed of juxtaglomerular cells,
lacis cells and macula densa of the distal tubules.
Junqueira and Carneiro 2005 described that, the juxtaglomerular
cells are myoepithelial cells derived from the smooth muscle of tunica
media of the afferent arteriole. The apices of these cells lie in contact
with the endothelium of the afferent arteriole. Basally, they reach the basal
lamina that lies
fine structural
between the cells of the macula densa. They contain
features including rough endoplasmic reticulum and
a prominent Golgi complex. Their cytoplasm contains granules that
secrete rennin hormone. This hormone is responsible for regulation of the
blood pressure. (Burkitt etal.,2000).
Glomerular filtration barrier
The barrier between circulating blood and the urinary space is the
glomerular filtration barrier. It is composed of the capillary endothelial inner
layer, the unusually thick glomerular capillary basement membrane and the
podocyte (the outer epithelial layer).(Vasmant, etal.,1984).
-16-
Review of literature
The proximal convoluted tubule (PCT)
It starts at the urinary pole of Malpighian corpuscle where, the
squamous parietal epithelium of Bowman's capsule is continuous with the
cuboidal epithelium of the proximal tubule of the nephron. The proximal
tubules are the longest segments of the nephron. The tubule consists of a
tortuous, convoluted portion and a straight portion. The convoluted
(former) portion is confined to the cortex, while the latter traverses the
cortex within its
adjacent medullary ray and becomes the thick
descending portion of loop of Henel (Bergman et al.,1996). Both the
convoluted and the straight parts of the proximal tubule have essentially
similar structure and function. A simple cuboidal type of epithelium lines
the proximal tubule. Their cytoplasms are eosinophilic and granular. Their
nuclei are spherical and basal .The cuboidal cells have prominent striated
brush border. The boundaries between adjacent cells interdigitate with each
other (Cormack,2002).
The brush border of the tubular cell is formed of numerous of closely
packed microvilli. Their tips contain glycocalyx and apical canaliculi that
open in the clefts in between them. (Cormack,2002)
The proximal tubular cells have a system of interlocking lateral cell
processes. They interdigitate with neighboring cells. The bases of tubular
cells are engorged with rod shaped mitochondria. They are arranged parallel to
cellular long axis. (Zamzam et al.,1998)
The supranuclear portion of the cytoplasm also contains rounded
mitochondria and organelles such as ribosomes, lysosomes and pinocytic
-17-
Review of literature
vesicles. The cells are poor with rough endoplasmic reticulum (Junqueira
and carneiro,2005).
In well- fixed histological preparations, the basal striations and the
apical brush border help to distinguish the cells of the proximal convoluted
tubule from those of the other tubules (Ross et al., 2003).
There are three ultrastructural distinct segments in the proximal
tubules. They are known as S1,S2 and S3. The first two thirds of the pars
convoluta is designated S1. But the remainder of the pars convoluta and much
of the pars recta is termed S2. Moreover, the remainder of the pars recta is
called S3. The cells of the S1 region have the common feature of tubular
cells in the form of closely packed microvilli, apical canaliculi,
mitochondria in different shapes, Golgi apparatus and extensive lateral cell
processes. The cells of S2 region are similar to those of S1 region. But they
have fewer mitochondria and apical canaliculi. They are lower in height and
have less intercellular process. Cells of the S3 region are low cuboidal with
few mitochondria. These cells have only infrequent intercellular processes
and no apical canaliculi. (Gartner and Hiatt, 2001)
The intermediate tubule (Loop of Henle)
In the outer medulla, the descending straight portion of the proximal
tubule, which is 60 mm in diameter, progressively narrows and continues as
the descending thin limb of loop of henle of about 15 um in diameter. At the
transitional area, the brush border ends and the cuboidal epithelium
continues as thin squamous epithelium that lines the thin limb (Fawcett
and jensh2002).
-18-
Review of literature
The descending thin limb of short looped nephrons are of small
diameter & wide lumen. They are lined by flat, simple squamous
epithelium. They have few microvilli, mitochondria, intermembranous
particles and tight junction. Inspite of that, the descending thin limb of
long looped nephrons has a larger lumen and shallow tight junctions.
They have numerous microvilli, many intermembranous particles, lateral
interdigitations and mitochondria. (Herbert and Kirz, et al., 1993)
The ascending thick limb starts just before the bend in the loop of
Henel. It is lined by simple flat epithelium. Their cells have few
mitochondria and shallow tight junctions. (Fawcett and jensh, 2002)
The cells are cuboidal, lack a brush border and have a lumen wider
than that of the proximal tubule. Nuclei tend to bulge into the lumen. The
lateral borders of the cells are more easily distinguished (Fawcett and
Jensh, 2002).
The distal convoluted tubule (DCT)
The distal tubule is subdivided into; the pars recta, the pars
convoluta and interposed between them the macula densa. The pars recta is
known as the ascending thick limb of Henle's loop. The pars convoluta is
termed also the distal convoluted tubule. The macula densa is the
interposed region between the ascending thick limb of Henle's loop and
the distal convoluted tubule. (Gartner and Hiatt, 2001)
The ascending thick limb of Henle's loop is 9 to 10 mm in length and
30 to 40 mm in diameter. It joins the ascending thin limb at the inner zone of
the medulla and ascends straight through the medulla to reach the cortex.
Low cuboidal epithelial cells line it. These cells have oval to round nuclei
-19-
Review of literature
and few short microvilli. However, the cells of the DCT have many basal
interdigitations and mitochondria. The basal interdigitations of these cells and
the mitochondria are greater than those present in the proximal convoluted
tubules (Cormack, 2002).
Distal convoluted tubules are short of 4 to 5 mm in length with a
diameter of 25 to 45 mm. Low cuboidal cells line them with aclear, pale
cytoplasm with a few, blunt apical microvilli. Their nuclei are more or less
rounded and apically located, having one or two dense nucleoli. Mitochondria
are not as numerous, nor are the basal interdigitations as extensive as those
of the ascending thick limb of Henle's loop (Bergman et al.,1996).
The distal tubules may be distinguished from the proximal in three
ways; their lumina are relatively more in their width and patency. Because
the distal convoluted tubules are much shorter than the proximal convoluted
tubules, any section of the kidney cortex will present more cross-sections of
proximal convoluted tubules. Surrounding any renal corpuscle, the ratio of
the proximal convoluted tubule to the distal is a bout seven to one. Also the
distal tubule has smaller epithelial cells with absence of the brush border and
more nuclei per cross sectional profile than proximal one (Young and
Health, 2000).
The collecting tubule
The distal convoluted tubules of several nephrons join to form a
short connecting tubule that leads to the collecting tubules. Collecting tubules
are about 20 mm in length. They-have three regions: cortical, medullary and
papillary (Gartner and Hiatt, 2001).
-20-
Review of literature
Cortical collecting tubules are located in the medullary rays and are
composed of two types of cuboidal cells: principal and intercalated
cells(Eroschenko,2000). Principal cells are termed light cells. They have
oval, centrally located nuclei, a few mitochondria and short microvilli. The
basal membrane of
these cells displays numerous infoldings. They are
clearly evident by light microscope because their lateral cell membranes
are not interdigitating (Jenqueira and Carneiro, 2005).
Intercalated cells are also known as dark cells. They have
numerous
apical
vesicles.
Their
cytoplasm
contains
abundant
mitochondria. The nuclei of these cells are rounded and centrally
located.(Burkitt etal.,2000).
Papillary collecting tubules are also called ducts of Bellini. Each duct
is formed by the confluence of several medullary collecting tubules. These
ducts are of large size and their diameter of 200 to 300 nm. They open at
the area cribrosa of renal papilla. Tall columnar princial cells line these
ducts only. (Stevens and Lowe,2005)
Renal interstitium
In the cortex, the interstitial space is small, but it increases in the
medulla. Small blood vessels and lymphatics occupy the cortical space. The
medullary interstitium is larger in amount. It increases in size during its
convergence towards the tip of the papillae. It is composed of electron lucent
material in which collagen fibers, lipid droplets, basal lamina like material
and interstitial cells are dispersed (Young and health, 2000)
The cortical interstitium contains fibroblast like cells, mononuclear
cells and small bundle of collagen fibers. The fibroblast like cells is irregular
-21-
Review of literature
in shape with long processes that often appear to contact those of adjacent
cells. They contain elongated nuclei that have small clumps of chromatin
along their nuclear envelope. Their cytoplasm contains lipid droplets and
dilated cisternae of rough endoplasmic reticulum . Their function is
suggested to be responsible for production and maintenance of the collagen
fibrils and glycosaminoglycans of the cortical interstitium. (Ross et al.,2003)
The medullary interstitial cells are fibroblast like cells. They differ
from those of the cortex in their orientation and ultrastrucure. They are
highly pleomorphic cells, which are oriented perpendicular to the axis of
the tubules. They have long processes that are more slender than those of the
fibroblasts of the cortex. They have multiple lipid droplets of variable size
and shape. These may be surrounded by smooth endoplasmic reticulum. It
has been suggested that, they secret a hormone that is involved in the
regulation of blood pressure. (Cormack,2002)
In the medulla, three types of interstitial cells have been described:
a. Type I interstitial cells: the most abundant type, are highly
polymorphic cells containing multiple small lipid droplets. The cells are
distributed at regular interval between the parallel tubules and vessels
(Moffat, 1967).
b. Type II interstitial cells: are generally rounded and lack lipid droplets
but the cytoplasm contains number of free ribosomes and lysosomes
(Bohman,1980).
c. Type III interstitial cells: corresponds to pericytes and these cells are
closely related to the descending vasa rectae. They usually lie between
layers of the basement membranes of these vessels (Bohman, 1980).
-22-
Review of literature
Cisplatinum
The chemotherapy involves the use of chemical agents to stop the
growth & eliminate cancer cells even at distant sites from the origin of
primary tumor (Bonadonna, et al. 1995 and Graff, et al. 1996) .
However, it doesn't distinguish between cancer & normal cells and
eliminates not only the fast growing cancer cells but also other fast growing
cells in the body including hair & blood cells (Graff, et al. 1996).
Cisplatin (cis- diamminedichloroplatinum (III) is an inorganic metal
complex discovered by Rosenberg and his colleagues, who made the
serendipitous observation that neutral platinum complexes inhibit division
and induce filamentous growth of Escherichia coli (Lin etal.,2006).Many
platinum analogs of this very important drug have been synthesized. While
the precise mechamism of action of cisplatin is still undefined, it is thought
to act analogously to alkylating agents. It kills cells in all stages of the cell
cycle, inhibits DNA biosynthesis, and binds DNA through the formation of
interstrand cross- links. The primary binding site is the N7 of guanine, but
covalent interaction with adenine and cytosine also occurs (Olivero, et al.
2003).
Uses of cisplatinum
Cisplatin (CP) represents a class of antineoplastic drugs containing a
heavy metal, platinum ,it was one of the most commonly used drugs in the
treatment of a wide spectrum of human malignancies. As a single agent
-23-
Review of literature
or in combination, cisplatinum was mainstay of treatment for cancer
testis, ovaries, urinary bladder, head and neck in addition to lung cancer
(Van Basten et al.,1997 and Jordan et al.,2000).Although the response
and cure rates with cisplatinum could be high (>90%), as in testicular
cancer; in other types of tumors such as ovarian cancer, the initial
response rate could be up to 70%, but a 5-year survival rate of only 1520% was recorded . It is particularly used for the treatment of ovarian,
testicular,head and neck cancers; (Dobyan et al.,1980; Gandara et al.,1991
and Sheikh, et al.,2003).
Pharmacokinetics
The clinical use of CP is often limited by its undesirable side
effects(Ajani, 2008 and Dank et al.,2008) nephrotoxicity and neurotoxicity
being the most severe and dose- limiting ones (Sadzuka,et al. 1992 and
Durak et al.,2002). Hepatotoxicity, a less- frequent toxic effect, is frequently
observed after the administration of high doses of CP (Yuan, et al.2008).
Formation of free radicals, leading to oxidative stress, has been shown to be
one of the pathogenic mechanisms of these side effects (Kawai, et al.2006).
Recent studies have focused on the role of antioxidants in CP toxicity, In
animals, supplementation with antioxidants seems to protect against CPinduced side effects (Antunes, et al., 2001 and Ajith et al., 2009).
Very high intraperitoneal concentration could be obtained and
systemic toxicities could be reduced by concomitant systemic
administration of thiosulfate. Cisplatinum had been also administered
intra-arterial for treatment of tumors in the extremities, brain tumors and
-24-
Review of literature
carcinomas of head and neck, liver and urinary bladder (Bogin, et al.,
1994).
Intravesicular instillation of cisplatinum had been used in the
treatment of superficial cancers of the urinary bladder. Cisplatinum had
been also instilled into pericardia! sac in the treatment of malignant
pericardial effusions (Jordan etal.,2000).
Intracellular accumulation of cisplatinum
Once cisplatinum entered the cell, the chloride concentration
dropped to 20 mM and the drug underwent strong hydration to form
positively charged active species for subsequent interaction with cellular
nucleophiles (Sheikh, et al.2003).
Cisplatinum cellular uptake was barely understood. The current
data indicated that cisplatinum entered cells through transmembrane
channels but this data were also consistent with high-capacity facilitated
transport. So far, the search for cisplatinum membrane transport system
had been unsuccessful (Naziroglu et al.,2004).
Cisplatin generates free radicals. These highly reactive oxygen species
can cause extensive tissue damage through reactions with all biological
macromolecule, e.g., lipids, proteins and nucleic acids, leading to the
formation of oxidized substance such as the membrane lipid peroxidation
product malondialdehyde (MDA) (Sugihara., et al 1992; Sadzuka., et al
1992).
Reactive oxygen species (ROS) produced via the xanthine- xanthine
oxidase system, mitochondria, and NADPH oxidase in cells in the presence
-25-
Review of literature
of cisplatin are implicated in the pathogenesis of acute cisplatin- induced
renal injury (Kawai, et al., 2006). Recent work has suggested a role of p53
activation mediated by oxidative stress, particularly hydroxy1 radicals, in
renal cell injury by cisplatin, which results in tubular cell apoptosis and
nephrotoxicity (Jiang, et al., 2007). Since oxidative stress is actively
involved in the pathogenesis of cisplatin- induced acute kidney injury.
Apoptosis known as a major mechanisms of cisplatin induced duced
cell death in renal tubular cells (Sheikh, et al., 2003).
Oxidative stress is caused by various free oxygen radicals including
superoxide anion , hydrogen peroxide and hydroxyl radicals . It has been
suggested that oxidative stress plays a critical role in the pathogenesis of cisplatin
induced nephrotoxicity (Naziroglu, et al., 2004) .
The nutritional status of cancer patients, especially the nutritional
intake of antioxidants
and their plasma and tissue concentrations may
determine the extent of oxidative organ damage by free radicals produced by
cytotoxic drugs (Salganik,2001).
-26-
Review of literature
Ascorbic acid (Vitamin C)
Ascorbic acid is an essential dietary vitamin. It was first isolated from
plants as orange and cabbage and from animal tissues as adrenal gland and
was first chemically synthesized in 1933 (Murray,2000).
Structure
Fig. (B): Chemical structure of L-Ascorbic acid (Passmore and
Eastwood, 1987).
Sources:
The best dietary sources of ascorbic acid appear to
be citrus
fruits, Green leafy vegetables, guava, tomato and potato. Much smaller
amount is contained in milk, meat and cereals. Care must be taken during
food preparation, as ascorbic acid is heat sensitive (Halliwell,1996)
-27-
Review of literature
Functions of vitamin C
Vitamin C plays a major role in synthesis of protein collagen (Choi,
et al., 2009) .The amino acids proline and lysine must be hydroxylated after
they have been incorporated in the polypeptid pro-collagen. Unless this
occurs, the final triple helix structure of collagen can not be formed. This
unique structure of collagen provides the structural integrity characteristic of
connective tissue. In hypovitaminosis C, collagen synthesis is reduced,
existing collagen fibers are destabilized and there is general dissolution of
intercellular ground substance. Reduction in effective amount of
collagen and matrix are the basis for connective tissue lesions and
impaired wound healing in the deficiency states ( Fang, et al. ,2002).
Ascorbic acid is essential for carnitine synthesis, which stimulates
fatty acid oxidation in mitochondria ( Ratiani et al., 2010). Decreased
levels of vitamin C are associated with lower energy levels and muscle
weakness, So high dietary fat exacerbates chronic vitamin C difficiency
(Frikke, et al. ,2011).
Ascorbic .acid serves in the biosynthesis of the neurotransmitter
adrenaline. behavioral changes associated with hypovitaminosis C may be
related to this function (Toma Ada, et al. ,2010). It is also essential in bile
acid synthesis. It promotes neutrophil chemotaxis and may possess a mild
antihistaminic. It helps dietary iron absorption, distribution and storage
(Chaney, 1986).
Vitamin C at a does of 0.5 to 3 grams per day had been used to acidify
the urine in cases of refractory urinary tract infection and reduce uremic
symptoms in kidney failure (Singer ,2011)
-28-
Review of literature
Vitamin C was suggested to play many important functions in the ocular
tissues including; aqueous humor formation and protection against ultraviolet
radiation ( Padh and block et al.,1991).
Vitamin C inhibited the formation of the carcinogenic N-nitrose
compounds in vitro and in vivo. Food rich in vitamin C was associated with
reduced risk of gastric and esophageal cancer in the work done by
(Gonzalez, and Riboli, 2010 ).
Seminal fluid had higher ascorbate levels than plasma, that was
needed for normal sperm function as proved by (Halliwell,1996).
The combination of iron and vitamin C will evoke weak pro-oxidant
properties of vitamin C and initiate lipid peroxidation. So the current
combination of iron and vitamin C to increase the absorption of iron from
intestine is better to be avoided. The pro-oxidant activity of vitamin C
results from reduction of Fe 3+ (Peneaus, et al., 2008).
The role of vitamin C as water soluble antioxidant scavenges
superoxide (O2 ) radical and protect against oxidative stress (Lagowska, et
al., 2010) .
Vitamin C Deficiency:
Urban poor, particularly the elderly are at risk of dietary
deficiency of ascorbic acid. Children develop scurvy when fed
unsuplemented cow's milk in the first year of life (Ghedira, et al., 2010).
In the early stages of deficiency, symptoms and signs may be fairly
non-specific and include general malaise, lethargy and weakness. As the
disease progresses, probably one to three months after the onset, patients
-29-
Review of literature
may complain of dyspnea as well as bones and joints pains. Petechiae are
often prominent. With progressive vitamin C depletion, there are purpura
and ecchymosis at areas of trauma and pressure. Swollen bleeding gums
and perifollicular hemorrhages are characteristic signs of advanced
deficiency (Michiels, et al., 2010). Joints, muscles and subcutaneous
tissues may also become the site of hemorrhage. Pallor and anemia may be
the result of prolonged bleeding or an associated folic acid deficiency with
which scurvy commonly occurs (Dolberg, et al., 2010 and Delangh et
al.,2011).
Excess vitamin C intake:
Prolonged ingestion of ascorbic acid in excess increases the urinary
output of oxalic acid and uric acid. It increases the intestinal absorption of
iron. Large doses of vitamin C are therefore dangerous to those with
liability to urinary stones (Auer, et al., 1998) or to iron-storage disease
(Gerster, 1999).
-30-
Review of literature
Vitamin E (Tocopherol)
There are several naturally occurring tocopherols. All are isoprenoid
substituted 6- hydroxychromanes (tocols).
Fig. (C): Forms of vitamin E (Murray, etal.,2000).
Pharmacological Aspects of Vitamin E
The protective effect can be explained by the scavenging of free
radicals before they damage cellular macromolecules. Vitamin E. is lipidsoluble antioxidant that quenches free radicals and stabilizes the molecular
composition of cellular membranes .However, the precise protective effect
of vitamin E is preventing apoptotic cell death (Fang et al., 2002).
Fat Absorption Promotes the Absorption of Vitamin E:
Impaired fat absorption leads to vitamin E deficiency because
tocopherol is found dissolved in the fat of the diet and is liberated and
-31-
Review of literature
absorbed during fat digestion. Further more, it is transported in the blood
by lipoproteins; first, by incorporation into chylomicrons, which distribute
the vitamin to the tissues containing lipoprotein lipase and then to the liver
in chylomicron remnants; and second, by export from the liver in very low
density lipoproteins. It is stored in adipose tissue. Thus, vitamin E deficiency
may be found in situations associated with dysfunction of the above
processes, eg, in chronic steatorrhea. abetalipoproteinemia, homeostatic liver
disease, cystic fibrosis, and in patients who have undergone intestinal
resection, (Roberts, et al.,2009)and (Bennett & Brown, 2003).
Functions:
The main function of alpha- tocopherol in humans appears to be that
of an antioxidant. Free radical damage has been implicated in a number of
degenerative esses including carcinogcnesis, aging, arthritis, platelet
hyperaggregability, ischemia and reperfusion injury, cataracts and lung
injury caused by pollutants. Thus vitamin E is involved in an extensive range
of protective systems. However, the exact daily intake of vitamin E for
optimal health protection has not been reached, people believe that the
scientific evidence is strong enough already, especially for cardiovascular
disease, to recommend daily intakes in the order of 87-100 mg alpha
tocopherol equivalents/day (Morrissey & Sheeny, 1999 )and Gohil
etal.,2010).
Vitamin E is the Most Important Natural Antioxidant:
Vitamin E appears to be the first line of defense against
peroxidation of polyunsaturated fatty acids contained in cellular and
subcellular membrane phospholipids. The phospholipids of mitochondria,
endoplasmic reticulum, and plasma membranes possess affinities for alpha-32-
Review of literature
tocopherol, and the vitamin appears to concentrate at these sites. The
tocopherols act as antioxidants, breaking free-radical chain reactions as a
result of their ability to transfer a phenolic hydrogen to a peroxyl free
radical of a per-oxidized polyunsaturated fatty acid. The phenoxy free
radical formed may react with vitamin C to regenerate tocopherol or it reacts
with a further peroxyl free radical so that the chromane ring and the side
chain are oxidized to the non-free-radical product shown in. This oxidation
product is conjugated with glucuronic acid via the 2-hydroxyl group and
excreted in the bile. If it reacts in this manner, tocopherol is not recycled
after carrying out its function but must be replaced totally to continue its
biologic role in the cell. The antioxidant action of tocopherol is effective
at high oxygen concentrations, and thus it is not surprising that it tends to be
concentrated in those lipid structures that are exposed to the highest 0 2
partial pressures, eg., the erythrocyte membrane, the membranes of the
respiratory tract and the retina, (Alexander & john, 2005)and (Barar,
2006).
Several other functions of alpha-tocopherol have been identified
which likely are not related to its antioxidant capacity. Alpha-tocopherol is
known to inhibit the activity of protein kinase C, an important cell signaling
molecule, as well as to affect the expression and activity of immune and
inflammatory cells. Additionally , alpha-tocopherol has been shown to
inhibit platelet aggregation and to enhance vasodilation (Traber, 2006).
Also, vitamin E works together with vitamin C and B-carotene to delay the
onset of cataracts (Korotkova etal.,2004).
Vitamin E may enhance the body's immune function and inhibit the
conversion of nitrites to nitrosamines in the stomach (Perkmezci,2011).
-33-
Review of literature
Vitamin E is thought to have a role in prevention of atherosclerosis,
through inhibition of oxidation of low-density lipoprotein. (Soni,2010).
A number of studies have examined vitamin E supplementation and
benefits for individuals with diabetes mellitus (Astley et al., 1999).
Vitamin E has been reported to successfully relieve the symptoms of
fibrocystic breast disease. Vitamin E has also been reported to relieve
menupausal symptoms such as hot flushes, sweats, vertigo, headaches,
parasthesia. fatigue, insomnia and nervousness (Gonzalez, 2010). it has been
reported that vitamin E has shown the most consistent and greatest-effect on
AIDS of all the antioxidants (Azzi and Stocker,2000)
Additionally, antioxidant nutrients including vitamin E may be
effective in slowing the progression of Parkinson's disease in those not
already receiving medication (Bramley,2000) and it has neuroprotective
(Pace et al.,2003)
- It plays very important role in prevention and treatment of cancer
(Sylvester et al.,2010) and (Wada,2011).
- It inhibits the inflammation and carcinogenesis in the lung and colon
(Yang et al.,2010).
- Alpha tocopherol protects against cisplatin induced toxicity without
interfering with antitumour efficacy.(Leonetti et al.,2003).
-34-
Review of literature
Deficiency:
Vitamin E deficiency has been observed in individuals with severe
malnutrition, genetic defects affecting the alpha-tocopherol transfer protein and
fat malabsorption syndromes. Severe vitamin E deficiency results mainly in
neurological symptoms, including impaired balance and coordination (ataxia)
(Donato et al.,2010), injury to the sensory nerves (peripheral neuropathy),
muscle weakness (myopathy), and damage to the retina of the eye (pigmented
retinopathy). For this reason.people who develop peripheral neuropathy,
ataxia or rennitis pigmentosa should be screened for vitamin E deficiency
(Traber, 2006). The developing nervous system appears to be especially
vulnerable to vitamin E deficiency (Muller, 2010) because children with
severe vitamin E deficiency from birth, who are not treated with vitamin E,
develop neurological symptoms rapidly.
Drug interactions and Excess intake:
Individuals on anticoagulant therapy or individuals who are vitamin K
deficient should not take alpha-tocopherol supplements without close medical
supervision because of the increased risk of hemorrhage
(Azzi and
Stocker,2000).
A number of medications may decrease the absorption of vitamin E.
including cholestyramine, isoniazid, sucralfate, Anticonvulsant drugs such
as
phenobarbitol.
phenytoin,
or carbamazepine may decrease plasma
levels of vitamin E (Aggarwal,2010,).
Some
physicians
recommend
that
high-dose
vitamin
E
supplementation should be discontinued one month before elective surgery to
decrease the risk of hemorrhage. Premature infants appear to be especiallyvulnerable to adverse effects of alpha-tocopherol supplementation, which should be
used only under controlled supervision by a pediatrician (Aggarwal,2010).
-35-