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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-