Introduction
Vasopressin (Anti diuretic hormone/ ADH or Arginine vasopressin/ AVP) is an important hormone in the body. Although it secrets from posterior pituitary, it is synthesized by hypothalamus. Vasopressin has several physiologic action in the body, While antidiuretic action predominately. Vasopressin synthesized as a hormone endogenously as well as it provide as a drug exogenously.
Knowing about vasopressin is very important in medical carrier, Because of deficiency, excessive secretion or ineffectiveness of this hormone cause various diseases. By using this book, can get proper knowledge about structure, analog, regulation of secretion, function, associated disorders and uses of vasopressin.
Formation of this book was based on information of medical text books and currently available information from web sites.

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Vasopressin
Vasopressin (Anti Diuretic Hormone ADH) is a peptide hormone, released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure. Vasopressin possesses antidiuretic & vasopressor properties. A deficiency of this hormone result in Diabetes insipidus.(7)

Structure
Vasopressin is composed of six-member disulfide ring with a three amino acid tail.(8)
Fig: Structure of vasopressin.
Arginine in the eight position appears essential for maximal antidiuretic action in most mammals.(5,7,10,) So mammalian ADH also call as Arginine vasopressin(AVP), except in the Pig & Hippopotamus.
Both Oxytocin & ADH are with similar structures, they differ only amino acid at position 3 & 8.(10)
Analogues There are also semi synthetic vasopressin, including Desmopressin(DDAVP or 1-deamino-8-D-arginine vasopressin) and Felypression(2-phenylalanine-8-lysin vasopressin). Lypressin(8-lysine vasopressin).(10)

Synthesis
Vasopressin is synthesized as a 145-aminoacid precursor comprising a signal peptide. ADH is synthesized in the nerve cell bodies in the supra optic & paraventricular nuclei in the hypothalamus together with oxytocin. The cell in the thus nuclei, shere the properties of neurons & endocrincells, and are often refered to as neurosecretory cells.

Bio essay shows that the supraoptic neucleous contain mostly Oxytocin & the paraventricular neucleous containg a mixture of the two hormones but ADH predominates.(10)

The ADH is stored in combination with their specific, cystine-rich binding protines called neurophysin-2. In hypothalamus ADH is always associated with it.(10)
The terminal amino group is essential for binding to the neurophysin. The secretary granules contain the hormone and the neurophysin. It appears that the neurophysin function as intracellular carrier molecule to maintain the hormone within the granules as they pass along the axons to the nerve terminals by a process that probably involves micro tubules.(10,1) In addition ,the same synthetic process may be concerned with formation of neurophysin and there associated hormone. A prohormone is formed initially and packaged in to granules, where it is subsequently cleaved in to the neurophysial hormone and neurophysin.

Secretion
ADH release from the nerve endings in responds to nerve impulses. Ionized Ca2+ is necessary for release ADH and Mg2+ antagonizes it’s action.(1,8) Ca2+ in the external medium is essential for release in response to depolarization. It has been assumed that depolarization allows Ca2+ to enter the axon and that this in turn somehow causes release the hormone, Ca2+ can disrupts the binding of ADH to neurophysin in vitro.(10,8) In this occurred in the cell it could possibly release the peptide from binding and leave it free to diffuse out of the cell.
In general, the release mechanism resembles that of transmitters release from nerve endings elsewhere. It differs only in that the hormone is not released at a synapse, but in to the capillaries of neuro hypophysis, from which it is transported by the circulation to act upon target organs. Electron micrograph shows the presence of smaller vesicles resembling acetylcholine vesicles within the nerve endings , along with the larger granules. The small vesicles may contain a release mediator and it has been suggested that is Ach .(10, However evidence against this is that there is not detectable choline acetyl transferase activity in the neuro hypophysis and the there fore no obvious mechanism for rapid Ach synthesis. Possibly the small vesicles contains a peptide enzyme that is feed by the nerve impales to split the hormones from their protein carrier , or may they simply be empty be granules.

Regulation of ADH secretion
The secretion of ADH by posterior pituitary can be influence by several factors.

1) Cellular regulation by neuro transmitters
The nerves cell bodies of the neurosecretory cell have both cholinergic and noradrenergic nerve endings impinging on them and activity in the these cells is probably controlled by the Ach and nor adrenaline. These transmitters may interact not only postsynaptcally , they may also have a reciprocal presynaptic inhibitory effect.(3) Ach and nicotine injected in to the carotid circulation course the release of ADH , noradrenalin inhibits its release.

2) Physiological regulation
The two primary physiological regulators of ADH secretion are osmotic (plasma osmolality) and homodynamic (blood volume and pressure)

2.1) Osmotic control of ADH secretion
Changes in the osmolality of the body fluids play the most important role in regulating ADH secretion. Changes in osmolality as small as 1% are sufficient to alter ADH secretion significantly.(2,4) Cell located in the hypothalamus, but distinct from those that synthesize ADH are involved in sensing changes in body fluid osmolality. These cells termed osmoreceptors, appear to behave as osmometers and sense changers in body fluid osmolality by either shrinking or swelling. Osmoreceptors respond only to the plasma solutes that are effective osmoles. For example urea is an ineffective osmole, when the function of the osmoreceptors is considered. Thus elevation of only the plasma urea concentration has little effect on ADH secretion.
When the effective osmolality of the plasma increases, the osmoreceptors send signals to ADH synthesizing cells located in the supraoptic and Para ventricular nuclei of the hypothalamus and ADH secretion is stimulated. Conversely when the effective osmolality of the plasma is reduced, secretion is inhibited, because ADH is rapidly degraded in the plasma. Circulating levels can be reduced to zero within minutes after secretion is inhibited(2). As a result the ADH system can respond rapidly to fluctuations in plasma osmolality .

A illustrates the effect of changes in plasma osmolality on circulating ADH levels. The set point of the system is defined as the plasma osmolality value at which ADH secretion begins to increase. Below this set point virtually no ADH is released. Above the set point the slope of the relationship is quite steep, this slope reflects the sensivity of this system, the set point varies among individuals and is genetically determined. In healthy adults the set point varies from 280 to 290 mOsm/Kg H2O . several physiological factors such as alterations in blood volume and pressure can also change the set point , pregnancy is also associated with a decrease in the set point.(2,4)

Fig: Osmotic regulation of vasopressin secretion.

2.2) Homodynamic control of ADH secretion
A decrease in blood volume or pressure also increase ADH secretion. The receptors activated by this response are located in both the low pressure (left atrium & pulmonary vessels) and the high pressure(aortic arch & carotid sinus) sides of the circulatory system. These receptors respond to stretch and are termed baroreceptors. Signals from these receptors are relayed to the ADH secretary cells of the Supraoptic and Para ventricular nuclei, via afferent fibers in the vagus and glossopharyngeal nerves. The sensivity of the barroreceptors system is less than that of the osmoreseptors, a 5% to 10% decrease in blood volume or pressure is required to stimulate ADH secretion.(2,4) .
Alterations in blood volume and pressure also effect the response to changes in body fluid osmolality. With a decrease in blood volume or pressure the set point is shifted to lower osmolality values and the slope of the relationship is steeper. In terms of survival of and individual faced with circulatory collapse. This means that the kidney continues to conserve water. Even through the water retention reduces the osmolality of the body fluids. With an increase in blood volume or pressure the opposite action occurs, the set point is shifted to higher osmolality values and the slope is decreased.(2)

2.3) Drugs effects on ADH release
In addition to changes in osmolality of extra cellular fluid(ECF) , release of the ADH is influenced by a variety of drugs. The existence of a cholinergic mechanism for this process has been suggested on the basis of experiments showing that injections of Ach or diisopropy-1,3-fluorophosphates in to the supra optic nuclei caused release of ADH . Nicotine has been shown to inhibit water diuresis in human, probably through the release of ADH. Alcohol inhibits the release of ADH in response to dehydration and produce inappropriate water diuresis in a dehydrated individual. Alcohol does not block the action of nicotine on the release of the ADH.(5)
Anti diuresis that occurs during general anesthesia and following the injection of histamine, morphine and barbiturates (but not thiopental) has also been attributed to the release of ADH. Since muscular exercise, pain & emotional excitement also cause inhibition of water diuresis, it is likely that some central control mechanism of ADH release is very susceptible to neural or neurohumoral influences. The large variety of drugs that can influence ADH release, many are known to alter neural activity or to act as stressful stimuli.(5)
2.4) Other effects Vasopressin is also released under nonspecific stress, particularly it associated with nausea or vomiting. Other factors that can alter ADH secretion include atrial natriuretic peptide (inhibits) and angiotensin-2(stimulate).(1,2,3,7)

Certain hyponatremic syndromes are associated with in appropriate secretion of ADH. They are characterized by primary water retention and associated with sodium retention & oedema. Some of underline diseases are bronchogenic carcinoma, head injury and tuberculosis meningitis.(1,11)

Fig: Regulation of vasopressin secretion and respond of vasopressin.

Vasopressin receptors and antagonist
Three subunits of vasopressin receptors have been identified.
V1a receptor-mediate the vasoconstrictor action
V1b receptor-potentiate the release of ACTH by anterior pituitary
V2 receptor-mediate the anti diuretic action
V1a effects are mediated by activation of phospholipase C, formation of inositol triphosphate, and increased intracellular Ca2+ concentration. V2 effect are mediated by activation of adenylylcyclase. (3,7)
Vasopressin like peptides selective for either vasoconstrictor or anti diuretic activity have been synthesized.
The specific antagonist of the vasoconstrictor action of ADH are also available. The peptide antagonist[1-(β-mercapto-β,β-cyclopentamethylene propionic acid)-2- (O-methyl ) tyrosine] AVP also has antioxytocic activity but does not antagonize the antidiuretic action of vasopressin. Recently, non-peptide orally active V1a receptor antagonists have been discovered (ex:OPC-21268 & SR-49059 ).(3,5,10)
Action of ADH
ADH is a posterior pituitary peptide hormone. It is important for its action on kidney. but is also a powerful vasoconstrictor in skin and some other vascular beds. Its effect are initiated by two distinct receptors (V1&V2) (3,7,6)

1) Renal action
The major physiological action of vasopressin is to increase urinary concentration. ADH bind to v2 receptor in the basolateral membrane of the cells of the distal convoluted tubule (DCT) and collecting ducts of the nephron. Its main effect in collecting ducts is to increase the rate of insertion of water channels in to luminal membrane , thus increasing the permeability of the membrane to water. Circulating AVP binds to specific V2 receptor. adenylcyclase is stimulated, via the coupled G-Protein, to produce cyclic 5’AMP , which activates intra cellular protein kinases and accelerate the expression and trafficking of aqua porin-2, the ,vasopressin-sensitive water channel protein.(4,7,6) ( Aqua porine 2 is organized in to a tetramer and inserted in to the luminal cellular membrane of the DCT , allowing water to flow from the tubular lumen in to the cellular compartment.
As renal prostaglandins(PG) reduces the generation of cyclic 5’AMP, they blunt the effect of vasopressin and there fore PGsynthetase inhibitors augment the antidiuretic action of AVP.
Fig: Anti diuretic action of vasopressin
It also activates urea transporters and transiently increase sodium absorption, particularly in the DCT . both of which enhance the osmotic radiant Several drugs effect the action of ADH. Nonsteroidal anti inflammatory drugs (NSAIDS) and carbamazepine increase ADH effects, lithium ,colchine and vinca alkaloids decrease it.(4,5) The latter two agents virture of their action on microtubules organelles required for the water channels. Demeclocycline counteracts the action of ADH and can be used to treat patient with hyponatremia,(& water retention) caused by excessive secretion of ADH.(4,5)
The other aquaporines (3&4) are located on the contra luminal cell membrane these are non-vasopressin responsive, but facilitate the osmotic gradient between the hypotonic urine within the tubular lumen and the hypertonic renal intestitium. Thus urine volume is decreased and urine is concentrated.

2)Non renal action
The first action attributed to vasopressin was the elevation of the systemic blood pressure by peripheral vasoconstriction by action on V1a receptors. That activate phospotidylinositol pathways, increase the intra cellular Ca2+ concentration and cause the contraction of vascular smooth muscle. (7,9) The affinity of these receptors for ADH is lower than that of the V2 receptors, and smooth muscle effect are only seen with doses larger than those effecting the kidney. So probably plays a little role in maintaining blood pressure, but it is involved in the pressure response to hypovolaemia or hypotension. ADH also stimulates blood platelets aggregation and coagulation factor release, plasma factor V111 and the von willebrand factor.(7,9) In the central nerve system, ADH act as a neuromodulator and neurotransmitter, releasing in to the pituitary portal circulation, it promotes the release of ACTH from the anterior pituitary by the action of V1b receptors.
Vasopressin has intrinsic oxytocin activity.(9,7) The non-pregnant human uterus is more responsive to oxytocin. Large dose of either hormone are needed to cause contraction. Uterine sensitivity to oxytocin increases tremendously during pregnancy while can however, produce tonic uterine contractions that could be deleterious to the fetus. Vasopressin has considerable milk ejection activity. Vasopressin in very large dose may also stimulate motility of large bowels.(7,9)
Disorders of arginine vasopressin secretion
Diabetes insipidus (DI)
Polyuria with dilute urine may result from vasopressin deficiency (Cranial DI), resistance to the actions of AVP (Nephrogenic DI).
Cranial Diabetes Insipidus.
Simple destruction or removal of the posterior pituitary gland, or damage to the distal part of the pituitary stalk, usually result in a temporary DI lasting for 6 week to 6 months, since the proximal nerve endings grow out to find systemic capillaries in any scar formed and begin direct secretion again.(9) Upper stalk, median eminence, more extreme hypothalamic damage or mutation of gene for AVP results in permanent diabetes insipidus.(9,11)
An individual deficient in AVP will pass approximately 40ml/kg or urine in 24h(between 3 and 20litres), leading to the clinical features of polyuria. Polydipsia, nocturia, and in children nocturnal enuresis and ultimately stuporous & comatous as a result of hyper osmolality.(9,11) In complete absence of AVP the maximally dilute urine has an osmolality of approximately 50mOsmol/kg.

Nephrogenic Diabetes Insipidus.
Nephrogenic D.I. has diverse causes. Congenital nephrogenic D.I. typically present with profound polyurea and hypernatraemia from birth, incontrast to congenital cranial D.I(9) The condition need urgent recognition since repeated episodes of hypernatraemia with polyurea , vomiting ,constipation ,fever ,irritability and failure to thrive may result in long term cognitive impairment. The drive to drink may impair eating and lead to delayed growth. The X-linked condition is associated with mutation of V2 receptor,(9,11) while it autosomal recessive disease there is deficiency of aquaporin, there will be an increase in blood pressure and circulating Von willebrand factor and factor 8 , two to three fold basal level.(9) As these effects are depend on intact V2 receptor signaling they will not be seen in the X-linked form.
Acquired nephrogenic D.I. is occurring as a result of electrolyte imbalance. There will be increased [Ca2+ ] and low [k+]. It is due to Kidney disease and administration of drug such as Lithium carbonate.(11)
The distinct feature of Nephrogenic D.I. from craniogenic D.I. is absent of response to administrative dose of vasopressin.(10,11)
Treatment of Cranial D.I.:- Desmopressin is a synthetic analogue of AVP with high selectivity for the V2 receptor activity, and a prolonged half-life.
Treatment of Nephrogenic D.I.:- Drugs such as lithium should be withdrawn is possible. Thiazied diuretics reduce urine output by enhancing sodium excretion. Amiloride may need to co-administration to avoid hypokalaemia…(9,10,11).

Syndrome of inappropriate anti diuresis (SIADH)
This disease condition is caused by excessive secretion of vasopressin. In this situation vasopressin secretion is inappropriate, because it is not stimulated by high serum osmolality or low plasma volume. As results of this disease increase volume of Extra cellular fluid, decrease concentration of sodium , chlorine & other substance and production of concentrated urine.(9,11) Symptoms may be acute or chronic,:-sudden or gradual loss of appetite, nausea, vomiting, sleepiness, confusion & disorientation and ultimately seizures, coma and death.(11,9) When the onset is very low, there may be few or even no symptoms. Excessive secretion of vasopressin is particularly due to tumors (not tumor in neurohypophysis) :lung tumors, central nervous system disorders, corticotrophin deficiency and several drugs (Opiates, carbamazepine, anti tumor drugs).(11)
Treatments:- Initial treatment for SIADH typically involves restriction of water intake. If patient with very low sodium concentration, intra venous administration salt solution along with diuretics. (11)

Vasopressin as a drug
This medicine act to lower the amount of urine that is made and to constrict small blood vessels It is used to treat D.I. It is also used to reduce stomach bloat for some procedure and after some surgeries. This medicine may be used for other purposes. Alcohol, Carbamazepine, Lithium, Heparin, Norepineprin, Urea and etc. may interact with this medicine…(12)

Therapeutic and diagnostic uses.

Diabetes insipidus remains the only clear indication for the therapeutic use of antiduretic hormones.(10) Very small doses can control polyuria and polydipsia in diabetes insipidus due to neurohypophysial insufficiency. Psychogenic polydipsia may be more difficult to distinguish from neurohypophysial insufficiency, Since vasopressin produces antidiuresis in both conditions.(10).
The anti diuretic action of subcutaneous vasopressin is fleeting, and injections must be repeated at frequent intervals to control urine flow in diabetes insipidus. Vasopressin solutions may also be administered intra nasally. Synthetic lysine vasopressin in a strong solution can be used as a nasal spray. This offers patients with diabetes insipidus a relatively easy method of self-medication that can be used repeatedly as needed to inhabit polyuria. Doses required are 4 to 10 times greater than those that are effective subcutaneously.
Commercial vasopressin solution may contain mixture of Arginine vasopressin and Lysine vasopressin. Synthetic 2-(phenylalanine)-8-lysinevasopressin (ociapressin) relatively more active as a vasoconstrictor It is about as effective as epinephrine for these purposes.(10) One potential advantage is that it does not appear to precipitate cardiac arrhythmias as epinephrine may when used in large quantities, particularly in anesthetized patients. The risk of myocardial ischemia following the use of this peptide, particularly if inadvertently given intravenously, should be considered (10). Systemic side effects, including pallor, hypertension, international cramps, nausea, and vomiting may occur following use of 2-phenylalanine lysine vasopressin as a local vasoconstrictor. Vasopressin may be used as diagnostic agents.(9,10)The antidiuretic response is ,of course, one of the key points in differentiating neurohypophysial diabetes insipidus front polyuria of renal origin. Large doses of vasopressin have also been used to test the concentrating ability of the kidney. Such use does not justify the risk of precipitating coronary constriction. Similar information can be safely obtained by dehydrating the patient overnight.

Toxicity

Water intoxication can occur in individuals receiving vasopressin injection if water intake is excessive chronic over hydration can produce significant hyponatremia45 if water intake is properly limited there is no danger involved in the use of antidiuretic doses of the vasopressin preparations contain inactive contaminants that can provoke local or generalized allergic responses in some patients.(10) These complications can be avoided by using synthetic lysine vasopressin.
Large doses of vasopressin cause pallor, hypertension nausea, vomiting, abdominal cramps and diarrhea. There is a serious danger of coronary constriction. The use of vasopressin in large (10)doses should be rigorously avoided, particularly in patients with coronary atherosclerosis or hypertension.

Introduction
Neurohypophysial antidiuretic hormone (ADH) is the agent most often employed to regulate the volume and osmolality of urine1 and is the major concern of this essay. Antidiuretic hormone is a posterior pituitary peptide hormone.2 Arginine vasopressin is the antidiuretic hormone of humans secreted by the posterior pituitary with oxytocin. This is important for its action on kidney but is also a powerful vasoconstrictor in skin and some other vascular beds. Arginine vasopressin is synthesized from a large precursor molecule in the supraoptic and paraventricular nuclei of the hypothalamus, transported in neurosecretory granules to the posterior pituitary, median eminence of the hypothalamus and to a lesser extent to other areas of the brain and brain stem.
The antidiuretic hormone (ADH) is elaborated by certain hypothalamic structures such as the supraoptic nuclei and is then transported to the neurohypophysis, where it is stored.3 The release of the antidiuretic hormone is influenced by the osmolarity of the extracellular fluid and by many drugs. Vasopressin possesses antidiuretic and vasopressor properties.4 A deficiency of this hormone results in diabetes insipidus. The gene for vasopressin is located on chromosome 20q13.5

History.
Pharmacologic activity in extracts of the posterior lobe of the pituitary was first described by Oliver and Shafer in 1895.3 They found that intravenous injections caused acute vasopressor responses in dogs. The antidiuretic action of posterior pituitary extracts was not immediately recognized. Posterior pituitary extracts were reported to increase urine flow in anesthetized animals. Anesthesia often depresses renal functions. Posterior pituitary extracts then enhance urine flow by raising the blood pressure. In 1913, however, Von den Veldin and Farini, quite independently, found that posterior pituitary extracts inhibit diuresis in patients with diabetes insipidus. These observations and subsequent animal studies, established that this syndrome results from a deficiency of neurohypophysial antidiuretic hormone.

Structure and physiology.
Vasopressin has molecular weight of 1087 Da.5 Vasopressin is a nonapeptide with a six-amino acid disulphide ring and a three –amino acid side chain.4 The residue at position 8 is arginine in humans and in most other mammals except pigs related species, whose vasopressin contains lysine at position 8. Vasopressin (in several species) contains the following amino acids: tyrosine, cystine, aspartic acid, glutamic acid, glysine, proline, arginine, and phenylalanine.3 Vasopressin is rich in cysteine, but contains no methionine.6 The structure of the natural hormones suggest that the amino acid in the and position is important to antidiuretic and vasopressor activities.1 Arginine in the 8 position appears essential for maximal antidiuretic activity in most mammals. In the pig, however, lysine vasopressin is approximately as effective as arginine vasopressin (AVP). Arginine vasopressin is about 10 times as antidiuretic as lysine vasopressin. A highly basic amino acid in the 8 position, either arginine or lysine, is essential to high antidiuretic and vasopressor activities. Substitution of a weakly basic amino acid, such as histidine, or a neutral amino acid, such as leucine, isoleucine, valine or citrulline, almost abolishes these activities.

Formation of Vasopressin.
The true origin of the neurohypophysial hormones was first clearly recognized by Bargmann, Scharrer, and their associates. In mammals, ADH is synthesized in the nerve cell bodies of the supraoptic & paraventricular nuclei of the hypothalamus.7 There is no certainty as to the exact site of vasopressin synthesis.1 Recent evidence suggests that vasopressin is synthesized as a 145-aminoacid precursor comprising a single peptide5, presumably in the cell bodies. The AVP precursor has a glycoprotein at C-terminus. The initial product contains vasopressin in an inactive form which is subsequently transformed into active vasopressin.1 This second step may occur during transport of the secretory product down the axons into the neural lobe. Although it is not certain that vasopressin cannot be synthesized in the axons as well as in the cell bodies, the neural lobe isolated from the hypothalamus cannot manufacture ADH. Whether the hypothalamic nuclei are the only sites of synthesis or not, their integrity is essential for production of the active peptides.
Synthesized ADH hormone stored in combination with specific, cysteine – rich binding proteins called neurophysin II, in secretory granules (of about 100 nm diameter) in the neurohypophysis.7 This neurophysin II is synthesized , along with the hormone, in the cell bodies of the neurons. One molecule of neurophysin binds with one molecule of hormone. In hypothalamus ADH is always associated with neurophysin II. Terminal amino group of ADH is essential for binding to the neurophysin.
The secretory granules containing the hormone & neurophysin migrate along the nerve axons by a process that probably involves the microtubules. (At a rate of about 3 mm per day.) The granules are stored in the nerve endings within the neurohypophysis.

Release of Vasopressin.
In general, the release mechanism resembles that of transmitter release from nerve endings elsewhere. Electric stimulation of the axons can release hormones. Neurosecretory granules within the nerve endings appear as empty vesicles after releasing the hormone.1 Depolarization of the axon membrane appears to release vasopressin from isolated neural lobes. Ionized Ca2+ is necessary for release in response to depolarization. Calcium ion can disrupt the binding of vasopressin to neurophysin in vitro. If this occurred in the cell, it could possibly release the peptide from binding and leave it free to diffuse out of the cell. There is evidence that neurophysin and vasopressin are both released by the appropriately stimulated neurohypophysis. The neurophysin-vasopressin complex would be expected to dissociate immediately when exposed to a solution having the pH, ionic strength and Ca2+ concentration found in plasma.
The releasing of ADH occurs into the capillaries of the neurohypophysis, from which they are transported by the circulation to act upon distant target organs.7 The secretion of ADH can be influenced by several factors.8 The 2 primary physiological regulators of ADH secretion are osmotic and hemodynamic.

Physiologic stimuli for release of vasopressin.
1) Dehydration is an important physiologic stimulus for release of vasopressin.1 Long- term water deprivation stimulates the synthesis of ADH.7
A rise in osmolality of blood entering hypothalamus evokes immediate antidiuresis.1 Hypothalamic saline injected into the cerebral circulation may release vasopressin. Specific osmoreceptors in the brain circulation that are sensitive to variations in the osmotic pressure of the blood have been postulated.7
2) Sudden reduction in blood volume causes massive release.1
• Hemorrhage is the most potent releasing stimulus known. Decreased blood volume and pressure(hemodynamic) enhance release.8 In this case the blood volume is monitored by baroreceptors which are located in the blood vessels of neck.7
3) Severe pain or strong emotion often cause antidiuresis(e.g.-nausea).1
• Endogenous neurohumoral agents also may play an important role in release of ADH.3
4) Diminished cardiac output.9

Baroreceptor control of vasopressin secretion.
A decreased extracellular volume, due to diarrhea or haemorrhage, elicits an increased aldosteron release via activation of the rennin-angiotensin system.10 But decreased extracellular volume also triggers increased vasopressin secretion. This increased vasopressin increases the water permeability of the collecting ducts. More water is reabsorbed and less is excreted, and so water is retained to help stabilize the extra cellular volume.
This reflex is initiated by several baroreceptors in the cardiovascular system baroreceptors decrease their rate of firing when cardiovascular pressures decrease, as occurs when blood volume decreases so, fewer impulses are transmitted form the baroreceptors via afferent neurons and ascending pathways to hypothalamus, and the result is increased vasopressin secretion conversely, increased cardiovascular pressure causes more firing by the baroreceptors , resulting in a decreased in vasopressin secretion.
The baroreceptor reflex, compared to osmoreceptor reflex, generally plays a lesser role under most physiological circumstances.
Osmoreceptor control of vasopressin secretion.
Osmoreceptors in hypothalamus responsive to changes in blood osmolality.
Rising blood osmolality is believed to cause water to flow out of the osmoreceptor cells, with cellular hypovolaemia, then initiating a neuronal signal that passes principally to the supraoptic nucleus and stimulates the process of vasopressin synthesis and secretion.5 There is an exquisitely sensitive linear relationship between blood osmolality and vasopressin secretion, the slope of the vasopressin osmoregulatory line being a measure of the sensitivity of the system and the abscissal interrupt representing the threshold for vasopressin release.(285mOsmol/kg)
There is a linear relationship between the plasma osmolality and plasma vasopressin.
Increase in blood osmolality above this threshold induces progressive vasopressin release, thus increasing urine concentration, so that at plasma vasopressin values of 2 to 4 pmol/litre, maximum antidiuresis occurs. Drinking inhibits osmoregulated vasopressin secretion. ADH controls water excretion and maintains water balance without altering the excretion and homeostatic control of other substances.

Other stimuli for release of vasopressin.
1) Several drugs influence vasopressin release.1
2) Cigarette smoking.
Drug effects on vasopressin release.
Acetylcholine or diisopropyl fluorophosphates and carbachol cause release of ADH, even after atropine.3 Nicotine is particularly effective.1
These drugs may act at the hypothalamic level, but it is also possible that they may act directly on the neurosecretory endings in the neural lobe.
Ethanol inhibits vasopressin release in response to dehydration or to small changes in blood volume but not in response to nicotine, or severe hemorrhage. Ethanol, therefore, provokes in appropriate water diuresis and dehydration if it is consumed with inadequate quantities of water.
Alcohol also inhibits the release of ADH; in response to dehydration.3 Alcohol does not block the action of nicotine on the release of hormone. Diphenylhydantion in relatively large doses may suppress release much as does ethanol.1
Several tranquillizing drugs have been reported to inhibit release, particularly in response to noxious stimuli. Morphine and its analogues may have diphasic effects. They initially cause vasopressin release but may subsequently inhibit release in response to painful stimuli.
Many general anesthetics inhibit water diuresis. Either, pentobarbital and urethane have been reported to elevate the blood levels of vasopressin. All barbiturates are not antidiuretic. Thiopental anesthesia, for example, does not cause antidiuresis in man. Histamine has also attributed to release of ADH.3
It is likely that some central control mechanism of ADH release is very susceptible to neural or neurohumoral influences of the large variety of drugs that can influence ADH release, many are known to alter neural activity or to act as stressful stimuli.

Inhibitors of ADH secretion.
1) Negative pressure breathing appears to inhibit vasopressin release.1
a. This has been attributed to stimulate of atrial stretch receptors by increased thoracic blood volume. These inhibit release by sending impulses through vagal afferent fibers.

2) Atrial natriuretic peptide (ANP).8
3) The ingestion of water and dilution of the extracellular fluid lead to inhibition of ADH secretion.3

Disorders of Arginine Vasopressin (AVP) secretion.
1. Diabetes insipidus.
2. Syndrome of inappropriate antidiuresis (SIADH)
 Excessive ADH secretion.
 Inappropriate secretion of ADH.

Diabetes insipidus (DI).
Polyuria with dilute urine may result from vasopressin deficiency (Cranial diabetes insipidus, DI), or resistance to the actions of AVP (nephrogenic DI), and excessive fluid drinking (primary polydipsia).5
An individual deficient in AVP will pass approximately 40ml/kg of urine in 24h, leading to clinical features of polyuria, polydipsia, and nocturia. In the complete absence of AVP the maximally dilute urine has an osmolality of approximately 50mOsmol/kg. In normal individual plasma osmalality will range from 285-295mOsmol/kg, but urine can be concentrated to more than twice the concentration of plasma. In diabetes insipidus, despite the raised plasma osmolality, the urine is inappropriately.
Drugs for DI.
This is treated with ADH or related synthetic drug, desmopressin. These replace naturally produced ADH and may be given by injection or in the form of a nasal spray. Chlorpropamide and Carbamazepine may be used to treat mild cases as they increase the effects of ADH on renal tubule. It works by increasing ADH release from pituitary and by sensitizing the kidneys to the effects of ADH.11
Excessive ADH secretion.
Excessive secretion of ADH occurs in some intracerebral disorders, notably tuberculous meningitis, and in some cases of lung cancer (Oat cell carcinoma of the bronchus) in which the tumor itself produces large quantities of the hormone.7 Limitation of fluid intake helps to control the resultant dilutional hyponatraemia, and treatment with a mineralocorticoid may be necessary to promote Na+ retention.
The ADH analogue in which the C-terminal glycinamide is replaced by glycine is called vasopressinoic acid: it inhibits the action of ADH on the kidney tubules. Drugs of this type may be of use in the treatment of excessive secretion of ADH.
Inappropriate secretion of ADH.
In certain central nervous system conditions vasopressin is secreted in a regulated fashion but inappropriately at a low plasma level.5
Drugs for the SIADH.
Carbamazepine, Chlorpropamide, Vasopressin, etc….

ADH receptors and antagonists.
At least three distinct receptors, V1a, V1b and V2, mediate the actions of AVP. Each of these is a member of the superfamily of seven-transmembrane-domain, G-protein-coupled receptors. The first 2 signals by inositol-phosphate pathways, whilst the V2 receptor activates adenylate cyclase with an increase in intracellular cAMP. The V2 receptor is expressed almost exclusively in the collecting tubules of the kidney. When AVP binds to the receptor, an increase in intracellular cAMP results in the insertion of a water-conducting channel (aquaporin 2) into the apical membrane of the collecting duct. This allows water to pass from the lumen of the tubule along a concentration gradient into the cell, and then into the renal interstitium, via the AVP-independent aquaporin channels that are constitutionally active in the basolateral cell membrane, thus accounting for the antidiuretic action of AVP. Activation of the V1a receptor in vascular smooth muscle results in vasoconstriction and increase blood pressure but at much higher blood concentrations. Activation of the V1b receptor in the anterior pituitary, in synergy with corticotrophin-releasing hormone (CRH),is involved in the release of ACTH, but ADH involved in ACTH release derives predominantly from the paraventricular nuclei and represents a separate neuroanatomical system.
The affinity of V1 receptors for ADH is lower than that of the V2-receptors.2 Vasopressin-like peptides selective for either vasoconstrictor or antidiuretic activity have been synthesized.5 The most specific V1 vasoconstrictor agonist synthesized is vasotocin. Specific antagonists of the vasoconstrictor action of vasopressin are available. Recently, nonpeptide, orally active V1a receptor antagonists have been discovered.
The vasopressor antagonists have been particularly useful in revealing the important role that vasopressin plays in blood pressure regulation in situations such as dehydration and hemorrhage. They have potential for the treatment of hypertension and heart failure.
Absorption, Metabolism and Excretion of ADH.
Routes of administration.
Vasopressin is administered by intravenous, intramuscular, or intranasal routes.4 vasopressin is ineffective orally, being destroyed by gastrointestinal enzymes.1 It is rapidly absorbed after subcutaneous or intramuscular injection.
Intranasal drug administration has been used successfully.12 The nasal epithelium is much more permeable than skin and allows the transfer of peptide drugs as well as low molecular weight substances and commercially available preparations have been developed for peptide hormones, such as vasopressin analogues, and others. The main disadvantages are that substances are quickly cleared from the nasal epithelium by ciliary action as well as being metabolized and the epithelial permeability is not sufficient to allow most proteins to give in this way and much larger doses must be used.
Intranasal application can control diabetes insipidus and avoids the need for repeated injections.1

Unwanted effects.
There are few unwanted effects if the antidiuretic peptides are used intranasally in therapeutic doses.2 Nausea and abdominal cramps, and hypersensitivity reactions have been reported. Intravenous vasopressin may cause spasm of coronary arteries with resultant angina and it frequently causes abdominal and uterine cramps.

Metabolism.
Vasopressin disappears rapidly from the blood.1 In man half-life of circulatory ADH is approximately 20 minutes.4 The kidneys appear to destroy most vasopressin injected into dogs and rats although there is some inactivation by the liver.1 This renal and hepatic catabolism occurs via reduction of the disulfide bond and peptide cleavage.4 Relatively little active hormone appears in the urine, about 5-15 percent of that injected into man.1
Vasopressin can also be activated by splitting the bond between cystine and tyrosine by plasma oxytocinase enzyme which appears early in pregnancy.

Excretion.
A small amount of vasopressin is excreted as such in urine.

Physiological role of Vasopressin.
1. Renal actions-
The major physiological actions of vasopressin is on kidney to increase urinary concentration.5 Circulating ADH binds to V2-receptors in the basolateral membrane of the cells of the distal tubule and collecting ducts of nephron.2 Adenylcyclase is stimulated, via the coupled G-protein, to produce cAMP which activates intracellular protein kinases and accelerates the rate of insertion of water channels into the luminal membrane, thus increasing the permeability of membrane to H2O.5 It also activates urea transporters and transiently increases Na+ absorption, particularly in the distal tubule.2
As renal prostaglandins reduce the generation of cAMP, they blunt effect of vasopressin and therefore prostaglandin synthetase inhibitors augment the antidiuretic action of arginine vasopressin.
2. Non-renal actions-
Vasopressin causes the elevation of systemic blood pressure by peripheral vasoconstriction.5 Arginine vasopressin binds to vascular smooth muscle receptors(V1 receptors) that activate phosphatidyl-inositol pathways, increase intracellular calcium concentration and cause the contraction of vascular smooth muscles high circulating concentrations of vasopressin are necessary to achieve the pressor effect: at physiological levels it probably plays little (if any)role maintaining blood pressure; but it is involved in the pressor response to hypovolaemia or hypotension.
Vasopressin appears to act primarily on arterioles and capillaries. The coronary circulation is also decreased; and large doses of vasopressin can precipitate fatal myocardial ischemia.
Smooth muscle effects are only seen with doses larger than those affecting the kidney.2
ADH also stimulates blood platelet aggregation and coagulation factor release.
In central nervous system (CNS) ADH acts as a neuromodulator and neurotransmitter; released into the pituitary ‘portal circulation’ it promotes the release of ACTH from the anterior pituitary by an action on V3- receptors.
Vasopressins have intrinsic oxytocic activity.1 The nonpregnant human uterus is more responsive to vasopressin than to oxytocin. Large doses of either hormone are needed to cause contraction. Uterine sensitivity to oxythcin increases tremendously during pregnancy while vasopressin remains relatively ineffective. Sufficient doses of vasopressin can; however, produce tonic uterine contractions that could be deleterious to fetus. Vasopressins have considerable milk ejection activity. This is probably of little physiologic importance during lactation since much more oxytocin than vasopressin is released by the milk ejection reflex. Vasopressin in very large doses may also stimulate motility of the large bowel.
Vasopressin with vasopressor actions also cause smooth muscle contraction elsewhere, notably in the gastrointestinal tract and uterus and those effects form the basis of some of the adverse effects of high –dose vasopressin.7
Drug effects on ADH action.
Several drugs affect the action of ADH. Non-steroidal anti-inflammatory drugs (NSAIDs) and carbamazepine increase ADH effects.2 Lithium, colchicines and vinca alkaloids decrease its action, the later two agents by virtue of their action on microtubules-organelles required for the movement of the water channels. Demeclocycline counteracts the action of ADH and can be used to treat patients with hyponatraemia (and thus water retention) caused by excessive secretion of ADH.
Analogues of vasopressin.
The naturally occurring human vasopressin is arginine vasopressin (AVP).7 Various analogues of ADH have been developed for clinical use.2 There are also semi-synthetic vasopressin, including desmopressin ( DDAVP or 1 –deamino-8-D-arginine vasopressin ) and felypressin (2 –phenylalanine -8-lysine vasopressin ). Lypressin (8 – lysine vasopressin ) is the naturally occurring porcine vasopressin.7 The aims of these analogues being (a ) to increase the duration of action and (b ) to shift the potency – between V1 – and V2 – receptors. 2

Desmopressin.
Because of the pressor properties of vasopressin this compound has been modified to desmopressin.13 This analog is now preferred for diabetes insipidus and nocturnal enuresis because it is largely free of pressor effects and is longer – acting than vasopressin. Desmopressin is conveniently administered intranasally. However, local irritation may occur. But it may be administered intravenously, subcutaneously or orally.4 Both vasopressin and lypressin are rapidly cleared from body after i.v administration.7 The relative potencies of vasopressin and its analogues as antidiuretic agents and as vasoconstrictors are show in following table.

Drug activity relative to arginine vasopressin.
Andiuretic Vasopressor
Arginine vasopressin 1 1
Desmopressin 12 0.004
Lypressin 0.8 0.6

Pharmacokinetic aspects.
The main analogues are vasopressin, desmopressin, terlipressin and felypressin.
Vasopressin.-
ADH itself: short duration of action, weak selectivity for V2–receptors, given by subcutaneous or intra muscular injection, or by intravenous infusion. Metabolism is by tissue peptidases and 33% is removed by kidney.

Desmopressin-
Increased duration of action, V2 selective and usually given as a nasal spray. Desmopressin is less subject to degradation by peptidases and its plasma half life is 75 minutes.
Terlipressin-
Increased duration of action, low but protracted vasopressor action and minimal antidiuretic properties.
Felypressin-
Short duration of action, vasoconstrictor effect is used with local anesthetics such as prilocaine to prolong its action.

Phamacodynamic aspects.
ADH interacts with two types of receptors. V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction. V2 receptors are found on renal tubule cells and mediate antidiuresis through increased water permeability and water resorption in the collecting tubules. External V2-like receptors mediate release of coagulation factor V111c and von willebrand factor.
Desmopressin acetate is a long- acting synthetic analog of vasopressin with minimal V1 activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin.

Antidiuretic preparations.
Posterior pituitary USP is available as a powder for topical application, administered by inhalation or directly to the nasal mucosa.3 It may cause mucosal irritation. The duration of its antidiuretic effect is such that the drug must be used several times a day. Posterior pituitary is contraindicated in pregnancy and should be used with caution in patients with coronary artery disease. The dose is 40 to 60 mg topically three or four times daily.
Posterior pituitary injection is no longer used being replaced by vasopressin injection.
Vasopressin injection (Pitressin) produces an antidiuretic effect lasting 2-8 hours when administered by subcutaneous or intramuscular injection. The solution may also be used topically. Vasopressin may cause fluid retention, hypertension, myocardial ischemia, gastrointestinal and uterine contractions and allergic reactions. The available solution for injection contains 10 pressor units /ml.
Vasopressin tannate injection (Pitressin tannate) is a suspension in peanut oil of the in soluble tannate of the hormone, suitable for intramuscular administration. The duration of action is 2-3 days. Vasopressin tannate injection is available in oil, 5 pressor units / ml.

Therapeutic and diagnostic uses of ADH.
Therapeutic uses:-Diabetes insipidus remains the only clear indication for the therapeutic use of ADH.1 Very small doses can control polyuria and polydipsia in diabetes insipidus due to neurohypophysial insufficiency.
Diagnostic uses:-
Vasopressin may be used as diagnostic agents.1 The antidiuretic response is, of course, one of the key points in differentiating neurohypophysial diabetes insipidus. From polyuria of renal origin. Large doses of vasopressin have also been used to test the concentrating ability of kidney. Such use does not justify the risk of precipitating coronary constriction. Similar information can be safely obtained by dehydrating the patient overnight.

Clinical use of vasopressin and analogues.
• Treatment of diabetes insipidus: lypressin, desmopressin.2
• The initial treatment of bleeding oesophageal varices: vasopressin, terlipressin, lypressin (octreotide is also used but sclerotherapy by direct injection of sclerosant via an endoscope is the main treatment.)
• As prophylactic against bleeding in haemophilia (e.g. before both extraction): vasopressin, desmopressin (by increasing the concentration of factor V111); somatostatin is also effective.
• Felypressin is used as a vasoconstrictor with local anaesthetics.
• Desmopressin is used for persistent nocturnal enuresis in older children and adults.

Toxicity.
Water intoxication can occur in individuals receiving vasopressin injections if water intake is excessive.1 Chronic over hydration can produce significant hyponatremia. If water intake is properly limited there is no danger involved in the use of antidiuretic doses of the vasopressin to control diabetes insipidus. Natural vasopressin preparations contain inactive contaminants that can provoke local or generalized allergic responses in some patients. These complications can be avoided by using synthetic lysine vasopressin.
Large doses of vasopressin cause pallor, hypertension, nausea, vomiting, abdominal cramps and diarrhea. There is a serious danger of coronary constriction. The use of ADH in large doses should be rigorously avoided, particularly in patients with coronary atherosclerosis or hypertension.

Introduction
Vasopressin is a man-made form of a hormone called “anti-diuretic hormone” that is normally secreted by the posterior pituitary gland. In the body, vasopressin acts on the kidneys and blood vessels.

Vasopressin helps prevent the loss of water from the body by reducing urine output and helping the kidneys reabsorb water in the body. Vasopressin also raises blood pressure by constricting (narrowing) blood vessels.

Vasopressin is used to treat diabetes insipidus, which is caused by a lack of this naturally occurring pituitary hormone in the body. Vasopressin is also used to treat or prevent certain conditions of the stomach after surgery or during abdominal x-rays.12, 11

Vasopressin may also be used for purposes other than those listed in this medication guide.
Definition of Vasopressin
Vasopressin: A relatively small (peptide) molecule that is released by the posterior pituitary gland at the base of the brain after being made nearby (in the hypothalamus). Vasopressin has an antidiuretic action that prevents the production of dilute urine (and so is antidiuretic). A syndrome of inappropriate secretion of vasopressin which results in the inability to put out dilute urine, perturbs fluid (and electrolyte) balance, and causes nausea, vomiting, muscle cramps, confusion and Hodgkin’s disease as well as a number of other disorders. Vasopressin has a vasopressor action and so can stimulate contraction of arteries and capillaries. Hence the name “vasopressin.” Vasopressin is also known as antidiuretic hormone (ADH).1, 15

Structure and relation to oxytocin
The vasopressins are peptides consisting of nine amino acids (nonapeptides). The amino acid sequence of arginine vasopressin is Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly, with the cysteine residues forming a sulfur bridge. Lysine vasopressin has a lysine in place of the arginine.
The structure of oxytocin is very similar to that of the vasopressins: it is also a nonapeptide with a sulfur bridge and its amino acid sequence differs at only two positions .The two genes are located on the same chromosome separated by a relatively small distance of less than 15,000 bases in various species. The magnocellular neurons that make vasopressin are adjacent to magnocellular neurons that make oxytocin, and are similar in many respects. The similarity of the two peptides can cause some cross-reactions: oxytocin has a slight antidiuretic function, and high levels of vasopressin can cause uterine contractions.
Vertebrate Vasopressin Family
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2/ Argipressin (AVP, ADH) /most mammals
Vertebrate Oxytocin Family
Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 /Oxytocin (OXT) /most mammals, ratfish.12.13

– Arginine vasopressin – 12

Physiology
SYNTHESIS

During axonal transport processing cleaves off the active hormone from the neurophysin and the products are stored in the nerve termini in the posterior pituitary. Arginine vasopressin (AVP) or oxytocins together with the relevant neurophysin are released into the systemic circulation. Most AVP circulates as free hormone and has a half-life of approximately 10 min. AVP is principally cleared by the liver and kidneys, whilst oxytocin is cleared in these sites and in the uterus.13.14

Mode of action
• Vasopressin is synthesized in the hypothalamus and transported to the posterior pituitary. It is then released in response to increases in plasma osmolaoity and decreases in extracellular fluid volume. It acts on the cortical and medullary segments of the nephron in the kidney, where it increases permeability to water and thus enhances water reabsorption without altering solute transport.

• Vasopressin also has effects on the cardiovascular system, but at considerably higer concentrations than are required to inhibit diuresis. It causes vasoconstriction of arteries and arterioles including the coronary, pulmonary, and splanchnic arteries.

• Vasopressin with Vasopressor action also causes smooth muscle contraction elsewhere, notably in the gastrointestinal tract and uterus, and those effects form the adverse effects of high dose vasopressin.

• Vasopressin acts on vasopressin V1 and V2 receptors, causing pressor and antidiuretic effects respectively. The relative potencies of vasopressin and its analogues as antidiuretic agents and as vasoconstrictors are shown in table below.5.11
Drug
Arignine vasopressin 1 1
Desmopresin 12 0.004
Lypressin 0.8 0.6

Actions of vasopressin
The major physiological action of vasopressin is to increase urinary concentration.Circulating arginine vasopressin binds to a specific renal tubular receptor, designated the V2 recepter , of the collecting ducts.Adenyl cyclase stimulated, via the coupled G protein, to produce cyclic S’AMP, which activates intracellular protein kinases and accelerates the expression and trafficking of aquaporin 2, the vasopressin- sensitive water channel protein. Aquaporin 2 is organized into a tetramer and inserted into the luminal cellular membrane of the distal tubule, allowing water to flow from the tubular lumen into the cellular compartment. Two other aquaporins (aquaporins 3 and 4) are located on the contraluminal cell membrane: these are not vasopressin responsive but facilitate the flow of water across the distal tubule under the influence of the osmotic gradient between the hypotonic urine within the tubular lumen and the hypertonic renal interstitium. Thus, urine volume is decreased and urine is concentrated.5

The first action attributed to vasopressin was the elevation of systemic blood pressure by peripheral vasoconstriction. Arginine vasopressin binds to vascular smooth muscle receptors (V, receptors) that activate phosphatidyl-inositol pathways, increase intracellular calcium concentration, and cause the contraction of vascular muscles. High circulating concentrations of vasopressin are necessary to achieve this pressor effect at physiological levels it probably plays little role in maintaining blood pressure, but it is involved in the pressor response to hypovolaemia or hypotension.2

Animal studies have indicated that vasopressin also stimulates the transport of urea across the collecting tubule and of sodium chloride across the medullary thick ascending limb of the loop of Henle, both of which enhance the osmotic gradient. As re al prostaglandins reduce the generation of cyclic 5’AMP, they blunt the effect of vasopressin, and therefore prostaglandin synthase inhibitors augment the antidiuretic action of arginine vasopressin. 3

Function
One of the most important roles of ADH is to regulate the body’s retention of water; it is released when the body is dehydrated and causes the kidneys to conserve water, thus concentrating the urine, and reducing urine volume. In high concentrations, it also raises blood pressure by inducing moderate vasoconstriction. In addition, it has a variety of neurological effects on the brain, having been found, for example, to influence pair-bonding in voles.
A very similar substance, lysine vasopressin (LVP) or lypressin has the same function in pigs and is often used in human therapy.1

Kidney
Antidiuretic hormone (ADH) has three effects by which it contributes to increased urine osmolarity (increased concentration), and decreased urine excretion. These are:

1) It increases the permeability to water of the distal convoluted tubules and collecting tubules in the nephrons of kidneys and thus allows water reabsorption and excretion of a smaller volume of concentrated urine – antidiuresis. This occurs through insertion of additional water channels (Aquaporin-2s) into the apical membrane of the tubules/collecting duct epithelial cells. The aquaporins allow water to pass out of the nephron (at the distal convoluted tubules and the conducting tubules) and into the cells, increasing the amount of water re-absorbed from the filtrate.

V2 receptors, G protein-coupled receptors coupled to Gs, on the basolateral membrane of the cells lining the distal convoluted tubules and conducting tubules (in the nephron) have an active site for AVP. The G protein, which is in contact with the V2 receptor inside the cell, move to adenylyl cyclase, triggering adenylyl cyclase to convert ATP into cAMP, plus 2 inorganic phosphates. The cAMP cascade then triggers the insertion of Aquaporin-2 water pores by exocytosis of storage vesicles.

The repressor protein that regulates the gene for protein kinase A (PKA) has a binding site for cAMP, causing the repressor protein to change its shape and leave the operator region of the gene. This allows for transcription of the gene for PKA. PKA then signals ATP to dephosphorylate, providing energy for vesicles (which contain aquaporin channel proteins in their membranes) to fuse with the apical membrane of the cell. Calcium ions may also be required in this process, therefore it may be possible that, PLC (phospholipase C- beta) has an associated role. It should be noted that PLC can be activated by a G-protein coupled receptor.

2) ADH’s second effect on the kidney is to increase the permeability of the papillary portion of the collecting duct to urea, allowing increased reabsorption of urea into the medullary interstitium, down the concentration gradient created from the removal of water in the cortical collecting duct.

3) The third effect that ADH has on the kidney is that it stimulates sodium reabsorption in the thick-ascending loop of Henle by increasing the activity of the Na+-K+-2Cl–cotransporter.1
Cardiovascular system
AVP-Vasopressin increases peripheral vascular resistance and thus increases arterial blood pressure. This effect appears small in healthy individuals; however it becomes an important compensatory mechanism for restoring blood pressure in hypovolemic shock such as occurs during hemorrhage.1

Central nervous system (CNS)
Vasopressin released within the brain has many actions:
It has been implicated in memory formation, including delayed reflexes, image, short- and long-term memory, though the mechanism remains unknown, and these findings are controversial. Vasopressin is released into the brain in a circadian rhythm by neurons of the Supraoptic nucleus.
Vasopressin released from centrally-projecting hypothalamic neurons is involved in aggression, blood pressure regulation and temperature regulation.
In recent years there has been particular interest in the role of vasopressin in social behavior. It is thought that vasopressin, released into the brain during sexual activity, initiates and sustains patterns of activity that support the pair-bond between the sexual partners; in particular, vasopressin seems to induce the male to become aggressive towards other males.

Evidence for this comes from experimental studies in several species, which indicate that the precise distribution of vasopressin and vasopressin receptors in the brain is associated with species-typical patterns of social behavior. In particular, there are consistent differences between monogamous species and promiscuous species in the distribution of vasopressin receptors, and sometimes in the distribution of vasopressin-containing axons, even when closely-related species are compared. Moreover, studies involving either injecting vasopressin agonists into the brain, or blocking the actions of vasopressin, support the hypothesis that vasopressin is involved in aggression towards other males. There is also evidence that differences in the vasopressin receptor gene between individual members of a species might be predictive of differences in social behavior.1

Control of arginine vasopressin secretion
There are three principal stimuli to AVP – a rise in circulating osmolality, a drop in blood pressure, and a stressful event. An increase in plasma osmolality is sensed in the osmoreceptor cells, and this is the major physiological stimulus to the secretion of AVP. There is a tight linear positive correlation between the plasma osmolality and the release of AVP.
A loss of extracellular water will stimulate vasopressin secretion to conserve water, accompanied by thirst and a drive to drink. 11.16

An increase in the plasma sodium concentration is a greater stimulus to AVP secretion than other solute, and in humans maximum antidiuresis is achieved at plasma vasopressin concentration between 2 and 4 pmol/l. Afteringestion of fluid, there is a fall in the plasma vasopressin levels before a charge in the osmolality, which is presumed to occur via a pharyngeal reflex that inhibits AVP release.
AVP release after a fall in blood pressure, as after haemorrhage, is sensed by baroreceptors in the heart, aorta, and the great vessels. The accompanying water retention helps, together with the sodium retention that follows aldosterone release, to restore the blood volume. AVP is also released under non-specific stress, particularly if associated with nausea or vomiting.

Many factors influence the secretion of vasopressin:

Ethanol (alcohol) acts as an antagonist for Vasopressin in the collecting ducts of the kidneys, which prevents aquaporins from binding to the collecting ducts, and prevents water reabsorption.
Angiotensin II may stimulate the secretion of vasopressin. 8
At plasma osmolality values below 285 mosmol/kg, on average, vasopressin secretion secretion is inhibited to allow a maximum water diuresis (15-25 litres/24h) with urine osmolality of 50 to 70 mosmol/kg. Increase in blood osmolality above this threshold induces progressive vasopressin release, thus increasing urine concentration, so that at plasma vasopressin values of 2 to 4 pmol/litre, maximum antidiuresis occurs. Drinking inhibits osmoregulated vasopressin secretion.1,16

Baroreceptor control of Vasopressin Secretion
A decreased extra cellular volume, due say to diarrhea or hemorrhage, elicits an increased aldosterone release via activation of the rennin-angiotensin system. But the decreased extracellular volume also triggers increased vasopressin secretion. This increased vasopressin increases the water permeability of the collecting ducts. More water is reabsorbed and less is cxcreted, and so water is retained to help stabilize the extracellular volume.
This reflex is initiated by several baroreceptors in the cardiovascular system.15,12

Plasma volume

Venous, atrial, and
Arterial pressures
Reflexes mediated by
Cardiovascular baroreceptors
Posterior pituitary

Vasopressin secretion

Plasma vasopressin

Colletin
Tubular permeability
To H2O
H2O reabsorption

H2O excretion

In addition to its effect on water excretion, vasopressinlike angiotensin II causes widespreadarteriolar construction. This helps restore arterial blood pressure toward normal.

Secretion
The main stimulus for secretion of vasopressin is increased osmolality of plasma. Reduced volume of extracellular fluid also has this effect, but is a less sensitive mechanism.

The vasopressin that is measured in peripheral blood is almost all derived from secretion from the posterior pituitary gland (except in cases of vasopressin-secreting tumours). However there are two other sources of vasopressin with important local effects:

Vasopressin is produced in the PVN and SON and travels down the axons through the infundibulum within neurosecretory granules that are found within Herring bodies, localized swellings of the axons and nerve terminals. These carry the peptide directly to the posterior pituitary gland, where it is stored until released into the blood. 14
Vasopressin is also released into the brain by several different populations of smaller neurons.

Disorders of arginine vasopressin secretion
Diabetes insipidus

Polyuria with dilute urine may result from vasopressin deficiency (cranial diabetes insipidus, DI), resistance to the actions of AVP (nephrogenic DI), and excessive fluid drinking (primary polydipsia).

Upper stalk, median eminence, or more extreme hypothalamic damage results in permanent diabetes insipidus.

An individual deficient in AVP will pass approximately 40 ml/kg of urine in 24 h (between 3 and 20 litres), leading to the clinical features of polyuria, polydipsia, nocturia, and in children nocturnal enuresis, in the complete absesnce of AVP the maximally dilute urine has an osmolality of approximately 50 mOsmol/kg.14

Receptors
Below is a table summarizing some of the actions of AVP at its three receptors, differently expressed in different tissues and exerting different actions.4
Type Second messenger system Locations Actions
AVPR1A phosphatidylinositol/calcium liver, kidney, peripheral vasculature, brain vasoconstriction, gluconeogenesis, platelet aggregation, and release of factor VIII and von Willebrand factor; social recognition,[3] circadian tau[4]
AVPR1B phosphatidylinositol/calcium pituitary gland, brain adrenocorticotropic hormone secretion in response to stress;[5] social interpretation of olfactory cues[6]
1AVPR2 adenylate cyclase/cAMP basolateral membrane of the cells lining the collecting ducts of the kidneys (especially the cortical and outer medullary collecting ducts) Insertion of aquaporin-2 (AQP2) channels (water channels). This allows water to be reabsorbed down an osmotic gradient, and so the urine is more concentrated. Release of von Willebrand factor and surface expression of P-selectin through exocytosis of Weibel-Palade bodies from endothelial cells[7][8]
VACM-1 phosphatidylinositol/calcium vascular endothelium and renal collecting tubules Increases cytosolic calcium and acts as an inverse agonist of cAMP accumulation [7]
4
VASOPRESSIN RECEPTORS & ANTAGONISTS.

Three subtypes of vasopressin receptors have identified. V receptors mediate the vasoconstrictor action of vasopressin; vasopressin vasopressin V, receptors potentiate the release of ACTH pituitary corticotropes; and V, receptors mediate the antiduretic action.10

Vasopressin and renal water excretion

The antidiuretic hormone of humans is arginine vasopressin (in contrast to lysine vasopressin which is specific to the pig family), a nonapeptide, the gene for which is located on chromosome 20. Arginine vasopressin is synthesized from a large precursor molecule in the supraoptic and paraventricular nudei of the hypothalamus, transported in neurosecretory granules to the posterior pituitary median eminence of the hypothalamus and to a lesser extent to other areas of the brain and brainstem. It is secreted from the posterior pituitary into the systemic circulation to influence renal function, and into the hypothalamopituitary portal circulation to enhance pituitary ACTH secretion.12,16

EXESSIVE ADH SECRETIONS

Excessive secretion of ADH occurs in some intracerebral disorders, notably tuberculosis meningitis, and in some intracerebral disorders, notably tuberculous meningitis, and in some cases of lung cancer (oat cell carcinomas of the bronchus) in which the tumor itself produces large quantities of the hormone. Limitation of fluid intake helps to the resultant dilutional hyponatraemia, and treatment mineralocorticold may be necessary to promote sodium retention.
The ADH analogue in which the C-terminal glycinamide is replaced by glycine is called vasopressinoic acid: it inhibits the action of ADH on the kidney tubules. Drugs of this type may be of use in the treatment of excessive secretion with a of ADH. 5,4

Role in disease
Decreased vasopressin release or decreased renal sensitivity to vasopressin leads to diabetes insipidus, a condition featuring hypernatremia (increased blood sodium concentration), polyuria (excess urine production), and polydipsia (thirst).

High levels of vasopressin secretion (syndrome of inappropriate antidiuretic hormone, SIADH) and resultant hyponatremia (low blood sodium levels) occurs in brain diseases and conditions of the lungs (Small cell lung carcinoma). In the perioperative period, the effects of surgical stress and some commonly used medications (e.g., opiates, syntocinon, anti-emetics) lead to a similar state of excess vasopressin secretion. This may cause mild hyponatremia for several days.

Behavioral Geneticist Hasse Walum of the Karolinska Institute in Stockholm has determined that a genetic variation in male humans dictates the placement of vasopressin receptors in the brain. The brain of males uses vasopressin as a reward for forming lasting bonds with a mate, and men with one or two of the genetic alleles are more likely to experience marital discord. The partners of the men with two of the alleles affecting vasopressin reception state disappointing levels of satisfaction, affection, and cohesion. 2.4
Pharmacology
Vasopressin analogues
Vasopressin agonists are used therapeutically in various conditions, and its long-acting synthetic analogue desmopressin is used in conditions featuring low vasopressin secretion, as well as for control of bleeding (in some forms of von Willebrand disease) and in extreme cases of bedwetting by children. Terlipressin and related analogues are used as vasoconstrictors in certain conditions. Use of vasopressin analogues for esophageal varices commenced in 1970.
Vasopressin infusion has been used as a second line of management in septic shock patients not responding to high dose of inotropes (e.g., dopamine or norepinephrine). It had been shown to be more effective than epinephrine in asystolic cardiac arrest.While not all studies are in agreement, a 2006 study of out-of hospital cardiac arrests has added to the evidence for the superiority of vasopressin in this situation, but these studies relied on sub-group analysis and better designed prospective studies show no benefit in ACLS.8

Clinical Pharmacology

Vasopressin is the alternative treatment of choice for pituitary diabetes insipidus. Vasopressin infusion is effective in some cases of esophageal variceal bleeding and colonic diverticular bleeding.14,16

Clinical Uses

• Cranial diabetes insipidus (long- term desmopressin: short-term, vasopressin, desmopressin, or lypressin).

• To arrest bleeding from oesophageal varices (vasopressin) (but drugs have been largely replaced by endo Vasopressin scopic techniques in the management of verices).
• With local anesthetics in delay their absorption and thus potentiate their effects (felypressin). 14,16

Dosage

AQUEOUS VASOPRESSIN

Synthetic aqueous vasopressin is a short – acting preparation for intramuscular, subcutaneous, or intravenous administration. The dose is 5 – 10 units subcutaneously or intramuscularly every 3 – 6 hours for transient diabetes insipidus and 0.1 – 0.5 units/min intravenously for gastrointestinal bleeding. 6,7

Vasopressin Dosing Information
Usual Adult Dose for Asystole:

40 units intravenously once, followed by 20 mL of normal saline. If spontaneous circulation is not restored within 3 minutes, another 40 units may be given intravenously. If spontaneous circulation is still not restored, 1 mg of epinephrine maybe given intravenously. All doses should be followed with 20 mL of normal saline.
•Usual Adult Dose for Diabetes Insipidus:
5 units to 10 units intramuscularly once.6,7
This dose may be repeated 2 to 3 times a day as needed.

Vasopressin side effects
Some people receiving vasopressin have had an immediate reaction to the medication. Tell your caregiver right away if you feel weak, nauseated, light-headed, sweaty, or have a fast heartbeat, chest tightness, or weak breathing just after receiving vasopressin. Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Tell your caregivers at once if you have any of these serious side effects: 1.13
•slow or uneven heart rate;

•gasping or trouble breathing;

•chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;

•tingling or loss of feeling in your hands or feet;

•skin changes or discoloration;

•swelling, rapid weight gain;

•feeling light-headed, fainting;

.Toxicity & Contraindications

Headache, nausea, abdominal cramps, agitation, and allergic reactions occur rarely. Therapy can result in hyponatremic convulsion.
Vaspressin (but not desmopressin) can cause vasoconstriction and should be used cautiously in patients with coronary artery disease. Nasal insufflation of desmopressin may be less effective when nasal congestion is present.12

Introduction – Kidney
Anatomy of Normal Kidneys and Their Function

The human kidneys are a pair of bean-shaped organs situated in the retroperitoneal space, positioned on either side of the vertebral column at the level of the lower thoracic and upper lumbar vertebrae. The right kidney is slightly lower than the left kidney because of the location of the liver. Each adult kidney weighs about 120 to 170 g and measures about 12 × 6 × 3 cm.1

Figure 1

A coronal section of the kidney shows two distinct regions. The pale outer region is called the cortex and is about 1 cm in thickness. The dark inner region is the medulla and contains 6 to 15 (average, conical structures called pyramids. The base of each pyramid is situated at the corticomedullary junction, and the apex extends into the hilum of the kidney as the papilla. Each kidney contains approximately one million filtering units called nephrons. Each nephron is made of a glomerulus and a tubule. The glomerulus is a miniature filtering or sieving device while the tubule is a tiny tube like structure attached to the glomerulus. The kidneys are connected to the urinary bladder by ureters. Urine is stored in the urinary bladder until the bladder is emptied by micturition.
The kidney contributes to body fluid homeostasis by excreting excess solute and water in the urine. The first step in the formation of urine by the kidney requires the production of an ultrafiltrate of plasma at the glomerulus. This fluid, which is relatively free of cellular elements and proteins, flows through the various tubular segments, which absorb solutes and water.2
It is important to recognize that the kidneys serve multiple functions, including the following:
Then it will be not difficult to understand how body functions are impaired due to renal failure.
• Excretion of metabolic waste products and foreign chemicals
• Regulation of water and electrolyte balances
• Regulation of body fluid osmolality and electrolyte concentrations
• Regulation of arterial pressure
• Regulation of acid-base balance
• Secretion, metabolism, and excretion of hormones
• Gluconeogenesis

General Introduction – Chronic Renal Failure
Chronic Renal Failure (CRF) refers to an irreversible deterioration in renal function which classically develops over a period of years. Because of the primacy of the kidney in regulating metabolism, the concentrations of many chemical constituents of the body are abnormal in patients with CRF. Initially, it is manifest only as a biochemical abnormality. Eventually, loss of excretory, metabolic and endocrine functions of the kidney leads to development of the clinical symptoms and signs of renal failure.3 Chronic renal failure results in an accumulation of fluid and waste products in the body, leading to a build up of nitrogen waste products in the blood and general ill health. Most body systems are affected by chronic renal failure. Knowledge of the expected abnormalities and of the patient’s baseline is necessary in evaluating patients with CRF.
In UK, the prevalence of chronic renal impairment is approximately 600 individuals per million populations per year.4Chronic renal failure affects more than 2 out of 1,000 people in the United States. Diabetes and high blood pressure are the two most common causes and account for most cases. Other major causes are Alport syndrome, Analgesic nephropathy, Glomerulonephritis of any type (one of the most common causes), Kidney stones and infection, Obstructive uropathy, Polycystic kidney disease and Reflux nephropathy.
Chronic renal failure usually occurs over a number of years as the internal structures of the kidney are slowly damaged. Unlike acute renal failure, chronic renal failure slowly gets worse. In the early stages, there may be no symptoms. In fact, progression may be so slow that symptoms do not occur until kidney function is less than one-tenth of normal. Initial symptoms may includes Fatigue, Frequent hiccups, General ill feeling, Generalized itching (pruritus), Headache, Nausea, vomiting and Unintentional weight loss. There are several stages in CRF.1
Stage 1 - Kidney damage with normal or increased GFR
Stage 2 - Kidney damage with slightly decreased GFR
Stage 3 - Moderately decreased GFR
Stage 4 - Severely decreased GFR
Stage 5 - Kidney failure
Definition – Chronic Renal Failure
1. Chronic renal failure implies long -standing, and usually progressive, impairment in renal function. It is a slowly worsening loss of the ability of the kidneys to remove wastes, concentrate urine, and conserve electrolytes. It can range from mild dysfunction to severe kidney failure.4
2. Kidney damage for 3 months or longer, as defined by structural or functional abnormalities of the kidney, with or without decreased glomerular filtration rate (GFR), manifest by either:
 Pathological abnormalities; or
 Markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests1
3. GFR of less than 60 mL per minute per 1.73 m2 for 3 months or longer, with or without kidney damage.5

Complications and reasons
A well known and major problem creating factor is uremia. Uremia refers to the more advanced stages of progressive renal insufficiency when the complex, multi organ systems derangements become clinically manifest. The uremic syndrome is likely the consequence of a combination of factors, including retained molecules, deficiencies of important hormones, and metabolic factors, rather than the effect of a single uremic toxin. Its breakdown product (cyanate) can result in carbamylation of lipoproteins and peptides, with adverse effects leading to multiple organ dysfunctions. Although not the major cause of overt uremic toxicity, urea may contribute to some of the clinical abnormalities, including anorexia, malaise, vomiting, and headache. Uremia leads to disturbances in the function of every organ system. A host of metabolic and endocrine functions normally sub served by the kidney are also impaired, resulting in anemia; malnutrition; impaired metabolism of carbohydrates, fats, and proteins; defective utilization of energy; and metabolic bone disease. Furthermore, plasma levels of many polypeptide hormones, including parathyroid hormone (PTH), insulin, glucagon, luteinizing hormone, and prolactin, rise with renal failure, not only because of impaired renal catabolism but also because of enhanced endocrine secretion, occurring as a secondary consequence of primary excretory or synthetic renal dysfynction. On the other hand, the renal Production of erythropoietin (EPO) and 1,25-dihydroxycholecalciferol is impaired.6/7

Figure 2

Well described some of possible complications are listed below.
• Anemia
• Cardiac tamponade
• Changes in blood sugar metabolism
• Congestive heart failure
• Decreased functioning of white blood cells
• Decreased immune response
• Decreased libido, impotence
• Dementia
• Electrolyte abnormalities including hyperkalemia
• Encephalopathy
• End-stage renal disease
• Fractures due to weakening of the bones
• Hemorrhage
• High blood pressure
• Increased infections
• Joint disorders
• Liver inflammation (hepatitis B or hepatitis C)
• Liver failure
• Loss of blood from the gastrointestinal tract
• Menstrual irregularities, infertility
• Nerve damage
• Pericarditis
• Peripheral neuropathy
• Platelet dysfunction
• Ulcers
• Seizures
• Skin dryness, itching /scratching with resultant skin infection

The most important, frequently encountered complications and their significant correlation with chronic renal failure are described here:
Figure 3
• HEMATOLOGIC ABNORMALITIES
Anaemia
Anemia is a condition where there is a lower than normal number of red blood cells in the blood, usually measured by a decrease in the amount of hemoglobin. A normocytic, normochromic anemia attributable to CRD is observed beginning at stage 3 CRD and is almost universal at stage 4. If untreated, the anemia of CRD is associated with a number of physiologic abnormalities, including decreased tissue oxygen delivery and utilization, increased cardiac output, cardiac enlargement, ventricular hypertrophy, angina, congestive heart failure, decreased cognition and mental acuity, altered menstrual cycles, and impaired host defense against infection. In addition, anemia may play a role in growth retardation in children with CRD. The primary cause of anemia in patients with CRD is insufficient production of erythropoietin by the diseased kidneys8.
Several other factors have been implicated:
• Bone marrow toxins retained in renal failure
• Bone marrow fibrosis secondary to hyperparathyroidism
• Haematinic deficiency – iron, vitamin B12, folate
• Increased red cell destruction m abnormal red cell membranes causing increased osmotic fragility
• Increased blood loss – occult gastrointestinal bleeding, blood sampling, blood loss during haemodialysis or because of platelet dysfunction
• ACE inhibitors (may cause anaemia in chronic renal failure, probably by interfering with the control of endogenous erythropoietin release).
Red cell survival is reduced in renal failure. Increased red cell destruction may occur during haemodialysis owing to mechanical, oxidant and thermal damage.

Abnormal Hemostasis
This is common in CRD and is associated with prolongation of bleeding time, decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption. Clinical manifestations include an increased tendency to abnormal bleeding and bruising; bleeding from surgical wounds; and spontaneous bleeding into the gastrointestinal tract, pericardial sac, or intracranial vault (in the form of subdural hematoma or intracerebral hemorrhage). Notwithstanding these abnormalities in hemostasis, CRD patients have a greater susceptibility to thromboembolic complications, particularly if their underlying disease was characterized by a nephrotic presentation.

• BONE DISEASE AND DISORDERS OF CALCIUM AND PHOSPHATE METABOLISM
The major disorders of bone disease in CRD can be classified into those associated with high bone turnover and high PTH levels (including osteitis fibrosa, the hallmark lesion of secondary hyperparathyroidism) and low bone turnover with low or normal PTH levels (osteomalacia and adynamic bone disease) 9/10.
The pathophysiology of bone disease due to secondary hyperparathyroidism is related to abnormal mineral metabolism.
(1) Decreased GFR leads to reduced inorganic phosphate excretion and consequent
Phosphate retention,
(2) Retained phosphate has a direct stimulatory effect on PTH synthesis and on cellular mass of the parathyroid glands,
(3) Retained phosphate also indirectly causes excessive production and secretion of PTH through lowering of ionized Calcium and by suppression of calcitriol (1, 25-dihydroxycholecalciferol) production, and
(4) Reduced calcitriol production in CRD results both from decreased synthesis due to reduced kidney mass and from hyperphosphatemia. Low calcitriol levels, in turn, lead to hyperparathyroidism via both direct and indirect mechanisms.
Calcitriol is known to have a direct suppressive effect on PTH transcription and therefore reduced calcitriol in CRD causes elevated levels of PTH. In addition, reduced calcitriol leads to impaired Calcium absorption from the gastrointestinal tract, thereby leading to hypocalcemia, which then increases PTH secretion and production. Taken together, hyperphosphatemia, hypocalcemia, and reduced calcitriol synthesis all promote the production of PTH and the proliferation of parathyroid cells, resulting in secondary hyperparathyroidism. In addition to excessive release of PTH from individual parathyroid cells, the mass of parathyroid cells increases progressively with CRD.
High PTH levels stimulate osteoblasts and result in high bone turnover, which leads to osteitis fibrosa cystica. The latter is characterized by irregularly woven abnormal osteoid, fibrosis, and cyst formation, which result in decreased cortical bone and bone strength and an increased risk of fracture.
Low-turnover bone disease can be classified into two categories—osteomalalcia and adynamic bone disease. Both lesions are characterized by a reduced number of osteoclasts and osteoblasts and decreased activity of the latter. In osteomalacia there is an accumulation of unmineralized bone matrix, or increased osteoid volume, which may be caused by vitamin D deficiency, excess aluminum deposition, or metabolic acidosis. Adynamic bone disease is now recognized to be as prevalent as the hyperparathyroid bone lesion in patients with CRD and ESRD, and is especially common among diabetic patients.

Figure 4

• DERMATOLOGIC ABNORMALITIES
The skin may show evidence of anemia (pallor), defective hemostasis (ecchymoses and hematomas), calcium phosphate deposition and secondary hyperparathyroidism (pruritus, excoriations), and deposition of pigmented metabolites or urochromes (yellow discoloration) or urea itself (uremic frost). Although many of these cutaneous abnormalities improve with dialysis, uremic pruritus often remains a problem. The first lines of management are to rule out unrelated skin disorders and to control phosphate concentration with avoidance of an elevated calcium-phosphate product. Occasionally, pruritus remains refractory to these measures and to other nonspecific systemic and topical therapies. Skin necrosis can occur as part of the calciphylaxis syndrome, which also includes subcutaneous, vascular, joint, and visceral calcification in patients with poorly controlled calcium-phosphate product.
Pruritus (itching) is common in severe renal failure and is usually attributed in the main to retention of nitrogenous waste products of protein catabolism. Certainly, marked improvement often follows the institution of dialysis. Other causes of pruritus include:
• Hypercalcaemia
• Hyperphosphataemia
• Elevated calcium x phosphate product
• Hyperparathyroidism (even if calcium and phosphate levels are normal)
• Iron deficiency

• GASTROINTESTINAL COMPLICATIONS
Uriniferous odor to the breath derives from the breakdown of urea to ammonia in saliva and is often associated with an unpleasant metallic taste sensation. Gastritis, peptic disease, and mucosal ulcerations at any level of the gastrointestinal tract occur in uremic patients and can lead to abdominal pain, nausea, vomiting, and blood loss. Other gastrointestinal complications of CRD include an increased incidence of diverticulosis, particularly in patients with polycystic kidney disease, and an increased incidence of pancreatitis. In addition, central nervous system effects of uremia contribute to anorexia, hiccups, nausea, and vomiting. Protein restriction is useful in diminishing nausea and vomiting late in the course of renal failure. However, protein restriction should not be implemented in patients with signs of protein-energy malnutrition, which is a consequence of low protein and caloric intake, resistance to anabolic actions of insulin and other hormones and growth factors, disturbed dietary protein utilization, proinflammatory cytokine activation, and metabolic acidosis.

• FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS
Sodium and Water Homeostasis
The underlying etiologic disease process may itself disrupt glomerulotubular balance and promote sodium retention or excessive sodium ingestion may lead to cumulative positive sodium balance and attendant extracellular fluid volume (ECFV) expansion. Such ECFV expansion contributes to hypertension, which in turn accelerates further the progression of nephron injury. As long as water intake does not exceed the capacity for free water clearance, the ECFV expansion will be isotonic and the patient will remain normonatremic.

Potassium Homeostasis
In CRD, the decline in GFR is not necessarily accompanied by a concomitant and proportionate decline in urinary Potassium excretion. In addition, Potassium excretion in the gastrointestinal tract is augmented in patients with CRD. However, hyperkalemia may be precipitated in a number of clinical situations, including constipation, augmented dietary intake, protein catabolism, hemolysis, hemorrhage, transfusion of stored red blood cells, metabolic acidosis, and following the exposure to a variety of medications that inhibit Potassium entry into cells or Potassium secretion in the distal nephron. Hyperkalemia is the most common clinically significant electrolyte abnormality in CRF.
• It is often asymptomatic until potentially lethal dysrhythmias occur.
• Hyperkalemia is uncommon when patients with ESRD are compliant with treatment and diet, unless an intercurrent illness such as acidosis or sepsis develops.
• Serum potassium usually should be measured in patients with CRF/ESRD who present with a systemic illness or major injury.
• History of hyperkalemia requiring treatment should lower the threshold for ordering a potassium level.

Metabolic Acidosis
Acidosis is a common disturbance during the advanced stages of CRD. Although in a majority of patients with CRD the urine can be acidified normally, these patients have a reduced ability to produce ammonia. Hyperkalemia further depresses urinary ammonium excretion.
Baseline anion gap metabolic acidosis is typical in patients with CRF, who have a decreased ability to excrete acid. These patients are very prone to developing severe acidosis when under physiologic stress (eg: sepsis, myocardial infarction, trauma).
• Dialysis is necessary if the patient has severe acidosis.
• Treat patients with significant chronic acidosis with oral alkalinizing agents to prevent bone loss.
• Shortness of breath in patients with CRF may be due to respiratory compensation for acidosis.

• CARDIOVASCULAR ABNORMALITIES12
Ischemic Cardiovascular Disease
CRD at all stages constitutes a major risk factor for ischemic cardiovascular disease, including occlusive coronary heart, cerebrovascular, and peripheral vascular diseases. Increased prevalence of coronary heart disease in CRD derives from both traditional (“classic”) and CRD-related (“nontraditional”) risk factors.
The former include hypertension, hypervolemia, dyslipidemia, sympathetic overactivitiy, and hyperhomocysteinemia. The CRD-related risks include anemia, hyperphosphatemia, hyperparathyroidism, and a state of “microinflammation” that can be found at all stages of CRD but is undoubtedly aggravated by dialysis. The inflammatory state elicits a rise in acute-phase reactants such as interleukin 6 and C-reactive protein, which contribute to the coronary occlusive process and are predictors of cardiovascular disease risk. Other abnormalities augment myocardial ischemia. These include reduced myocardial tolerance to ischemia due to left ventricular hypertrophy (see below) and microvascular disease. Also, coronary reserve, defined as the increase in coronary blood flow in response to greater demand, is attenuated. Nitric oxide is an important mediator for vascular dilatation.
Its availability in CRD is decreased because of increased concentrations of asymmetric dimethyl-l-arginine, even at early stages of CRD, and also because nitric oxide is scavenged by reactive oxygen species. In addition, coronary arteriolar hypertrophy/hyperplasia limits vasodilatory capacity.

Congestive Heart Failure
Abnormal cardiac function secondary to myocardial ischemic disease and/or left ventricular hypertrophy, together with salt and water retention in uremia, often result in congestive heart failure and/or pulmonary edema. A unique form of pulmonary congestion and edema may occur even in the absence of volume overload and is associated with normal or mildly elevated intracardiac and pulmonary capillary wedge pressures

Hypertension and Left Ventricular Hypertrophy
Hypertension is the most common complication of CRD and ESRD. It may develop early during the course of CRD and is associated with adverse outcomes in particular, more rapid loss of renal function and development of cardiovascular disease Left ventricular hypertrophy and dilated cardiomyopathy are among the most ominous risk factors for excess cardiovascular morbidity and mortality in patients with CRD and ESRD and are thought to be related primarily to prolonged hypertension and ECFV overload. In addition, anemia and the surgical placement of an arteriovenous anastomosis for future or ongoing dialysis access may generate a high cardiac output state and pulmonary hypertension, which also intensify the burden placed on the left ventricle.

• NEUROMUSCULAR ABNORMALITIES
Central, peripheral, and autonomic neuropathy, as well as abnormalities in muscle composition and function, are all common complications in CRD. Retained nitrogenous metabolites and middle molecules as well as PTH all contribute to the pathophysiology of neuromuscular abnormalities. Subtle clinical manifestations of uremic neuromuscular disease usually become evident beginning at stage 3 CRD. Early manifestations of central nervous system complications include mild disturbances in memory and concentration and sleep disturbance. Neuromuscular irritability, including hiccups, cramps, and fasciculations, twitching of muscles, becomes evident at later stages. Asterixis, myoclonus, and chorea are common in terminal uremia, which may also be associated with seizures and coma.
Peripheral neuropathy usually becomes clinically evident when the patient has been at stage 4 CRD for 6 months, although electrophysiologic and histologic evidence of peripheral neuropathy occurs earlier. Initially, sensory nerves are involved more than motor nerves,
lower extremities more than upper, and distal portions of the extremities more than proximal. The “restless legs syndrome” is characterized by ill-defined sensations of discomfort in the legs and feet requiring frequent leg movement. If dialysis is not instituted soon after onset of sensory abnormalities, motor involvement follows, including muscle weakness and loss of deep tendon reflexes. Accordingly, evidence of peripheralneuropathy is a firm indication for renal replacement therapy.
Some of the central nervous system and neuromuscular complications of advanced uremia resolve with dialysis, although nonspecific electroencephalographic abnormalities may persist. Successful transplantation may reverse residual peripheral neuropathy.

• ENDOCRINE-METABOLIC DISTURBANCES
Disturbances in parathyroid function have already been considered. Glucose metabolism is impaired in CRD, as evidenced by a slowing of the rate at which blood glucose levels decline after a glucose load. Fasting blood glucose is usually normal or only slightly elevated, and the mild glucose intolerance related to uremia per se, when present, does not require specific therapy. Because the kidney contributes significantly to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic subjects, both in the fasting and postprandialstates. However, the response to insulin and glucose utilization is impaired in CRD. Many hypoglycemic drugs require dose reduction in renal failure, and some, such as metformin, are contraindicated when the GFR has diminished by more than approximately 25 to 50%.
In women, estrogen levels are low, and amenorrhea and inability to carry pregnancies to term are common manifestations of uremia. When the GFR has declined by 30%, pregnancy may hasten the progression of CRD. In men with CRD, including those receiving chronic dialysis, impotence, oligospermia, and germinal cell dysplasia are common, as are reduced plasma testosterone levels. Like growth, sexual maturation is often impaired in adolescent children with CRD, even among those treated with chronic dialysis. Many of these abnormalities improve or reverse with successful renal transplantation.

DEFINITION OF CHRONIC RENAL FAILURE.
Chronic renal failure is a slowly worsening loss of the ability of the kidneys to remove wastes,
Concentrate Urine, and conserve electrolytes.1
Four stages of decreased renal function may be visualized:
1. Silent – GER. up to 50 ml/min.
2. Renal insufficiency – GER. 25 to 50 ml/min. 3. Renal failure – GER. 5 to 25 ml/min
4. End-stage renal failure – GER. less than 5 ml/min.
Chronic renal failure results in an accumulation of fluid and waste products in the body, leading to a build up of nitrogen waste products in the blood and general ill health. Most body systems are affected bychronic renal failure.
Uremia is a term applied to the manifestations of organ dysfunction seen in stages 3 and 4 as outlined above. Literally, uremia means urine in the blood. The accumulation of nitrogenous waste products, chiefly urea, in the blood is the hall mark of renal failure. It is a clinical syndrome resulting from retention of certain substances which are normally excreted into the urine and thus accumulate causing toxicity.

CAUSES OF CHRONIC RENAL FAILURE.2
Chronic renal failure usually occurs over a number of years as the internal structures of the kidney are slowly damaged. In the early stages, there may be no symptoms. In fact, progression may be so slow that symptoms do not occur until kidney function is less than one-tenth of normal.
Any disorder that permanently destroys nephrons can result in chronic renal failure. Most Common Causes of CRF are:
•Analgesic nephropathy
•Glomerulonephritis of any type (one of the most common causes)
•Kidney stones and infection
•Obstructive uropathy
•Polycystic kidney disease
eflux nephropathy
•Diabetic nephropathy
•Hypertensive nephrosclerosis
•Glomerulonephritis

SOLUTE HANDLING IN CHRONIC RENAL FAILURE
A) Creatinine and Urea Balance.
Although creatinine is secreted and urea is reabsorbed through tubules, balance depends on their rates of filtration. Balance (rate of filtration) is maintained by allowing plasma concentrations to rise until renal excretion equals production. Urea reabsorption falls with the solute diuresis per nephron and thus the blood urea nitrogen need not rise as much as expected to maintain balance. Creatinine secretion is enhanced and thus excretion also is balanced to production at a plasma concentration less than anticipated.
In addition, urea is metabolized in increased amounts by gut bacteria as the blood urea nitrogen rises and creatinine production is reduced by metabolic suppression.

The figure shows the affect of a single decrease in GFR on creatinine balance. Note that CRF is consists of multiple decreases in GFR over time. If production of creatinine is assumed constant, then this figure illustrates the change in creatinine balance. The top panel shows a decrease in GFR of 50%. The excretion of creatinine falls with accumulation in total body reflected by an increase in serum creatinine (lower panel). A new steady state was reached when excretion again equaled production of creatinine. This occurred at the expense of an elevated serum creatinine and total body creatinine. Another way of visualizing this new steady states is that the product of the new serum cr and new GFR must equal the product of the old serum cr and Old GFR (if creatinine production remains stable).3

B) Water Balance:
In order to maintain water balance, the fraction of water reabsorbed by the kidney must decrease. Thus, an increased flow per nephron ensues. With progressive CRF, the ability to excrete a water load is compromised and the patient may develop hypo-osmolarlity. Urine concentration ability of the kidney becomes fixed around 300 mosm/kg of water and thus the patient is also susceptible to dehydration if water intake is lowered. Thus, a CRF patient is prone to both excess and deficit of water. Nocturia develops early in CRF because of decreased concentrating ability of urine during sleep.

C) Sodium Balance:
In order to maintain sodium balance, the fraction of sodium reabsorbed must be decreased, thereby increased excretion of sodium fraction because of decreased GFR. A humoral natriuretic factor in CRF helps to increase sodium excretion.3
In CRF, the kidneys are unable to reduce sodium excretion rapidly in response to a sudden decrease in intake or extrarenal losses (e.g. G.I. loss). Thus, major increase in
sodium intake results in edema and major decreases in intake or increases in extrarenal losses result in volume depletion. The hallmark of CRF is the loss of flexibility in responding to challenges to external load of solutes and water.
While normal subjects can excrete sodium promptly following a sodium load with minimal effect on ECF, in CRF subjects delayed excretion results in ECF expansion. While normal subjects on salt restricted diet reduce urine Na to 20 mEq in 48 hours, CRF subjects may require 1-2 weeks for similar sodium conservation and thus are prone to sodium depletion.

D) Potassium Balance:
Increased tubular secretion of potassium helps maintain potassium balance until renal failure is severe. In normal subjects, 90% of potassium is excreted in urine and 10% in stool. In advanced CRF, fecal excretion of potassium increases to 50% of the potassium load. Thus, plasma potassium and body potassium are maintained on normal dietary intake. However the patient is susceptible to hyperkalemia from sudden potassium loads.

E) Calcium and Phosphorus Balance:
Decreased GFR leads to a sequence of events outlined in the syllabus in the section of Ca and P metabolism. A trade-off occurs in the development of secondary hyperparathyroidism in that the elevated PTH increases phosphate excretion but contributes to bone disease and perhaps other system dysfunction as described earlier.4

F) Hydrogen Ion Balance:
CRF is associated with a continuous positive balance (retention) of hydrogen ions due to a decrease in the tubular ammonia production to excrete hydrogen ion .
Retained anions such as SO4 and PO4 contribute to acidosis. The bottom line is that bone serves as a sump for excess hydrogen ion and plasma HCO3 concentration is preserved at only a modestly reduced concentration (about 15 mmol/L). However, flexibility is lost and severe acidosis may occur from small challenges.

PROGRESSION OF CHRONIC RENAL FAILURE
A variety of chronic renal diseases progress to end-stage renal disease, including chronic glomerulonephritis, diabetic nephropathy, and polycystic kidney disease. Although the underlying problem often cannot be treated, extensive studies in experimental animals and preliminary studies in humans suggest that progression in chronic renal disease may be largely due to secondary factors that are unrelated to the activity of the initial disease. Secondary factors and progression of chronic renal failure.5

• Retained “uremic” toxins
• Intraglomerular hypertension and hypertrophy
• Phosphate retention, with interstitial CaPO4 deposition
• Increased prostaglandin synthesis
• Hyperlipidemia, especially in the nephrotic syndrome
• Metabolic acidosis
• Proteinuria
• Tubulointerstitial disease
• Filtered iron in nephrotic syndrome
The major histologic manifestation of these secondary causes of renal injury is focal segmental glomerulosclerosis. Thus, glomerular damage and proteinuria typically occur with progressive renal failure.

A) INTRAGLOMERULAR HYPERTENSION AND GLOMERULAR HYPERTROPHY
In animal models, for example, a rise in intraglomerular pressure, due either to the compensatory response to nephron loss or to primary renal vasodilatation (as in diabetes mellitus), appears to play an important role in the progressive glomerular scarring. The mechanisms by which intraglomerular hypertension might promote glomerular injury are incompletely understood. At least two factors may be involved.6
Direct endothelial cell damage, similar to that induced by systemic hypertension
Increased pressure-induced movement of circulating macromolecules (such as IgM and fibrinogen and complement metabolites) through the fenestrated endothelial cells into the subendothelial space in the glomerular capillary wall. The characteristic accumulation of these “hyaline” deposits can progressively narrow the capillary lumens, thereby decreasing glomerular perfusion and filtration.
An increase in glomerular size, as well as intraglomerular pressure, also may occur in these settings. This change can contribute to glomerular injury both by increasing wall stress and by causing detachment of the glomerular epithelial cells from the glomerular capillary wall.
Non-hemodynamic factors also may be important in the development of secondary glomerulosclerosis. Marked nephron loss in experimental animals can lead to glomerular cell proliferation, macrophage influx and accumulation of extracellular matrix components (leading to narrowing of the capillary lumens).
How these changes occur is not well understood, but cytokines such as platelet-derived growth factor and transforming growth factor (TGF) may play a contributory role. Experimental studies, for example, suggest that TGF may contribute to increased extracellular matrix production and the development of glomerulosclerosis in a variety of renal diseases.
Thus glomerulosclerosis results from the glomerular hypertension itself or from increased glomerular capillary flow and filtration
In addition to processes affecting the glomeruli, secondary tubulointerstitial disease also is commonly seen. This change is often under-appreciated, but both the glomerular filtration rate and long-term prognosis are more closely related to the degree of tubulointerstitial, rather than glomerular injury.

B) OTHER SECONDARY FACTOR7 Identification of the role of these secondary factors is important clinically because they can be treated, possibly preventing or at least minimizing further renal injury. Dietary protein restriction and the use of anti-hypertensive agents (particularly angiotensin converting enzyme inhibitors) have been most widely studied. In addition to the potential importance of intraglomerular hypertension and glomerular hypertrophy, the following factors also may contribute to secondary renal injury:
Phosphate retention. A tendency to phosphate retention is an early problem in renal disease, beginning as soon as the glomerular filtration rate starts to fall. In addition to promoting bone disease, the excess phosphate also may contribute to progression of the renal failure. This may occur at least in part by phosphate precipitation with calcium in the renal interstitium, leading to an increase in renal calcium content even before the plasma creatinine concentration exceeds 1.5 mg/dL (132 mol/L). The calcium phosphate salts may then initiate an inflammatory reaction, resulting in interstitial fibrosis and tubular atrophy.
These problems can be minimized by decreasing phosphate intake or by the use of oral phosphate binders. It has been suggested, for example, that the efficacy of protein restriction may be related in part to a concurrent decline in phosphate intake.
Altered prostanoid metabolism. Glomerular prostaglandin production tends to be increased in glomerular disease. This response may represent an appropriate intra-nephronal adaptation, since the ensuing renal vasodilatation helps to maintain the GFR in the presence of an often marked reduction in glomerular capillary permeability induced by the underlying disease. This adapation is reversed by an NSAID, leading to renal vasoconstriction and a subsequent fall in intraglomerular pressure. These changes are manifested clinically by reductions in glomerular filtration rate (usually by about 20 percent) and protein excretion (often by more than 50 percent) in many patients with chronic glomerular disease.
Non-randomized studies suggest that long-term therapy in responders (those with a substantial decline in proteinuria) may be associated with a lesser rate of progression to end-stage renal disease.
Hyperlipidemia – Hyperlipidemia is common in patients with chronic renal disease, particularly those with the nephrotic syndrome. In addition to accelerating the development of systemic atherosclerosis, experimental studies suggest that high lipid levels also may promote progression of the renal disease. The major evidence in support of this hypothesis are the observations in experimental animals that cholesterol loading enhances glomerular injury and that reducing lipid levels with a drug such as lovastatin slows the rate of progressive injury.
The factors responsible for the lipid effects are incompletely understood. In different animal models, a high cholesterol intake may be deleterious in association with a rise in intraglomerular pressure, while lipid-lowering agents may be beneficial without affecting glomerular hemodynamics. These disparate observations suggest that mechanisms other than intraglomerular pressure alone may play a contributory role. It has been shown experimentally, for example, that hyperlipidemia activates the mesangial cells (which have LDL receptors), leading to increased production of fibronectin (a component of the extracelluar matrix) and of a chemo-attractant for monocytes. Both of these changes could contribute to glomerular injury. In addition, HMG CoA reductase inhibitors such as lovastatin may act independent of plasma lipid levels by directly inhibiting mesangial cell proliferation.
The applicability of these findings to human disease is unproven, since there are no studies evaluating the possible protective effect of lowering lipid levels. However, both increased mesangial lipid deposition and enhanced expression of LDL-receptors on mesangial and epithelial cells have been demonstrated in patients with chronic glomerular diseases. Mesangial phagocytosis and increased traffic of macromolecules through the more permeable glomerular capillary wall could be responsible for the lipoprotein deposition; in addition, the increase in receptors could promote lipid accumulation even in the absence of hyperlipidemia. Whether the deposited lipid contributes to the glomerular injury is uncertain.
Metabolic acidosis and increased ammonium production – As the number of functioning nephrons declines, each remaining nephron excretes more acid (primarily as ammonium). The local accumulation of ammonia can directly activate complement, leading to secondary tubulointestitial damage (at least in experimental animals). On the other hand, buffering the acid with alkali therapy prevents the increase in ammonium production and minimizes the renal injury.
Although the renal protective effect of alkali therapy unproven in humans, there are other reasons (prevention of osteopenia and muscle wasting) why correction of the acidemia might be desirable. Sodium bicarbonate is preferred to sodium cirtrate in this setting, since citrate leads to a marked increase in intestinal aluminum absorption, possibly promoting the development of aluminum toxicity; this is most likely to occur in those patients treated with aluminum-containing antacids to bind dietary phosphate. The effect of citrate may be mediated both by keeping aluminum soluble (via the formation of aluminum citrate) and by binding of calcium in the intestinal lumen; the ensuing fall in free calcium then may lead to increased permeability of the tight junctions between the cells and a rise in passive aluminum absorption. Bicarbonate, on the other hand, does not produce these effects and therefore does not increase aluminum transport.
of progression.
Proteinuria – It has been suggested that proteinuria itself may contribute to disease progression, both by overloading the mesangium with macromolecules and by promoting tubulointerstital disease. It is possible, for example, that a marked increase in protein filtration and subsequent proximal reabsorption leads to tubular cell injury and the release of lysozymes into the interstitium. Thus, reversing intraglomerular hypertension with protein restriction or antihypertensive therapy may be beneficial both by diminishing hemodynamic injury to the glomeruli and by reducing protein filtration (which is in part dependent upon the intraglomerular pressure).
Tubulointerstital disease – All forms of chronic renal failure are associated with marked tubulointerstial injury (tubular dilatation, interstitial fibrosis), even if the primary process is a glomerulopathy. Furthermore, the degree of tubulointerstital disease is a better predictor of the glomerular filtration rate and long-term prognosis than is the severity of glomerular damage in almost all chronic progressive glomerular diseases, including IgA nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, and lupus nephritis.
The mechanism by which the tubulointerstitial disease occurs is not well understood. As described above, both calcium phosphate deposition and metabolic acidosis with secondary interstitial ammonia accumulation may play a contributory role. There is also evidence that an active immuniologic process is involved, beginning early in the course of the disease and in some cases being an extension of the inflammatory process in the glomeruli. In some experimental models of renal disease, conticosteroid therapy can ameliorate the tubulointerstitial damage (without effect on the glomerular injury).
However, even effective therapy of the intersitial inflammation may not prevent progressive injury. In this setting, healing may be associated with interstitial fibrosis mediated in part by the release of cytokines such as transforming growth factor.
Retained toxins – Dialysis of nonuremic animals with glomerulosclerosis preserves the glomerular filtration rate and slows the rate of further glomerular damage. This observation suggests that retention of ultrafiltrable toxins during the course of progress renal disease contributes to secondary glomerular injury. How this might occur is not clear.
Iron toxicity – Increased glomerular permeability can result in the filtration of the normally nonfiltered iron-transferrin complex. Dissociation of this complex in the tubular lumen leads to the release of free iron which can promote tubular injury by promoting the formation of hydroxyl radicals.

CLINICAL MANIFESTATIONS OF CRF.
Clinical Manifestations:
The symptoms and signs which constitute the uremic syndrome are summarized below:
Neurological Disorders: Fatigue, lethargy, sleep disturbances, headache, seizures, encephalopathy, peripheral neuropathy including restless leg syndrome, paraesthesia, motor weakness, paralysis.
Hematologic Disorders: Anemia, bleeding tendency due in part to platelet dysfunction.
Cardiovascular Disorders: Pericarditis, hypertension, congestive heart failure, coronary artery disease, myocardiopathy.
Pulmonary Disorders: Pleuritis, uremic lung.
Gastrointestinal Disorders: Anorexia, nausea, vomiting gastroenteritis, GI bleeding, peptic ulcer.
Metabolic-Endocrine Disorders: Glucose intolerance, hyperllipidemia, hyperuricemia, malnutrition, sexual dysfunction and infertility.
Bone, Calcium, Phosphorus Disorders: Hyperphosphatemia, hypocalcemia, tetany, metastatic calcification, secondary hyperparathyroidism, 1,25-dihydroxy vitamin D deficiency, osteomalacia, osteitis fibrosa, osteoporosis, osteosclerosis.
Skin Disorders: Pruritus, pigmentation, easy bruising, uremic frost.
Psychological Disorders: Depression, anxiety, denial, psychosis.7
Fluid and Electrolyte Disorders: Hyponatremia, hyperkalemia, hypermagnesemia, metabolic acidosis, volume expansion or depletion.
Some of the important manifestations are elaborated below:

A) Anemia:
Anemia is universal as GFR falls below 25 ml/min.; in certain disorders it may occur with mild renal insufficiency. Several factors contribute:
a. Erythropoiesis is markedly depressed, mainly due to reduced erythropoietin production; in addition, there may be reduced end-organ response to erythropoietin with reduced heme synthesis.
b. Red cell survival is shortened with a mild to moderate decrease in red cell life span, possible due to a “uremic” toxin.
c. Blood loss is common in uremic patients, possibly secondary to abnormal coagulation due to decreased platelet function.
d. Marrow space fibrosis occurs with osteitis fibrosa of secondary hyperparathyroidism resulting in decreased erythropoiesis.8

B) Hypertension:
Hypertension occurs in 80% to 90% of patients with renal insufficiency. Several factors contribute:
a. Expansion of extracellular fluid volume; this may arise because of reduced ability of the kidney to excrete ingested sodium.
b. Increased activity of the renin-angiotensin system is common; many patients with advanced renal failure have renin levels that are not completely suppressed by the elevated blood pressure.
c. Dysfunction of the autonomic nervous system occurs with insensitive baroreceptor sensitive and with increased sympathetic tone.
d. Possible diminished presence of vasodilators: there may be decreased renal generation of prostaglandins or of factors in the kallikrein-kinin system.9

C) Altered Calcium and Phosphorus Metabolism (Renal can lead to hypocalcemia, which stimulates PTH. The latter causes phosphaturia, with restoration of serum phosphorus and calcium Osteodystrophy)
a. As GFR decreases there is a slight retention of phosphorus; this phosphorus retention toward normal. However, this occurs only at the expense of elevated serum PTH levels. This cycle repeats itself in progressive renal failure with PTH levels increasing progressively. Ultimately, the renal tubule can no longer respond to higher levels of PTH with a further decrease in phosphorus reabsorption. When this occurs, hyperphosphatemia develops, hypocalcemia may become prominent and PTH level can increase to very high levels. High PTH levels cause bone disease with severe osteitis fibrosa.
b. Altered vitamin D metabolism occurs secondary to decreased renal mass or to phosphate retention, with decreased synthesis of 1,25 (OH)2 D3. This deficiency leads to: 1. Diminished intestinal absorption of calcium, 2. decreased calcemic response of the skeleton to PTH, 3. impaired suppression of PTH secretion for any increase in serum calcium level, and 4. altered collagen synthesis. With advanced renal failure, these events can lead to secondary hyperparathyroidism and osteomalacia.10
c. Skeletal resistance to the calcemic action of PTH develops; thus an increased PTH is required to maintain serum calcium at any level.
d. Finally, accumulation of aluminum from aluminum binding antacids may contribute to the bone disease.

MANAGEMENT OF CHRONIC RENAL FAILURE
A) Treatment of primary renal disease:
The primary disease can be responsible for the continuous deterioration in renal function. It is important to recognize and to treat the primary renal disease. (e.g. certain disorders such as crescentic glomerulonephriti, membranous glomerulonephronpathy or analgesic nephropathy are potentially treatable or can be stabilized).

B) Treatment of reversible aggravating factors:
The progression of the decrease in GFR may be documented by plotting the reciprocal of the serum creatinine (1/S cr) against time. Conceptually, this means that GFR (nephrons) is being lost at a constant rate. A relatively linear course should be displayed. Deviation from this course should alert one to the presence of disorders which can acutely worsen renal function as shown below.

These factors aggravate the progression of renal failure and are known as reversible aggravating factors. The appropriate treatment of these factors can reverse or stabilize renal function to its pre exacerbation level. Various reversible factors are:
1. Salt and water depletion leading to hypovolemia
2. Systemic or renal infection
3. Accelerated hypertension
4. Nephrotoxic drugs
5. Urinary obstruction
6. Acute heart failure
7. Hypercalcemia

C) Treatment of secondary factors to prevent or slow the progression of renal disease
Human studies that are currently under way should determine the efficacy of treating at least some of these secondary hemodynamic and metabolic abnormalities in an attempt to preserve renal function. If these modalities are effective, the benefit is likely to be greatest if begun before a great deal of irreversible scarring has occurred. Thus, protective therapy may have the greatest impact if initiated relatively early in the course, before the plasma creatinine concentration exceeds 1.5 to 2 mg/dL (132 to 176 mol/L).
Despite the lack of conclusive evidence, many physicians have already begun using some of the above modalities in patients with progressive renal disease. Current recommendations might include: Treatment of hypertension at any stage of the disease, preferably beginning with an angiotensin converting enzyme inhibitor or possibly diltiazem or verapamil. Concurrent diuretic therapy will often be necessary in patients with fluid overload.
The optimal level of blood pressure control is uncertain, but diastolic pressures of < 80 mmHg may be desirable. Even normotenisve patients should be treated if they have proteinuria, which is a marker for possible hemodynamically-mediated glomerular injury. The aim of therapy in this setting (or in patients with overt hypertension) is to diminish protein excretion, which may be a marker for reduced intraglomerular pressure and improved glomerular permselectivity.
The optimal level of protein intake has also not been determined but it may be reasonable to restrict intake to 0.8 to 1 g/kg of high biologic value protein in mild to moderate disease (plasma creatinine concentration less than 2.0 mg/dL {176 mol/L}) and to 0.6 to 0.7 g/kg in more advanced renal insufficiency. This should be accompanied by phosphate restriction and , if present, treatment of hyperphosphatemia with calcium carbonate or calcium acetate. If present, both hyperlipidemia and metabolic acidosis (plasma bicarbonate concentration less than 21 meq/L with a reduced extracellular pH) should probably be treated. In addition to possible renal protection, these modalities also may diminish systemic atherosclerosis and muscle and bone breakdown, respectively.

D) Treatment of end stage renal failure:
When GFR falls below 5 ml/min, the patient usually can not live without renal replacement therapy. Renal replacement therapy includes dialysis and kidney transplantation.Various social or medical factors influence decisions about peritoneal or hemodialysis, and transplantation in the treatment of end-stage renal failure. It should also be noted that none of the above are panaceas and each, modality is associated with complications and failures.

The kidneys are dark-red, bean-shaped organs.
The normal kidney location is towards the back of the abdominal cavity, just above the waist. One kidney is normally located just below the liver, on the right side of the abdomen and the other is just below the spleen on the left side.
The normal kidney size of an adult human is about 10 to 13 cm (4 to 5 inches) long and about 5 to 7.5 cm (2 to 3 inches) wide.
A kidney weighs approximately 150 grams. Kidneys weigh about 0.5 percent of total body weight.
One side of the kidney bulges outward (convex) and the other side is indented (concave). There is a cavity attached to the indented side of the kidney, called the Renal Pelvis… which extends into the ureter.1
Each Kidney is enclosed in a transparent membrane called the renal capsule. The kidney is divided into two main areas. A light outer area called the renal cortex, and a darker inner area called the renal medulla. Within the medulla there are 8 or more cone-shaped sections known as renal pyramids. The areas between the pyramids are called renal columns.2
The most basic structures of the kidneys, are nephrons. Inside each kidney there are about one million of these microscopic structures. They are responsible for filtering the blood & removing waste products.

The kidney is full of blood vessels. Blood vessels are integral to efficient kidney function. Every function of the kidney involves blood, therefore, it requires a lot of blood vessels to facilitate these functions.
The process of separating wastes from the body fluids and eliminating them, is known as excretion. The body has four organ systems which are responsible for excretion. The urinary system is one of the organ systems responsible for excretion. It excretes a broad variety of metabolic wastes, toxins, drugs, hormones, salts, hydrogen irons, and water. The kidneys are the main organs of the urinary system.2
The human kidney anatomy, though relatively simple, enables it to perform extremely complex but essential functions. If any area of the kidney is damaged or becomes diseased, this could significantly affect its ability to perform these functions.

Chronic Renal Failure
Definition
Chronic Renal Failure implies long standing and usually progressive impairment in renal function.3

Causes
The cause for CRF sometimes can be determined by a detailed medical history, a comprehensive physical examination, and laboratory studies.

• The most common causes of CKD are diabetic nephropathy, hypertension, and glomerulonephritis. Together, these cause approximately 75% of all adult cases. Certain geographic areas have a high incidence of HIV nephropathy.
• Historically, kidney disease has been classified according to the part of the renal anatomy that is involved.
• Vascular, includes large vessel disease such as bilateral renal artery stenosis and small vessel disease such as ischemic nephropathy, hemolytic-uremic syndrome and vasculitis
• Glomerular, comprising a diverse group and subclassified into,
Primary Glomerular disease such as focal segmental glomerulosclerosis and IgA nephritis
Secondary Glomerular disease such as diabetic nephropathy and lupus nephritis
• Tubulointerstitial including polycystic kidney disease, drug and toxin-induced chronic tubulointerstitial nephritis and reflux nephropathy
• Obstructive such as with bilateral kidney stones and diseases of the prostate4

Pathophysiology
CKD can be roughly categorized as diminished renal reserve, renal insufficiency, or renal failure (end-stage renal disease). ). Initially, as renal tissue loses function, there are few abnormalities because the remaining tissue increases its performance (renal functional adaptation); a loss of 75% of renal tissue produces a fall in GFR to only 50% of normal.3,5
Decreased renal function interferes with the kidneys’ ability to maintain fluid and electrolyte homeostasis. Changes proceed predictably, but considerable overlap and individual variation exist. The ability to concentrate urine declines early and is followed by decreases in ability to excrete phosphate, acid, and K. When renal failure is advanced (GFR ≤ 10 mL/min/1.73 m2), the ability to dilute urine is lost; thus urine osmolality is usually fixed close to that of plasma (300 to 320 mosm/kg), and urinary volume does not respond readily to variations in water intake.
Plasma concentrations of creatinine and urea (which are highly dependent on glomerular filtration) begin a nonlinear rise as GFR diminishes.These changes are minimal early on. When the GFR falls below 10 mL/min/1.73 m2 (normal = 100 mL/min/1.73 m2), their levels increase rapidly and are usually associated with systemic manifestations. Urea and creatinine are not major contributors to the uremic symptoms; they are markers for many other substances (some not yet well defined) that cause the symptoms.4
Despite a diminishing GFR, Na and water balance is well maintained by increased fractional excretion of Na and a normal response to thirst. Thus, the plasma Na concentration is typically normal, and hypervolemia is infrequent unless dietary intake of Na or water is very restricted or excessive. Heart failure can occur from Na and water overload, particularly in patients with decreased cardiac reserve5.
Abnormalities of Ca, phosphate, parathyroid hormone (PTH), vitamin D metabolism, and renal osteodystrophy can occur3. Decreased renal production of calcitriol contributes to hypocalcemia. Decreased renal excretion of phosphate results in hyperphosphatemia. Secondary hyperparathyroidism is common and can develop in renal failure before abnormalities in Ca or phosphate concentrations occur. For this reason, monitoring para thyroid hormone in moderate chronic kidney disease, even prior to hyperphosphatemia occurs, has been recommended5.
Renal osteodystrophy (abnormal bone mineralization resulting from hyperparathyroidism, calcitriol deficiency, elevated serum phosphate, or low or normal serum Ca) usually takes the form of increased bone turnover due to hyperparathyroid bone disease (osteitis fibrosa) but can also involve decreased bone turnover due to adynamic bone disease (with increased parathyroid suppression) or osteomalacia. Calcitriol deficiency may cause osteopenia or osteomalacia3.
Moderate acidosis (plasma HCO3 content 15 to 20 mmol/L) and anemia are characteristic. The anemia of CKD is normochromic-normocytic, with an Hematocrit of 20 to 30% (35 to 50% in patients with polycystic kidney disease). It is usually caused by deficient erythropoietin production due to a reduction of functional renal mass.Other causes include deficiencies of iron, folate, and vitamin B12.3
Stages
All individuals with a Glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for 3 months are classified as having chronic kidney disease, irrespective of the presence or absence of kidney damage. The rationale for including these individuals is that reduction in kidney function to this level or lower represents loss of half or more of the adult level of normal kidney function, which may be associated with a number of complications.

All individuals with kidney damage are classified as having chronic kidney disease, irrespective of the level of GFR. The rationale for including individuals with GFR 60 mL/min/1.73 m2 is that GFR may be sustained at normal or increased levels despite substantial kidney damage and that patients with kidney damage are at increased risk of the two major outcomes of chronic kidney disease.
1. loss of kidney function
2. development of cardiovascular disease.
The loss of protein in the urine is regarded as an independent marker for worsening of renal function and cardiovascular disease.
There are several stages of chronic renal failure.
Stage 1
Slightly diminished function; Kidney damage with normal or relatively high GFR (>90 mL/min/1.73 m2). Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies.
Stage 2
Mild reduction in GFR (60-89 mL/min/1.73 m2) with kidney damage. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies.
Stage 3
Moderate reduction in GFR (30-59 mL/min/1.73 m2). British guidelines distinguish between stage 3A (GFR 45-59) and stage 3B (GFR 30-44) for purposes of screening and referral.

Stage 4
Severe reduction in GFR (15-29 mL/min/1.73 m2).Shoud be preparation for renal replacement therapy.
Stage 5
Established kidney failure (GFR <15 mL/min/1.73 m2, or permanent renal replacement therapy (RRT)6

Pre-Renal CRF

Some medical conditions cause continuous hypoperfusion (Hyperperfusion means low blood flow) of the kidneys.
This leads to
• leading to kidney atrophy (shrinking)
• loss of nephron function
• chronic renal failure (CRF)
These conditions include poor cardiac function, chronic liver failure, and atherosclerosis ("hardening") of the renal arteries. Each of these conditions can induce ischemic nephropathy.7

Post-Renal CRF

Interference with the normal flow of urine can produce backpressure within the kidneys, can damage nephrons, and lead to obstructive uropathy, a disease of the urinary tract. Abnormalities that may hamper urine flow and cause post-renal CRF include the following:
• Bladder outlet obstruction due to an enlarged prostate gland or bladder stone
• Neurogenic bladder, an overdistended bladder caused by impaired communicator nerve fibers from the bladder to the spinal cord
• Kidney stones in both ureters, the tubes that pass urine from each kidney to the bladder
• Obstruction of the tubules,the end channels of the renal nephrons
• Retroperitoneal fibrosis, the formation of fiberlike tissue behind the peritoneum, the membrane that lines the abdominal cavity
• Vesicoureteral reflux (VUR), the backward flow of urine from the bladder into a ureter.7

Signs and symptom

Initially it is without specific symptoms and can only be detected as an increase in serum creatinine or protein in the urine. As the kidney function decreases.4
Even patients with mild to moderate renal insufficiency may have no symptoms despite elevated BUN and creatinine.
Nocturia is often noted, principally due to a failure to concentrate the urine.
Lassitude, fatigue, anorexia, and decreased mental acuity often are the earliest manifestations of uremia.
With more severe renal insufficiency (eg, creatinine clearance < 10 mL/min for patients without diabetes and < 15 mL/min for those with diabetes), neuromuscular symptoms may be present, including coarse muscular twitches, peripheral sensory and motor neuropathies, muscle cramps, hyperreflexia, and seizures (usually the result of hypertensive or metabolic encephalopathy). Anorexia, nausea, vomiting, weight loss, stomatitis, and an unpleasant taste in the mouth are almost uniformly present.
The skin may be yellow-brown.
Occasionally, urea from sweat crystallizes on the skin (uremic frost). Pruritus may be especially uncomfortable. Undernutrition leading to generalized tissue wasting is a prominent feature of chronic uremia.3

In advanced CKD, pericarditis and GI ulceration and bleeding are common. Hypertension is present in > 80% of patients with advanced CKD, is usually related to hypervolemia, and is occasionally the result of activation of the renin-angiotensin-aldosterone system. Cardiomyopathy (hypertensive of Na and water may lead to dependent edema and heart failure.
Urea accumulates, leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy).4
Urea is excreted by sweating and crystallizes on skin (“uremic frost”).
Potassium accumulates in the blood (known as hyperkalemia with a range of symptoms including malaise and potentially fatal cardiac arrhythmias)
Erythropoietin synthesis is decreased (potentially leading to anemia, which causes fatigue)
Fluid volume overload – symptoms may range from mild edema to life-threatening pulmonary edema.4
Hyperphosphatemia – due to reduced phosphate excretion, associated with hypocalcemia (due to vitamin D3 deficiency).
The major sign of hypocalcemia being tetany.
Later this progresses to tertiary hyperparathyroidism, with hypercalcaemia, renal osteodystrophy and vascular calcification that further impairs cardiac function.
Metabolic acidosis, due to accumulation of sulfates, phosphates, uric acid etc. This may cause altered enzyme activity by excess acid acting on enzymes and also increased excitability of cardiac and neuronal membranes by the promotion of hyperkalemia due to excess acid academia.8
People with chronic kidney disease suffer from accelerated atherosclerosis and are more likely to develop cardiovascular disease than the general population. Patients afflicted with chronic kidney disease and cardiovascular disease tend to have significantly worse prognoses than those suffering only from the latter.

Diagnosis
• Electrolytes, BUN, creatinine, phosphate, Ca, urinalysis (including urinary sediment examination)

• Ultrasonography

• Sometimes, renal biopsy

It is important to differentiate chronic renal failure from acute renal failure (ARF) because ARF can be reversible. The diagnostic that helps differentiate and ARF is a gradual rise in serum creatinine (over several months or years) as opposed to a sudden increase in the serum creatinine (several days to weeks). If these levels are unavailable (because the patient has been well and has had no blood tests) it is occasionally necessary to treat a patient briefly as having acute renal failure until it has been established that the renal impairment is irreversible.
Testing includes urinalysis with examination of the urinary sediment, electrolytes, urea nitrogen, and creatinine, phosphate, Ca. Distinguishing acute from chronic renal failure is most helped by a history of an elevated creatinine level or abnormal urinalysis.3
In chronic renal failure treated with standard dialysis, numerous uremic toxins accumulate.These toxins show various cytotoxic activities in the serum, have different molecular weights and some of them are bound to other proteins, primarily to albumin.
An ultrasound examination of the kidneys is usually helpful in evaluating for obstructive uropathy and in distinguishing acute from chronic renal failure based on kidney size. Except in certain conditions patients with chronic renal failure have small shrunken kidneys (usually < 10 cm in length) with thinned, hyperechoic cortex.4
Obtaining a precise diagnosis becomes increasingly difficult as renal function reaches values close to those of end-stage renal disease. The definitive diagnostic tool is renal biopsy, but it is not recommended when ultrasonography indicates small, fibrotic kidneys.3,4,9

Treatment
Once chronic renal failure has been diagnosed, the physician must determine the cause and, if possible, plan a specific treatment. Nonspecific treatments are implemented to delay or possibly arrest the progressive loss of kidney function.
• Control of underlying disorders

• Possible restriction of dietary protein, phosphate, and K

• Vitamin D supplements

• Treatment of anemia and heart failure

• Doses of all drugs adjusted as needed

• Preparation for renal replacement therapy (RRT)

Underlying disorders and contributory factors must be controlled. In particular, controlling hyperglycemia in patients with diabetic nephropathy and controlling hypertension in all patients substantially slows deterioration of GFR.
Control hypertension (high blood pressure)
Target systolic blood pressure (BP) is 120 – 135 mm Hg.Target diastolic BP is 70 – 80 mm Hg. Generally, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are used, as they have been found to slow the progression of chronic renal failure. Although the use of ACE inhibitors and ARBs represents the current standard of care for patients with chronic renal failure patients progressively lose kidney function.8,9

Diet is an important consideration for those with impaired kidney function. Consultation with a dietician may be helpful to understand what foods may or may not be appropriate. Since the kidneys cannot easily remove excess water, salt, or potassium, they may need to be consumed in limited quantities. Foods high in potassium include bananas, apricots, and salt substitutes.10
Restrict dietary protein- Dietary protein is broken down into amino acids and absorbed from the stomach into the blood. The amino acids are taken from the bloodstream and used to build muscle and perform other essential functions. Excess amino acids are further broken down into carbohydrates and nitrogen-containing waste that is eliminated by the kidneys. Amino acid disposal further burdens the kidneys, and is believed to speed the progression of CRF. This process is like forcing a damaged machine to work harder, causing it to break down sooner than expected.3
Because dietary restrictions may reduce necessary vitamin intake, patients should take a multivitamin containing water-soluble vitamins. Administration of vitamin A and E is unnecessary. Vitamin D in the form of 1,25-dihydroxyvitamin D.3,8
K intake is closely related to meat, vegetable, and fruit ingestion and usually does not require adjustment. However, foods (especially salt substitutes) rich in K should generally be avoided. Identify and Treat Secondary Hyperparathyroidism With the loss of kidney function, phosphate accumulates in the blood. Excess phosphate in the blood reduces levels of blood calcium, and low blood calcium levels trigger the parathyroid gland (located in the neck) to release more parathyroid hormone (PTH). PTH then dissolves bone tissue to release stored calcium and raise the level of calcium in the blood. This chronic cycle of events is called secondary hyperthyroidism.
The net result of this condition is the development of metabolic bone disease (renal osteodystrophy).8
These patients are at risk for bone fractures, bone and muscle pain, which can sometimes be accompanied by severe itching, and cardiovascular complications. Severe itching is thought to be in part due to the elevated circulating PTH level itself.
Patients with secondary hyperthyroidism should limit their intake of foods that are high in phosphate.
Phosphate restriction to < 1 g/day is often sufficient to maintain phosphate level in the target range during the early phase of chronic kidney disease.
Replacement of erythropoietin and vitamin D3, two hormones processed by the kidney, is usually necessary in patients with chronic renal failure.3
Most patients who recieve a potent vitamin D supplement (e.g., calcitrol, hexitrol), which helps to suppress excess PTH production. The final metabolic step in the synthesis of vitamin D occurs normally in the kidney and there is often a deficiency of this vitamin in these patients.
Early preparation for renal replacement therapy is important. The health care team educates the patient about the different procedures involved in RRT, which include the following:
Hemodialysis – removal of toxic elements from the blood, which is filtered through a membrane while circulated outside of the body.3
Peritoneal dialysis- filtration through the lining membrane of the abdominal cavity; fluid is instilled into the peritoneal space, then drained.
While renal replacement therapies can maintain patients indefinitely and prolong life, the quality of life is severely affected. Renal transplantation increases the survival of patients with final stage of chronic renal failure significantly when compared to other therapeutic options. However, it is associated with an increased short-term mortality (due to complications of the surgery).Transplantation aside, high intensity home hemodialysis appears to be associated with improved survival and a greater quality of life, when compared to the conventional three times a week hemodialysis and peritoneal dialysis.
Kidney transplantation
Kidney transplantation is replacement of nonworking kidneys with a healthy kidney from another person (the donor).10
The healthy kidney takes over the functions of nonworking kidneys. Patient can live normally with only one kidney as long as it functions properly.
The transplantation itself is a surgical operations. The surgeon places the new kidney in the abdomen and attaches it to the artery that supplied blood to one of kidneys and to the vein that carries blood away from the kidney. The kidney is also attached to the ureter, which carries urine from the kidney to the bladder. Own kidneys are usually left in place unless they are causing problems, such as infection.10

INTRODUCTION

Alternate Names : Chronic Kidney Failure , Chronic Renal Insufficiency, CRF, Kidney Failure – Chronic, Renal Failure – ChronicChronic5 renal failure is a gradual and progressive loss of the ability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes.1,2
.

Chronic renal failure usually occurs over a number of years as the internal structures of the kidney are slowly damaged. In the early stages, there may be no symptoms. In fact, progression may be so gradual that symptoms do not occur until kidney function is less than one-tenth of normal.

Chronic renal failure and ESRD affect more than 2 out of 1,000 people in the United States. Diabetes and hypertension are the two commonest causes and account for approximately two thirds of the cases of chronic renal failure and ESRD. Other major causes include the following:4 Glomerulonephritis of any type (one of the most common causes)
• Polycystic kidney disease
• Alport syndrome
• Reflux nephropathy
• Obstructive uropathy
• Kidney stones and infection
• Analgesic nephropathy
Patients with end-stage renal disease (ESRD) are commonly encountered in the ED with problems related to the metabolic complications of their renal disease or dialysis complications. Various problems related to vascular access in patients on hemodialysis and to abdominal catheters in patients using continuous ambulatory peritoneal dialysis (CAPD) are also.4 Background
Chronic kidney disease (CKD) is a worldwide public health problem and is now recognized as a common condition that is associated with an increased risk of cardiovascular disease and chronic renal failure (CRF).6,7 The Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) defines chronic kidney disease as either kidney damage or a decreased kidney glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for 3 or more months. Whatever the underlying etiology, the destruction of renal mass with irreversible sclerosis and loss of nephrons leads to a progressive decline in GFR. The different stages of chronic kidney disease form a continuum in time; prior to February 2002, no uniform classification of the stages of chronic kidney disease existed. At that time, K/DOQI published a classification of the stages of chronic kidney disease, as follows:
• Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2)
• Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2)
• Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m2)
• Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2)
• Stage 5: Kidney failure (GFR <15 mL/min/1.73 m2 or dialysis)6,7
In stage 1 and stage 2 chronic kidney disease, GFR alone does not clinch the diagnosis. Other markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities in imaging tests, should also be present in establishing a diagnosis of stage 1 and stage 2 chronic kidney disease.
The K/DOQI definition and the classification of chronic kidney disease allow better communication and intervention at the different stages.6,7
Pathophysiology
All major organ systems are affected by renal failure. Prevalence of symptoms is a function of the glomerular filtration rate (GFR), which averages 120 mL/min in a healthy adult.3,4 As the GFR falls to less than approximately 20% of normal, symptoms of uremia may begin to occur. They almost are invariably present when the GFR decreases to less than 10% of normal. Measuring GFR requires a timed urine collection as well as measurement of serum creatinine. However, it can be accurately estimated from a patient's age, weight, gender, and serum creatinine level. Online calculators are available to automate the calculation 1,2,6
Signs and symptoms of renal failure are due to overt metabolic derangements resulting from inability of failed kidneys to regulate electrolyte, fluid, and acid-base balance; they are also due to accumulation of toxic products of amino acid metabolism in the serum. Signs and symptoms include the following:2,6
Systemic signs

Malaise, weakness, and fatigue are very common1,7,8,9 Gastrointestinal signs

GI disturbances include anorexia, nausea, vomiting, and hiccups. Peptic ulcer disease and symptomatic diverticular disease are common in patients with CRF.1,7,8 Neurological signs

Peripheral neuropathy and restless legs syndrome are the most common neurologic complications of CRF. Seizures may occur due to uremia, and the prevalence of stroke is increased.1,7,8 Hematologic signs

Anemia is inevitable in CRF because of loss of erythropoietin production. Abnormalities in white cell and platelet functions lead to increased susceptibility to infection and easy bruising1,.7,8
Dermatologic signs

Pruritus is a common dermatologic complication assumed to be secondary to accumulation of toxic pigments (urochromes) in the dermis.1,7,8
Metabolic/endocrine signs

Volume overload occurs when salt and water intake exceeds losses and excretion. This causes congestive heart failure (CHF) and exacerbates hypertension. Hyperkalemia is the most common immediately life-threatening metabolic complication of renal failure and may develop suddenly when GFR is severely reduced. Anion gap acidosis results from decreased hydrogen ion excretion and may exacerbate hyperkalemia. Hypocalcemia is potentially life threatening and results from loss of vitamin D and increased parathyroid hormone levels. Hypermagnesemia also may occur1,7,8

Cardiac signs

Volume overload may cause CHF and pulmonary edema. Hypertension contributes to cardiovascular disease. Dyslipidemia is a primary risk factor for cardiovascular disease and a common complication of ESRD. Uremia may also lead to pericardial effusion and, in rare cases, pericardial tamponade. Cardiovascular mortality is 10-20 times higher in dialysis patients than in the normal population.1,7,8

Vascular signs

Vascular access complications are similar to those seen in any patient with a vascular surgical procedure (eg, bleeding, local or disseminated intravascular infections, vessel [graft] occlusion).7
Dialysis catheters

A peritoneal dialysis catheter subjects patients to the risks of peritonitis and local infection. The catheter acts as a foreign body and provides a portal of entry for pathogens from the external environment.8
Infection/immunologic

Patients who have received renal transplants may experience recurrent renal failure due to rejection or other graft complications. In addition, chronic immunosuppression makes them prone to infection.
Mortality/Morbidity
Chronic kidney disease is a major cause of morbidity and mortality, particularly at the later stages. Although the diabetic population is at highest risk, in the United States, the general hemodialysis and peritoneal dialysis populations have 2 hospital admissions per patient per year; patients who have a renal transplant have an average of 1 hospital admission per year. The 5-year survival rate for a patient undergoing chronic dialysis in the United States is approximately 35%. This is approximately 25% in patients with diabetes. The most common cause of death in the dialysis population is cardiovascular disease.6

Among patients with ESRD aged 65 years and older, the mortality rates are 6 times higher than in the general population. In 2003, over 69,000 dialysis patients enrolled in the ESRD program died (annual adjusted mortality rate of 210.7 per 1000 patient-years at risk for the dialysis population, which represents a 14% decrease since peaking at 244.5 per 1000 patient-years in 1988). The highest mortality rate is within the first 6 months of initiating dialysis, which then tends to improve over the next 6 months, before increasing gradually over the next 4 years.
The mortality rates associated with hemodialysis are striking and indicate that the life expectancy of patients entering into hemodialysis is markedly shortened. At every age, patients with ESRD on dialysis have significantly increased mortality when compared with nondialysis patients and individuals without kidney disease. At age 60 years, a healthy person can expect to live for more than 20 years, whereas the life expectancy of a 60-year-old patient starting hemodialysis is closer to 4 years.1,6

Sex
Presentation and treatment of chronic renal failure (CRF) and end-stage renal disease (ESRD) do not differ significantly between men and women. Differences in causes of renal failure are related to the types of underlying conditions prevalent in men and women.6,8
Age
Chronic kidney disease is found in persons of all ages. The normal annual mean decline in the GFR with age from the peak GFR (approximately 120 mL/min/1.73 m2) attained during the third decade of life is approximately 1 mL/min/y/1.73 m2, reaching a mean value of 70 mL/min/1.73 m2 at age 70 years. Nonetheless, in the United States, the highest incidence rate of ESRD occurs in patients older than 65 years. As per NHANES III data, the prevalence of chronic kidney disease was 37.8% among patients older than 70 years. Besides diabetes mellitus and hypertension, age is an independent major predictor of chronic kidney disease. The geriatric population is the most rapidly growing kidney failure (chronic kidney disease stage 5) population in the United States.1,6
The biologic process of aging initiates various structural and functional changes within the kidney. Renal mass progressively declines with advancing age. Glomerulosclerosis leads to a decrease in renal weight. Histologic examination is notable for a decrease in glomerular number of as much as 30-50% by age 70 years.
Ischemic obsolescence of cortical glomeruli is predominant, with relative sparing of the renal medulla. Juxtamedullary glomeruli see a shunting of blood from the afferent to efferent arterioles, resulting in redistribution of blood flow favoring the renal medulla. These anatomical and functional changes in renal vasculature appear to contribute to an age-related decrease in renal blood flow. Renal hemodynamic measurements in aged human and animals suggest that altered functional response of the renal vasculature may be an underlying factor in diminished renal blood flow and increased filtration noted with progressive renal aging. The vasodilatory response is blunted in the elderly when compared to younger patients. However, the vasoconstrictor response to intrarenal angiotensin is identical in both young and older human subjects. A blunted vasodilatory capacity with appropriate vasoconstrictor response may indicate that the aged kidney is in a state of vasodilatation to compensate for the underlying sclerotic damage.
Given the histologic evidence for nephronal senescence with age, a decline in the GFR is expected. However, a wide variation in the rate of decline in the GFR is reported because of measurement methods, race, gender, genetic variance, and other risk factors for renal dysfunction. Because of these anatomical and physiological changes, elderly patients with chronic kidney disease may behave differently, in terms of progression and response to pharmacological treatment, than younger patients.6
Therefore, a serum creatinine value of 1.2 mg/dL in a 70-kg, 25-year-old man versus a 70-kg, 80-year-old man represents an eGFR of 74 mL/min/1.73m2 and 58 mL/min/1.73m2, respectively. What can appear as only mild renal impairment in a 70-kg, 80-year-old man with a pathologically elevated serum creatinine of 2 mg/dL actually represents severe renal impairment when the eGFR is calculated to be 32 mL/min/1.73m2. Therefore, an eGFR must be determined simply by using the Modification of Diet in Renal Disease (MDRD) equation (see Other Tests) in elderly people so that appropriate drug dosing adjustments can be made and nephrotoxins can be avoided in patients who have more extensive chronic kidney disease than would be suggested by the serum creatinine value alone.6

Clinical
History
Renal failure produces no symptoms early in the course of the disease. At this stage, symptoms of the underlying illness may bring the patient to medical attention and renal insufficiency is noted on laboratory testing.4,6
Chronic renal failure (CRF) potentially affects all organ systems. History for the presenting disorder is similar to that encountered when the same disorder exists in patients without renal failure.
The following presentations are seen frequently in CRF. Moreover, some problems are unique to patients with CRF/ESRD; many of these are related to treatments, such as dialysis or transplantation.
Electrolyte abnormalities include life-threatening hyperkalemia, which is usually asymptomatic.
Dilutional hyponatremia may cause mental status changes or seizures.
Hypocalcemia or hypermagnesemia may cause weakness and life-threatening dysrhythmias.4,6
• Neuromuscular irritability is seen with hypocalcemia and may present as tetany or paresthesia.
• Hypermagnesemia causes neuromuscular depression with weakness and loss of reflexes.
• Acidosis may present as shortness of breath due to the work of breathing from compensatory hyperpnea.
• Pericarditis and asymptomatic pericardial effusion are common in patients with ESRD. Cardiac tamponade may occur but is rare. Presentation of pericarditis and tamponade are typical, with pleuritic chest pain being the most common presentation.
• Tamponade presents as fatigue, weakness, syncope, or dyspnea.
• Hypotension is usually present, and, if advanced, frank shock and cardiovascular collapse occur.
• Hypotension with postural weakness or syncope may occur as a complication of fluid shifts from dialysis or from any other cause. Sepsis is a serious cause of hypotension.
• Myocardial ischemia or infarction is common in patients with ESRD; consider this diagnosis in hypotensive patients along with other conditions, such as GI bleeding.
• Dialysis dysequilibrium syndrome is a common neurologic complication seen in dialysis patients.
• Syndrome is characterized by weakness, dizziness, headache, and in severe cases, mental status changes. Diagnosis is one of exclusion.
• A prime characteristic of the syndrome is that it is nonfocal.
• Peritonitis is common in patients being treated with continuous ambulatory peritoneal dialysis (CAPD), occurring approximately once per patient year. Patients present with abdominal pain, which may be mild, or complain of a cloudy effluent. Fever often is absent.4,6
• Infection at the catheter exit site manifests as expected local pain, erythema, warmth, and/or fluctuance.
• Other abdominal conditions, such as appendicitis, pancreatitis, or diverticulitis, should be considered when patients present with abdominal pain, especially if signs and symptoms are localized.
• Vascular access problems include infections, which are usually manifest with typical signs and symptoms such as local pain, redness, warmth, or fluctuance. Fever may be present without local signs.
• Clotting of the vascular access presents as loss of normal bruit or thrill. There may be signs or symptoms of distal limb ischemia.
• Patients may present after dialysis or minor trauma with bleeding from their vascular access. Bleeding usually can be controlled with elevation and firm but nonocclusive pressure. In the immediate postdialysis period, protamine may be needed to reverse the effect of heparin (routinely used in dialysis to prevent clotting). Life-threatening bleeding may occur.4,6
Physical
• Chronic renal failure (CRF) produces no specific physical findings.
• Patients with an arteriovenous fistula or graft should have the site examined regularly. Abnormal findings include loss of palpable thrill, overlying erythema, or active bleeding from the incisional wound of a newly placed fistula or graft.
• Physical findings of chronic renal failure complications generally are those expected with the specific complication and do not differ from those encountered when the condition occurs in patients with normal renal function.
• Certain complications are very common in renal failure.
• CAPD-associated peritonitis
• Abdominal pain and tenderness usually are generalized and relatively mild.
• Localized pain and tenderness suggest a local process, such as incarcerated hernia or appendicitis.
• Severe generalized peritonitis may be due to a perforated viscus as in any other patient.
• Transplant-related problems: Pain and tenderness over a transplanted kidney may be due to infection (pyelonephritis), obstruction (stone or extrinsic compression), or graft rejection.
• Vascular access aneurysms or pseudoaneurysms : These present as localized swelling, which may be pulsatile, and are often chronic. A rapid increase in size may indicate active bleeding.1
Causes
Unlike acute renal failure, chronic renal failure slowly gets worse. It most often results from any disease that causes gradual loss of kidney function. It can range from mild dysfunction to severe kidney failure. The disease may lead to end-stage renal disease (ESRD).
Chronic renal failure usually occurs over a number of years as the internal structures of the kidney are slowly damaged. In the early stages, there may be no symptoms. In fact, progression may be so slow that symptoms do not occur until kidney function is less than one-tenth of normal.
Chronic renal failure and ESRD affect more than 2 out of 1,000 people in the United States. Diabetes and high blood pressure are the two most common causes and account for most cases. Other major causes include:
• Alport syndrome
• Analgesic nephropathy
• Glomerulonephritis of any type (one of the most common causes)
• Kidney stones and infection
• Obstructive uropathy
• Polycystic kidney disease
• Reflux nephropathy
Chronic renal failure results in an accumulation of fluid and waste products in the body, leading system are affected by chronic renal failure.1,4

Symptoms
Initial symptoms may include the following:
• Fatigue
• Frequent hiccups
• General ill feeling
• Generalized itching (pruritus)
• Headache
• Nausea, vomiting
• Unintentional weight loss
Later symptoms may include the following:
• Blood in the vomit or in stools
• Decreased alertness, including drowsiness,confusion, delirium, orcoma
• Decreased sensation in the hands, feet, or other areas
• Easy bruising or bleeding
• Increased or decreased urine output
• Muscle twitching or cramps
• Seizures
• White crystals in and on the skin (uremic frost)4,7
Additional symptoms that may be associated with this disease:
• Abnormally dark or light skin
• Agitation
• Breath odor
• Excessive nighttime urination
• Excessive thirst
• High blood pressure
• Loss of appetite
• Nail abnormalities
• Paleness 4
Exams and Tests
There may be mild to severe high blood pressure. A neurologic examination may show polyneuropathy. Abnormal heart or lung sounds may be heard with a stethoscope.4
A urinalysis may show protein or other abnormalities. An abnormal urinalysis may occur 6 months to 10 or more years before symptoms appear.4
• Creatinine levels progressively increase.
• BUN is progressively increased.
• Creatinine clearance progressively decreases.
• Potassium test may show elevated levels.
• Arterial blood gas and blood chemistry analysis may show metabolic acidosis.3,4
Signs of chronic renal failure, including both kidneys being smaller than normal, may be seen on:
• Abdominal CT scan
• Abdominal MRI
• Abdominal ultrasound
• X-rays of the kidneys and abdomen
This disease may also alter the results of the following tests:
• Erythropoietin
• PTH
• Renal scan
• Serum magnesium - test
• Urinary casts
Treatment
The goal of treatment is to control symptoms, reduce complications, and slow the progression of the disease.
Diseases that cause or result from chronic kidney failure must be controlled and treated as appropriate.
Blood transfusions or medications such as iron and erythropoietin supplements may be needed to control anemia.
Fluids may be restricted, often to an amount equal to the volume of urine produced. Restricting the amount of protein in the diet may slow the build up of wastes in the blood and control associated symptoms such as nausea and vomiting.
Salt, potassium, phosphorus, and other electrolytes may be restricted.
Dialysis or kidney transplant may eventually be needed.3,4,7 Prognosis
The prognosis of patients with chronic kidney disease is guarded as epidemiological data has shown that all cause mortality (the overall death rate) increases as kidney function decreases The leading cause of death in patients with chronic kidney disease is cardiovascular disease, regardless of whether there is progression to stage 5. fileWhile renal replacement therapies can maintain patients indefinitely and prolong life, the quality of life is severely affected.[13][14] Renal transplantation increases the survival of patients with stage 5 CKD significantly when compared to other therapeutic options; however, it is associated with an increased short-term mortality (due to complications of the surgery). Transplantation aside, high intensity home hemodialysis appears to be associated with improved survival and a greater quality of life, when compared to the conventional three times a week hemodialysis and peritoneal dialysis.3,4,7 Nutrition
Severe protein restriction in renal disease is controversial. However, moderate restriction (0.8 g/kg/day) is safe and easy for most patients to tolerate. Some experts recommend 0.6 g/kg/day for patients with diabetes and, for patients without diabetes, > 0.8 g/kg/day if GFR is 25 to 55 mL/min/1.73 m2 or 0.6 g/kg/day if GFR is 13 to 24 mL/min/1.73 m2. Many uremic symptoms markedly lessen when protein catabolism and urea generation are reduced. Sufficient carbohydrate and fat are given to meet energy requirements and prevent ketosis. Patients for whom < 0.8 g/kg/day has been prescribed should be closely followed by a dietician.
Because dietary restrictions may reduce necessary vitamin intake, patients should take a multivitamin containing water-soluble vitamins. Administration of vitamin A and E is unnecessary. Vitamin D in the form of 1,25-dihydroxyvitamin D ( calcitriol Some Trade Names
ROCALTROL
Click for Drug Monograph
) or its analogs should be given as indicated by PTH concentrations. Dose is determined by stage of chronic kidney disease, PTH concentration, and phosphate concentrations (see Table 6: Renal Failure: Target Levels for PTH and Phosphate in Chronic Kidney Disease ). Target levels for Ca are 8.4 to 9.5 mg/dL (2.10 to 2.37 mmol/L); for Ca-phosphate product, < 55 mg2/dL2. 9

Possible Complications
1. Anemia
2. Cardiac tamponade
3. Changes in blood sugar metabolism
4. Congestive heart failure
5. Decreased functioning of white blood cells
6. Decreased immune response
7. Decreased libido, impotence 10
8. Dementia
9. Electrolyte abnormalities including hyperkalemia
10. Encephalopathy
11. End-stage renal disease
12. Fractures
13. Hemorrhage
14. High blood pressure
15. Increased infections
16. Joint disorders
17. Liver inflammation (hepatitis B or hepatitis C)
18. Liver failure
19. Loss of blood from the gastrointestinal tract
20. Menstrual irregularities,mscarriage, infertility
21. Nerve damage
22. Pericarditis
23. Peripheral neuropathy
24. Platelet dysfunction
25. Ulcers
26. Seizures
27. Skin dryness, itching /scratching with resultant skin infection
28. Weakening of the bones10

DEFINITION
Bronchiolar carcinoma, alveolar cell carcinoma; a carcinoma, thought to be derived from epithelium of terminal bronchioles, in which the neoplastic tissue extends along the alveolar walls and grows in small masses within the alveoli; involvement may be uniformly diffuse and massive, or nodular, or lobular; microscopically, the neoplastic cells are cuboidal or columnar and form papillary structures; mucin may be demonstrated in some of the cells and in the material in the alveoli, which also includes denuded cells; metastases in regional lymph nodes, and even in more distant sites, are known to occur, but are infrequent1.

AETIOLOGY
Cigarette smoking is by far the important single factor in the causationof lung cancer.It is thought be directly responsible for at least 90% ofiung carcinomas, the risk being directly proportional to the amount of smoked and to the tar content of cigarettes. For example,the death rate from the disease in heavy smokers is 40 times that in non smokers.Risk falls slowly after smoking cessation, but remains above the risk in non smokers for many years. The effect of ‘passive’ smoking is more difficult to quantify but is currently believed to be a factor in 5% of all lung cancer deaths. Exposure naturally occurring radon is another known risk. The incidence of lung cancer is also slightly higher in urban than in rural dwellers; this may reflect differences in atmospheric pollution ( including tobacco smoke ) or occupation since number of industrial products (e.g. asbestos, beryllium , cadmium and chromium) are associated with lung cancer2.

RADIOGRAPHIC APPEARANCE
Carcinoma of the bronchus is so common and has such a variety of symptoms and signs that it should be considered in mist heavy smokers. Diagnosis is usually straightforward and the first important investigation is a chest X-ray. In a smoker, clubbing, haemoptysis, persistent chest infection or weight loss demand an immediate X-ray of the chest. A common radiological manifestation of bronchial carcinoma at presentation is a pleural effusion, usually of large volume, which rapidly re-accumulates following aspiration, is commonly blood- stained and often contains malignant cells. CT is useful for evaluating the infiltration, and construction of the lesion3.

PATHOLOGY OF BRONCHIAL CARCINOMA

Lung cancer refers to a group of neoplastic growths arising from the epithelium of the air passages or lung. Neoplasia is the word given to the process by which tumours form in animals. These neoplastic growths may be described crudely as benign or malignant depending on their likelihood to invade other structures and spread throughout the body. In this dissertation more time will be spent on malignant cancers, as they are both more common in the lungs, and more clinically important4.

There are several types of cancers affecting the lungs, they each have different aetiology (though smoking is a recurring factor in most), pathology, characteristic histological features, treatment regimes and prognosis. Understanding the processes by which these cancers develop and cause harm we can work to reduce the incidence of lung cancers and improve the prognosis of sufferers. Here I look at the major cancers, and those with the greatest clinical impact4.

Cancers of the lung mainly affect the bronchi and hence bronchial carcinoma is synonymous with carcinoma of the lung, however peripheral adenocarcinomas are increasing in incidence. Cancers of the lung generally share some common characteristics, these are discussed below and any deviations from this will be noted later under each type4.

Carcinomas commonly affect the upper lobes more frequently than lower and the right lung more than the left. They often present late, when local invasion and metastases are already present, this has encouraged the development of screening programs in an attempt to diagnose at an earlier stage4.

There are two ways that cancers can arise in lungs; they can be new, primary tumours arising in the lungs or metastases from distant sites4.

Primary Tumours

In this dissertation I will be concentrating on Primary Lung Tumours. Primary tumours of the lung can arise from the different tissues present such as epithelium, lymphatics, mesothelium and soft tissue, and diagnosis is based on the histological findings of biopsy seen by light microscopy. By far the most common, and exhibiting the greatest diversity are epithelial tumours. Mixed tumours exist and these are often classified according to the most predominant cell type found, it is likely that all lung cancers exhibit this to some extent. However this requires examination with electron microscopy, and yields little of clinical benefit.
Epithelial tumours consist of four principal types; squamous cell carcinoma, small cell carcinoma, large cell carcinoma and adenocarcinoma. Clinically the most important distinction is between small cell carcinomas and the others, grouped together as ‘non-small cell.’ This is because small cell cancers respond to chemotherapy, whereas non small cell tumours are removed surgically if possible4.

Small (Oat) cell carcinoma
Small (Oat) cell carcinoma accounts for about 20-30% of all lung cancers, these cells secrete a large amount of polypeptide hormones, thought to be as a result of their development from cells of the APUD system. This produces extra-pulmonary manifestations such as SIADH and ectopic adrenocorticotrophin syndrome. This form of lung cancer is responsive to chemotherapy. Under the microscope they form sheets of darkly staining cells with prominent nuclei and little cytoplasm, their secretory activity can be seen as the presence of neurosecretory granules in the cytoplasm seen by electron microscopy. This form is very strongly linked to smoking as a causative factor4.

Squamous cell carcinoma
Squamous cell carcinoma (epidermoid carcinoma) accounts for about 30 or 40% of primary lung tumours. They grow most commonly in the central areas in or around major bronchi. They grow in a stratified or pseudoductal arrangement, the cells have an epithelial pearl formation with individual cell keratinization. These tumours deposit keratin, and as they grow develop a necrotic, keratinous mass which appears cheesy on dissection. Widespread Metastases occur relatively late. Some results can be achieved if slow growing and treated with radiotherapy4.
As a tumour grows it secretes substances called tumour angiogenesis factors (TAF) which cause blood vessels to grow into the mass of tumour cells. This allows a tumour to grow more rapidly and increase in size. If the tumour grows too large for its blood supply then the central areas can become deprived of oxygen and nutrients and will undergo necrosis, they die. This is the process by which squamous cell carcinomas frequently develop into necrotic masses. Some work into the treatment of various cancers has looked at the possibility of suppressing or counteracting the effect of TAF in the hope that restricting the flow of blood to a tumour will restrict growth and spread4.

Adenocarcinoma

Adenocarcinomas arise peripherally from mucous glands and the cells retain some of the tubular, acinar or papillary differentiation and mucus production. They commonly invade pleura and mediastinal lymph nodes and often metastasise to the brain and bones. They bear similarity to secondary tumours and must be distinguished by CT scans and other investigations to check for presence of a primary. Adenocarcinoma commonly arises around scar tissue and is also associated with asbestos exposure. One form of adenocarcinoma is often distinguished from others, bronchiolo-alveolar carcinoma, these characteristically have well differentiated ‘bland’ cells which grow along alveolar ducts. Adenocarcinomas are proportionally less common in non-smokers4.
Large cell carcinoma
Large cell carcinoma metastasises early and may simply be considered to be those cancers which do not fit into the categories above. Close study by electron microscopy indicates that these types can probably be included with squamous or adenocarcinomas4.

Mesotheliomas

Tumours arising from the mesothelium, mesotheliomas, were only well recognised about 25 years ago. The tumour grows over serosal surfaces, and interlobar fissures. The cells are epithelial and spindle types and occur in differing ratios, mitosis is infrequently seen. A common complication of mesothelioma is pleural effusion, particularly recurrent effusion, and it may present as such. Distinction between benign and malignant effusions is difficult. Evidence relating this form of lung cancer to asbestos exposure (particularly crocidolite) has lead to several industrial court cases. There appears to be a latent period of between twenty and forty years between exposure and diagnosis4.

Secondery Tumours

Secondary tumours of the lung are very common, usually affecting the parenchyma, and often arise from primary tumours in; kidney, prostate, breast, bone, gastrointestinal tract, cervix or ovary. These usually present as round shadows of about 1.5-3 cm diameter on chest X-rays, in patients previously diagnosed with the primary. Sometimes, they can present in undiagnosed asymptomatic patients, and the primary found later on CT scans or other investigations4.

TUMOUR FORMATIONT

Tumours arise via a process of carcinogenesis, the most accepted model for this process is the multistage model. Carcinogenic agents affect DNA by several molecular mechanisms, generally they form electrophilic intermediates that bind to DNA causing mispairing or base substitutions during DNA synthesis. It has been demonstrated that in lung cancer large areas ‘fields’ of genetic mutations are found throughout the lung, even when no histological abnormality is seen4.

The first step is when carcinogenic agents mutate DNA to give altered gene expression (initiation). The altered gene expression leads to ‘promotion,’ an initiated cell undergoes clonal expansion to form a preneoplastic lesion. Should this lesion undergo further genetic change (conversion) a malignant tumour develops. The changes that lead to tumour formation occur in the genetic material that is responsible for regulating cell growth and differentiation. Proto-oncogenes and tumour suppressor genes play an important role in the multistage model of carcinogenesis. Proto-oncogenes are important to the regulatory mechanisms of growth, cell-cycle control, programmed cell death and terminal differentiation. It has been demonstrated that activation of the ras proto-oncogenes leads to tumour formation, angiogenesis and metastasis. It is thought that K-ras activation is particularly important in the development of adenocarcinomas of the lung4.Tumour suppressor genes code for products that enhance neoplastic activity when mutated. The most commonly altered tumour suppressor gene is the p53 gene found on chromosome 17 , it codes for a phosphoprotein involved in the control of cell proliferation and loss of function can be caused by single base substitutions. It is found to be mutated in 90% of Small Cell lung cancer and 50% of Non Small Cell lung cancer4.

CLINICAL SYMPTOMS IN BRONCHIAL CARCINOMA
The frequencies of the common symptoms of lung cancer on presenstation are described below.
Pain and discomfort are often described as fullness and pressure in the chest. Sometimes
the pain may be pleuritic owing to invasion of the pleura or ribs. Commonly there are no abnormal physical signs. Enlarged supraclavicular lymph nodes are frequently found with small cell carcinoma5. There may be signs of a pleural effusion or of lobar collapse. Signs of an unresolved pneumonia or of associated underlying disease (eg, diffuse pulmonary fibrosis in asbestos) may be present5.

Symptoms due to tumour in the bronchus:

Cough:
This is the most common early symptom. Sputum is purulent if there is secondary bacterial infection. The bronchial carcinoma itself does not produce sputum, but patients often have associated chronic bronchitis which is also caused by cigarette smoking5.

Haemoptysis:
This is a common symptom of carcinomas arising in large central bronchi but is less frequent in the peripheral tumours. Repeated slight Haemoptysis is a common and characteristic feature. Centrally situated tumours can invade large pulmonary vessels causing massive Haemoptysis, which is often fatal5.

Breathlessness:
This may occur early when the tumour obstructs a large bronchus resulting in collapse of a lobe or lung. The large pleural effusion may also cause breathlessness of rapid onset5.

Stridor:
The noise heard on breathing on when the trachea or larynx is obstructed.It tends to be louder & harsher than wheezing. This develops when spread of the tumour to the subcarinal and paratracheal glands causes compression of the main bronchi and lower end of trachea.Bronchial obstruction often causes distal infection because there is interference with bronchial drainage. This permits the development of pneumonia which may either be slow to respond to treatment or recurs at the same site. A lung abscess can develop in the infected lung distal to a bronchial tumour5.

DIRECT SPREAD OF BRONCHIAL CARCINOMA

The tumour may directly involve the pleura and ribs. Carcinoma in the apex of the lung can erode the ribs and in volve the lower part of the brachial plexus(C8, T1 and T2), causing severe pain in the shoulder and down the inner surface of the arm (Pancoast’s tumour)5.
The sympathetic ganglion may also be involved, producing Horner’s syndrome. Further extension may involve the recurrent laryngeal nerve as it passes down the aortic arch, causing unilateral vocal cord paresis with hoarseness and a bovine cough, and rarely the tumour may cause spinal cord compression5.
Bronchial carcinoma can also directly invade the phrenic nerve, causing paralysis of the diaphragm. It can involve the oesophagus, producing progressive dysphagia, and the pericardium, producing pericardial effusion and malignant dysrhynthmias5. It can also involve the superior vena cava, producing superior vena caval obstruction leading to early morning headache, facial congestion and oedema involving the upper limbs, the jugular veins are distended as the veins on the chest that form a collateral circulation with veins arising from the abdomen5.

INVESTIGATIONS
CXR
tumour mass needs to be 1-2 cm to be recognized reliably, however, 90% are detectable at clinical presentation 70% arise in hilar region the rest arise peripherally, especially adenocarcinomas round shadows with fluffy or spiked edges may cause collapse of the lung may show secondary pneumonia at presentation may be involvement of hilar nodes on affected side may be large pleural effusion6.

Investigations Bloods
FBC – detection of anaemia6.

CT
useful for identifying mediastinal pathology – enlarged lymph nodes, local spread of tumour, secondary spread to opposite lung a normal CT scan before surgery excludes the need for mediastinoscopy and lymph node biopsy. also CT of liver, adrenal glands and brain to identify distant metastases6.

MRI
used in staging.

Fibreoptic bronchoscopy
for cytological specimens and biopsies of any tumours seen tumours involving the first 2 cm of either main bronchus are inoperable widening of angle of carina indicates enlarged mediastinal lymph nodes, which can be biopsied through the bronchial wall, left vocal cord paresis demonstrates involvement of the recurrent laryngeal nerve and inoperability6

MANAGEMNT / TREATMENTS
Surgery
Gross appearance of the cut surface of a pneumonectomy specimen containing a lung cancer, here a squamous cell carcinoma (the whitish tumor near the bronchi).If investigations confirm lung cancer, CT scan and often positron emission tomography (PET) are used to determine whether the disease is localized and amenable to surgery or whether it has spread to the point where it cannot be cured surgically7.

Blood tests and spirometry are also necessary to assess whether the patient is well enough to be operated on. If spirometry reveals poor respiratory reserve (often due to chronic obstructive pulmonary disease), surgery may be contraindicated7.

Surgery itself has an operative death rate of about 4.4%, depending on the patient’s lung function and other risk factors.Surgery is usually only an option in non-small cell lung carcinoma limited to one lung, up to stage IIIA. This is assessed with medical imaging . A sufficient preoperative respiratory reserve must be present to allow adequate lung function after the tissue is removed7.

Procedures include wedge resection (removal of part of a lobe), segmentectomy (removal of an anatomic division of a particular lobe of the lung), lobectomy (one lobe), bilobectomy (two lobes), or pneumonectomy (whole lung). In patients with adequate respiratory reserve, lobectomy is the preferred option, as this minimizes the chance of local recurrence. If the patient does not have enough functional lung for this, wedge resection may be performed. Radioactive iodine brachytherapy at the margins of wedge excision may reduce recurrence to that of lobectomy7.

Radiation therapy
High dose radiotherapy can have similar results to surgery in fit patients with slow-growing squamous carcinoma. CHART may be of use in small-cell carcinoma radiation pneumonitis develops in 10-15%; radiation fibrosis occurs to some extent in all cases6.
Bone pain, haemoptysis and SVC obstruction may respond to radiotherapy in the short term6.

Chemotherapy
Single and combination chemotherapy have increased mean survival in small cell carcinoma to 10 months. Mitomycin, Isofosfamide, Cisplatin combination gives good results.Some patients go into remkission for several years. Response rates in non-small cell carcinoma exceed 20% with e.g. gemcitabine, cisplatin
Adjuvant chemotherapy with radiotherapy increases survival.Adjuvant chometherapy increases the number of previously inoperable patients who can undergo surgery and increases survival6.

Insulin potentiation therapy (IPT)
is an alternative medicine pharmacologic strategy for the chemotherapy of cancer using insulin and low-dose chemotherapy. Whilst formal studies were recognized as being required back in 1986, no conventionally recognized study has been published in the subsequent 20 years8.
The therapeutic approach is said to take advantage of the endogenous molecular biology of cancer cells, specifically insulin and insulin like growth factor secretion, and the interaction of these biochemicals with their specific receptors. By using insulin in conjunction with chemotherapy drugs, significantly less drug (about 10-15 % of a standard dose) can be targeted more specifically and more effectively to cancer cell populations, thus virtually eliminating dose-related side effects while claiming enhancing antineoplastic effects8.

Palliation
laser therapy, endobronchial irradiation, tracheobronchial stents6.

Terminal care
Prednisolone 15 mg can improve appetite.Morphine or diamorphine for pain; sustained release preparations or regular. Elixirs/injections, continuous release pumps; laxatives for constipation6.

BRONCHIAL CARCINOMA- CAUSES & PREVENTION

Smoking
This is the commonest cancer in males and second commonest cancer in females after breast cancer. It is also the most preventable cancer as over 90% is directly related to cigarette smoking. For practical purposes lung cancer can be divided into small cell lung cancer, comprising about 20 percent and non-small cell lung cancer, comprising 80 percent9.
Mortality rates worldwide are highest in Scotland, closely followed by England and Wales. In the UK, 35000 people die each year from bronchial carcinoma, with a male to female ration . Although the rising mortality from this disease has leveled off in men, it continues to rise in women, accounting for 1 in 8 of all deaths from malignant disease in women, second only to carcinoma of the breast. The strength of the association between cigarette smoking and bronchial carcinoma overshadows any other aetiological factors but there is a higher incidence of bronchial carcinoma in urban compared with rural areas, even when allowance is made for cigarette smoking9.
Passive smoking (the inhalation of other people’s smoke by non smokers) increases the risk of bronchial carcinoma by a factor of 1.5. Occupational factors include exposure to asbestos, and an association is also claimed for workers in contact with arsenic, chromium, iron oxide, petroleum products and oils, coal tar, products of coal combustion and radiation9.

Tumours associated with occupational factors are mostly adenocarcinomas and appear to be less related to cigarette smoking. Bronchial carcinoma accounts for more than 50 percent of all male deaths from malignant disease. It is more common in men than women although the gap between the sexes is now narrowing and occurs most frequently between the ages of 50 and 75 years. Cigarette smoking is responsible for most cases of bronchial carcinoma and the increased risk is directly proportional to the amount smoked and to the tar content of the cigarettes. For example the death rate from the disease in heavy cigarette smokers ins 40 times that in non smokers. The incidence is slightly higher in urban than in rural dwellers presumably because of atmospheric pollution9.

Asbestos
There is a higher incidence of bronchial carcinoma in pulmonary fibrosis induced by the inhalation of asbestos. This is an uncommon tumour occurring in a younger age group than carcinoma and affecting equally females and males9.

Radon gas
Radon is a colorless and odorless gas generated by the breakdown of radioactive radium, which in turn is the decay product of uranium, found in the Earth’s crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous. Radon exposure is the second major cause of lung cancer, after smoking. Radon gas levels vary by locality and the composition of the underlying soil and rocks. For example, in areas such as Cornwall in the UK , radon gas is a major problem, and buildings have to be force-ventilated with fans to lower radon gas concentrations. The United States Environmental Protection Agency (EPA) estimates that one in 15 homes in the U.S. has radon levels above the recommended guideline of 4 picocuries per liter (pCi/L) (148 Bq/m³) Iowa has the highest average radon concentration in the United States; studies performed there have demonstrated a 50% increased lung cancer risk, with prolonged radon exposure above the EPA’s action level of 4 pCi/L7.

Genetics
Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes. Oncogenes are genes that are believed to make people more susceptible to cancer. Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens. Mutations in the K-ras proto-oncogene are responsible for 10–30% of lung adenocarcinomas. The epidermal growth factor receptor (EGFR) regulates cell proliferation, apoptosis, angiogenesis, and tumor invasion.Mutations and amplification of EGFR are common in non-small cell lung cancer and provide the basis for treatment with EGFR-inhibitors. Her2/neu is affected less frequently. Chromosomal damage can lead to loss of heterozygosity. This can cause inactivation of tumor suppressor genes. Damage to chromosomes 3p, 5q, 13q, and 17p are particularly common in small cell lung carcinoma. The tumor suppressor gene, located on chromosome 17p, is affected in 60-75% of cases. Other genes that are often mutated or amplified are c-MET, NKX2-1, LKB1, PIK3CA, and BRAF7.

Several genetic polymorphisms are associated with lung cancer. These include polymorphisms in genes coding for interleukin-1, cytochrome , apoptosis promoters such as caspase-8, and DNA repair molecules such as XRCC1. People with these polymorphisms are more likely to develop lung cancer after exposure to carcinogens.A recent study suggested that the MDM2 309G allele is a low-penetrant risk factor for developing lung cancer in Asians7.

BRONCHORRHEA

Bronchorrhea is the production of more than 100 mL per day of watery sputum.[Chronic bronchitis is a common cause, but it may also be caused by asthma, pulmonary contusion, bronchiectasis, tuberculosis, cancer, scorpion stings, and poisoning by organophosphates and other poisons. Massive bronchorrhea may occur in either bronchioloalveolar cancer, or in metastatic cancer that is growing in a bronchioloalveolar pattern10.

Lung cancer is a disease of uncontrolled cell growth in tissues of the lung. This growth may lead to metastasis, which is the invasion of adjacent tissue and infiltration beyond the lungs. The vast majority of primary lung cancers are carcinomas of the lung, derived from epithelial cells. Lung cancer, the most common cause of cancer-related death in men and the second most common in women (after breast cancer), is responsible for 1.3 million deaths worldwide annually. The most common symptoms are shortness of breath, coughing (including coughing up blood), and weight loss.
The main types of lung cancer are small cell lung carcinoma and non-small cell lung carcinoma1. This distinction is important, because the treatment varies; non-small cell lung carcinoma (NSCLC) is sometimes treated with surgery, while small cell lung carcinoma (SCLC) usually responds better to chemotherapy and radiation.The most common cause of lung cancer is long-term exposure to tobacco smoke1. The occurrence of lung cancer in nonsmokers, who account for as many as 15% of cases, is often attributed to a combination of genetic factors, radon gas, asbestos, and air pollution, including secondhand smoke.

Definition
Bronchiolar carcinoma, alveolar cell carcinoma; a carcinoma, thought to be derived from epithelium of terminal bronchioles, in which the neoplastic tissue extends along the alveolar walls and grows in small masses within the alveoli; involvement may be uniformly diffuse and massive, or nodular, or lobular; microscopically, the neoplastic cells are cuboidal or columnar and form papillary structures; mucin may be demonstrated in some of the cells and in the material in the alveoli, which also includes denuded cells; metastases in regional lymph nodes, and even in more distant sites, are known to occur, but are infrequent1.

Classifiation

Non- small cell carcinoma
Squamous or epidermoid carcinoma is the commonesr type, accounting for approximately 40% of all carcinomas. Most present as obstructive lesions of the bronchus leading to infection. It occasionally cavitates(10%) at presentation3. The cells are usually well differentiated, but occasionally anaplastic. Local spread is common but wide spread occur relatively late.

Adenocarcinoma arises from the mucus cells in bronchial epithelium. Invasion of the plurae and the mediastinal lymph nodes is common, as are metastases to the bone and brain. Adenocarcinoma accounts for approximately 10% of bronchial carcinomas3. It is the most common bronchial carcinoma associated with asbestos and is proportionally most common in non-smokers, in women, in the elderly, and in the far East.

Large cell carcinomas are less differentiated forms of squamous cell and Adenocarcinomas. These account for about 25% of the lung cancers and metastasize early4.

Bronchoalveolar cell carcinomas account for only 1- 2 % of lung tumours and occur either as a peripheral solitary nodules or as diffuse nodular lesions of multicentric origns. Occasionally this tumour is associated with expectoration of very large volumes of mucoid sputum.

Small cell carcinoma
This tumour is often called Oat cell Carcinoma, accounts for 20-30% of lung cancers. It arises from endocrine cells (Kulchitsky cells) 2. These cells are members of APUD system, which explains why many polypeptide hormones are secreted by these tumours2. Some of these polypeptides act in an autocrine fashion. They feed back on the cell and cause cell growth. Small cell carcinomas spread early and almost always is inoperable at presentation3. The tumour is rapidly growing and highly malignant. It respronds to chemotherapy but the prognosis remains poor.
Others
In infants and children, the most common primary lung cancers are pleuropulmonary blastoma and carcinoid tumor.
Secondary cancers
The lung is a common place for metastasis from tumors in other parts of the body. These secondary cancers are identified by the site of origin; thus, a breast cancer metastasis to the lung is still known as breast cancer. They often have a characteristic round appearance on chest radiograph. In children, the majority of lung cancers are secondary5.
Primary lung cancers themselves most commonly metastasize to the adrenal glands, liver, brain, and bone.
Staging
Lung cancer staging is an assessment of the degree of spread of the cancer from its original source. It is an important factor affecting the prognosis and potential treatment of lung cancer. Non-small cell lung carcinoma is staged from IA (“one A”; best prognosis) to IV (“four”; worst prognosis). Small cell lung carcinoma is classified as limited stage if it is confined to one half of the chest and within the scope of a single radiotherapy field; otherwise, it is extensive stage6.
Signs and symptoms
Lung cancer presents in many different ways but most commonly symptoms reflect local involvement of the bronchus,but may also arise from spread to the chest wall or mediastinum, from distant blood borne spread, or less commonly as result of a variety of non-metastatic paraneoplastic syndromes.

• dyspnea (shortness of breath)
• hemoptysis (coughing up blood)
• chronic coughing or change in regular coughing pattern
• wheezing
• chest pain or pain in the abdomen
• cachexia (weight loss), fatigue, and loss of appetite
• dysphonia (hoarse voice)
• clubbing of the fingernails (uncommon)
• dysphagia (difficulty swallowing).

Cough is the most common early symptom,it is often dry but sputum may be purulent if there is secondary infection. A change in the character of the regular cough of a smoker particularly if it is associated with other new respiratory symptoms, should always alert the clinician to the possibility of bronchial carcinoma.

Hemoptysis is a common symptom specially in central tumours arising in the central bronchi. Occasionally tumours invade large vessels, causing massively hemoptysis which may be fatal1.

Bronchial obstruction is a common presentation and the clinical and radiological manifestations. and depend on the site of the obstruction whether the obsrtuctionis complete or partial2. The presence or absence of secondary infections, and the extend of preexisting lung disease. Bronchial obstruction may lead Pneumonia which is often the first clinical manifestation of bronchial carcinoma, even when the degree of obstruction is insuffitient to cause collapse.

Breathlessness may reflect occlusion of a large bronchus, resulting in collapse of a lobe or lung or the development of a large pleural effusion1.

The tumor may directly involve the pleurae and the ribs. Carcinoma in the apex of the lung can erode the ribs and involve the lower part of the brachial plexus causing severe pain in the shoulder and down the inner surface of the arm (pancoast tumors).the sympathetic ganglion can also be involved, producing Horner’s syndrome. Hilar tumors may involve the recurrent laryngeal nerve, causing unilateral vocal cord paresis, with hoarseness and bovine cough7.
Bronchial carcinoma can also directly invade the phrenic nerve, causing paralysis of the ipsilateral hemi diaphragm. It can involve the oesophagus, producing progressive dysphagia, and the pericardium, causing pericardial effusion and malignant dysrhythmias.
Radiographic Appearance
Carcinoma of the bronchus is so common and has such a variety of symptoms and signs that it should be considered in mist heavy smokers9. Diagnosis is usually straightforward and the first important investigation is a chest X-ray. In a smoker, clubbing, haemoptysis, persistent chest infection or weight loss demand an immediate X-ray of the chest.
A common radiological manifestation of bronchial carcinoma at presentation is a pleural effusion, usually of large volume, which rapidly re-accumulates following aspiration, is commonly blood- stained and often contains malignant cells.
CT is useful for evaluating the infiltration, and construction of the lesion.

PA Chest radiograph and corresponding CT of a bronchial carcinoma9

Aetiology

Atmosheric pollution and industrial exposure to dusts, particularly asbestos, increase the incidence of lung cancer, but the dominant causative agent is tobacco smoke, which is responsible for 90% of cases. The disease is unusual in non- smokers and the increased incidence in smokers is related to the number of cigarettes consumed. Passive smoking causes lung cancer in non-smokers.
Cigarette smoking is by far the most important single factor in the causation of lung cancer. It is thought to be directly responsible for atleast 90% of lung carcinomas, the risk being directly proportional to the amount smoked and to the tar content of cigarettes. For example ,the death rate from the disease in heavy smokers is 40 times that in non-smokers10.
In a 20-year prospective study on British doctors, smoking habits were ascertained by questionnaire and lung cancer incidence was monitored. Among cigarette smokers who started smoking at ages 16-25 and who smoked 40 or less per day, the annual lung cancer incidence in the age range 40-79 was:0.273X10(-12). (cigarettes/day+6)2. (age–22.5)4.5. The form of the dependence on dose in this relationship is subject not only to random error but also to serious systematic biases

The incidence of lung cancer is also slightly higher in urban than in rural dwellers,thismay reflect difference in atmospheric pollution(including tobacco smoke).

other environmental causes of respiratory cancer deserve attention however because they are potentially preventable and because they can pose a high risk to certain small groups of people, notably in relation to work exposures. Thirdly, they may synergise with tobacco smoking in raising the lung cancer risk11.
Physical factors, mainly radiation, are the first to be considered. Lung cancer is not an important consequence of external radiation as such. However, inhalation of alpha particle emitters can carry a very high risk9. Thus, workers in the nuclear industry are classical occupational examples. For the community at large, the biggest concerns arise from inhalation of radon gas (and the closely related to thoron). Typically these arise from uranium bearing feldspars from some forms of pink granite of igneous origin but might arise in other circumstances as well11. The gases decay to so-called “daughters” and it is these isotopes which release alpha particles in the lung. The national average radon activity in houses in the UK is 20 becquerels per cubic metre and this is associated with the life-time risk of lung cancer of 1 in 30010. At the “action level” which is 10 times this national average (ie 200 becquerels per cubic metre), the life-time risk of lung cancer is similarly increased 10 fold (1 in 30). It is possible to measure exposures through appropriate dosemeters and to reduce the risk by adaptation of building techniques to prevent radon gas rising through the ground into the house.
The single most important occupational “chemical” cause is asbestos. There is evidence that because of the long latency of mesothelioma of the pleura (up to 40 years or so) the UK has not yet experienced its peak incidence of these cases11. A similar rising incidence might be expected in other countries with comparable exposure patterns in the last few decades. While a histolological picture of mesothelioma of the pleura peritoneum can fairly confidently be clinically attributed to asbestos exposure, the same is not true of bronchogenic carcinoma. In most of these cases since the subject gives a history of smoking, this is clinically assumed to be the cause. In round figures, smokers may have a 10 fold risk of bronchogenic carcinoma when compared to non-smokers5. If they have had a heavy occupational asbestos exposure this risk may rise to fifty-fold. Indeed the epidemiologic evidence suggests that to the order of twice as many cases of bronchogenic carcinoma are caused by asbestos as cases of mesothelioma from the same exposure.
Many other respiratory cancers have got occupational causes. Indeed estimates suggest that, depending on the exposures and how they are assessed, anything between 0.6 and 40% of lung cancers in occupational populations may be attributed to their work11. Thus exposure to hard wood dusts and to certain compounds of nickel in its refining are associated with high risks of adeno-carcinoma and of squamous carcinoma respectively of the paranasal sinuses. Other occupational causes include mustard gas and some other organic compounds such as bis (chloromethyl) ether7. Certain compounds of nickel, chromium and arsenic have also been important causes of occupational lung cancer, as have polycyclic aromatic hydrocarbons. This raises the question as to whether or not polycyclic aromatic hydrocarbons or other pollutants would explain the clear urban/rural gradient in the incidence of lung cancer11. Epidemiologic studies are divided on this issue since smoking and other social factors might not necessarily explain all the difference.
Pathogenesis
Tumours arise via a process of carcinogenesis, the most accepted model for this process is the multistage model13. Carcinogenic agents affect DNA by several molecular mechanisms, generally they form electrophilic intermediates that bind to DNA causing mispairing or base substitutions during DNA synthesis15. It has been demonstrated that in lung cancer large areas ‘fields’ of genetic mutations are found throughout the lung, even when no histological abnormality is seen.
The first step is when carcinogenic agents mutate DNA to give altered gene expression (initiation). The altered gene expression leads to ‘promotion,’ an initiated cell undergoes clonal expansion to form a preneoplastic lesion12. Should this lesion undergo further genetic change (conversion) a malignant tumour develops. The changes that lead to tumour formation occur in the genetic material that is responsible for regulating cell growth and differentiation. Proto-oncogenes and tumour suppressor genes play an important role in the multistage model of carcinogenesis16. Proto-oncogenes are important to the regulatory mechanisms of growth, cell-cycle control, programmed cell death and terminal differentiation. It has been demonstrated that activation of the ras proto-oncogenes leads to tumour formation,angiogenesis and metastasis19.It is thought that K-ras activation is particularly important in the development of adenocarcinomas of the lung.
Tumour suppressor genes code for products that enhance neoplastic activity when mutated17. The most commonly altered tumour suppressor gene is the p53 gene found on chromosome 17 ,it codes for a phosphoprotein involved in the control of cell proliferation and loss of function can be caused by single base substitutions. It is found to be mutated in 90% of Small Cell lung cancer and 50% of Non Small Cell lung cancer.

Diagnosis
The main aims of investigations is to confirm the diagnosis,establish the histological cell type and define the extent of the disease.
Chest x-rays
By the time the lung cancer is causing symptoms, it will almost always be visible in chest x-rays. Asymptomatic tumors may be seen on chest x-rays if they are more than 1cm in diameter. Lateral views are useful to assess the hilum and mases behind the heart.CT scanning will detect smaller masses.
A minority of tumors are confined to the central airways and mediastinum without obvious change in the plain chest xray. About 70% of all primary lung cancers present with a mass, including virtually all small cell lung cancers and most squamous cell carcinomas18. Adenocarcinomas occur more often in the periphery than the other cell types.
The common radiological features of bronchial carcinoma are illustrated below.
Common radiological presentations of bronchial carcinoma

Carcinoma causing partial obstruction of a bronchus interrupt the muco-cillary escalator, and bacteria are retained in the affected lobe2. This gives rise to the so called 2ndary pneumonia that is commonly seen on the chest x-ray.
Computed Tomography (CT scan)
CT is useful for identifying disease in the mediastinum, such as enlarged lymph nodes or local spread of the tumor and for identifying secondary spread of carcinoma to the opposite lung by detecting masses too small to be seen on the chest x-ray2. CT is a poor guide to whether nodes are involved by tumor but a normal CT scan prior to surgery excludes the need to mediastinoscopy and node biopsy.CT scanning should include the liver adrenal glands and the brain as these are common sites for metastases.
Other imaging modalities
MRI is not useful for the diagnosis of primary lung tumors1. PET scanning now the investigation of choice for the assessment of the mediastinum.
Fibreoptic broncoscopy
This technique is used to define the bronchial anatomy and to obtain biopsy and cytological specimens.
Percutaneous aspiration and biopsy
Peripheral lung lesions cannot be seened by fibreoptic bronchoscopy and samples may be obtained by direct aspiration or biopsy through the chest wall under the appropriate x-ray or CT screening20.

Abnormal findings in cells (“atypia”) in sputum are associated with an increased risk of lung cancer. Sputum cytological examination combined with other screening examinations may have a role in the early detection of lung cancer.

Prevention
Prevention is the most cost-effective means of fighting lung cancer. While in most countries industrial and domestic carcinogens have been identified and banned, tobacco smoking is still widespread. Eliminating tobacco smoking is a primary goal in the prevention of lung cancer, and smoking cessation is an important preventative tool in this process21. Most importantly, are prevention programs that target the young. In 1998 the Master Settlement Agreement entitled 46 states in the USA to an annual payout from the tobacco companies. Between the settlement money and tobacco taxes, each state’s public health department funds their prevention programs, although none of the states are living up to the Center for Disease Control’s recommended amount by spending 15 percent of tobacco taxes and settlement revenues on these prevention efforts21.
Policy interventions to decrease passive smoking in public areas such as restaurants and workplaces have become more common in many Western countries, with California taking a lead in banning smoking in public establishments in 199821. Ireland played a similar role in Europe in 2004, followed by Italy and Norway in 2005, Scotland as well as several others in 2006, England in 2007, France in 2008 and Turkey in 200923. New Zealand has banned smoking in public places as of 2004. The state of Bhutan has had a complete smoking ban since 2005. In many countries, pressure groups are campaigning for similar bans. In 2007, Chandigarh became the first city in India to become smoke-free22. India introduced a total ban on smoking at public places on Oct 2 2008.
Arguments cited against such bans are criminalization of smoking, increased risk of smuggling, and the risk that such a ban cannot be enforced.
The long-term use of supplemental multivitamins—such as vitamin C, vitamin E, and folate—does not reduce the risk of lung cancer25. Indeed long-term intake of high doses of vitamin E supplements may even increase the risk of lung cancer.
The World Health Organization has called for governments to institute a total ban on tobacco advertising in order to prevent young people from taking up smoking23. They assess that such bans have reduced tobacco consumption by 16% where already instituted.

Treatment
Surgical resection carries the best hope of long term survival, however, some patients treated with radical radiotherapy also achieve prolonged remission or cure22. Unfortunately, in the majority of cases surgery is not possible or is inappropriate due to extensive spread or core morbidity, and such patients can only be offered palliative therapy21. Radiotherapy and in some cases chemotherapy, can relieve distressing symptoms.
Surgical treatment
Careful staging and assessment of the patients respiratory reserve and cardiac status are essential perquisites to surgery24. This coupled with improvements in surgical and post-operative care, now offers 5 year survival rates of over 75% instage 1 disease and 55% in stage 2 disease, which includes resection in patients with ipsilateral peri bronchial or hilar node involvement.
Radiotherapy
Radiotherapy is often given together with chemotherapy, and may be used with curative intent in patients with non-small cell lung carcinoma who are not eligible for surgery25. This form of high intensity radiotherapy is called radical radiotherapy. A refinement of this technique is continuous hyperfractionated accelerated radiotherapy (CHART), in which a high dose of radiotherapy is given in a short time period. For small cell lung carcinoma cases that are potentially curable, chest radiation is often recommended in addition to chemotherapy23. The use of adjuvant thoracic radiotherapy following curative intent surgery for non-small cell lung carcinoma is not well established and is controversial. Benefits, if any, may only be limited to those in whom the tumor has spread to the mediastinal lymph nodes.
For both non-small cell lung carcinoma and small cell lung carcinoma patients, smaller doses of radiation to the chest may be used for symptom control (palliative radiotherapy). Unlike other treatments, it is possible to deliver palliative radiotherapy without confirming the histological diagnosis of lung cancer26.

Chemotherapy
Small cell lung carcinoma is treated primarily with chemotherapy and radiation, as surgery has no demonstrable influence on survival. Primary chemotherapy is also given in metastatic non-small cell lung carcinoma.
The combination regimen depends on the tumor type24. Non-small cell lung carcinoma is often treated with cisplatin or carboplatin, in combination with gemcitabine, paclitaxel, docetaxel, etoposide, or vinorelbine. In small cell lung carcinoma, cisplatin and etoposide are most commonly used.Combinations with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan, and irinotecan are also used. in extensive-stage small-cell lung cancer celecoxib may safely be combined with etoposide, this combination showed improve outcomes.

Adjuvant chemotherapy for NSCLC
Adjuvant chemotherapy refers to the use of chemotherapy after surgery to improve the outcome. During surgery, samples are taken from the lymph nodes25. If these samples contain cancer, the patient has stage II or III disease. In this situation, adjuvant chemotherapy may improve survival by up to 15%. Standard practice is to offer platinum-based chemotherapy (including either cisplatin or carboplatin).
Adjuvant chemotherapy for patients with stage IB cancer is controversial, as clinical trials have not clearly demonstrated a survival benefit27. Trials of preoperative chemotherapy (neoadjuvant chemotherapy) in resectable non-small cell lung carcinoma have been inconclusive.
Laser therapy and stenting
Laser treatment via a fibreoptic bronchocopy is essentially palliative.
Targeted therapy
In recent years, various molecular targeted therapies have been developed for the treatment of advanced lung cancer28. Gefitinib (Iressa) is one such drug, which targets the tyrosine kinase domain of the epidermal growth factor receptor (EGFR), expressed in many cases of non-small cell lung carcinoma. It was not shown to increase survival, although females, Asians, nonsmokers, and those with bronchioloalveolar carcinoma appear to derive the most benefit from gefitinib28.
Erlotinib (Tarceva), another tyrosine kinase inhibitor, has been shown to increase survival in lung cancer patients and has recently been approved by the FDA for second-line treatment of advanced non-small cell lung carcinoma26. Similar to gefitinib, it also appeared to work best in females, Asians, nonsmokers, and those with bronchioloalveolar carcinoma.
The angiogenesis inhibitor bevacizumab, (in combination with paclitaxel and carboplatin), improves the survival of patients with advanced non-small cell lung carcinoma. However, this increases the risk of lung bleeding, particularly in patients with squamous cell carcinoma.
Advances in cytotoxic drugs, pharmacogenetics and targeted drug design show promise30. A number of targeted agents are at the early stages of clinical research, such as cyclo-oxygenase-2 inhibitors, the apoptosis promoter exisulind, proteasome inhibitors, bexarotene, the epidermal growth factor receptor inhibitor cetuximab, and vaccines27. Future areas of research include ras proto-oncogene inhibition, phosphoinositide 3-kinase inhibition, histone deacetylase inhibition, and tumor suppressor gene replacement.

Prognosis
Prognostic factors in non-small cell lung cancer include presence or absence of pulmonary symptoms, tumor size, cell type (histology) degree of spread (stage) and metastases to multiple lymph nodes, and vascular invasion29. For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%. Prognostic factors in small-cell lung cancer include performance status, gender, stage of disease, and involvement of the central nervous system or liver at the time of diagnosis.
For non-small cell lung carcinoma, prognosis is generally poor. Following complete surgical resection of stage IA disease, five-year survival is 67%. With stage IB disease, five-year survival is 57%. The five-year survival rate of patients with stage IV NSCLC is about 1%.
For small cell lung carcinoma, prognosis is also generally poor29. The overall five-year survival for patients with SCLC is about 5%.Patients with extensive-stage SCLC have an average five-year survival rate of less than 1%. The median survival time for limited-stage disease is 20 months, with a five-year survival rate of 20%.
According to data provided by the National Cancer Institute, the median age of incidence of lung cancer is 70 years, and the median age of death by lung cancer is 71 years27.
Epidemiology
Worldwide, lung cancer is the most common cancer in terms of both incidence and mortality (1.35 million new cases per year and 1.18 million deaths), with the highest rates in Europe and North America30. The population segment most likely to develop lung cancer is over-fifties who have a history of smoking. Lung cancer is the second most commonly occurring form of cancer in most Western countries, and it is the leading cancer-related cause of death. Although the rate of men dying from lung cancer is declining in Western countries, it is increasing for women, due to the increased takeup of smoking by this group27. The evolution of “Big Tobacco” plays a significant role in the smoking culture. Tobacco companies have focused their efforts since the 1970s at marketing their product toward women and girls, especially with “light” and “low-tar” cigarettes Among lifetime nonsmokers, men have higher age-standardized lung cancer death rates than women.
Not all cases of lung cancer are due to smoking, but the role of passive smoking is increasingly being recognized as a risk factor for lung cancer—leading to policy interventions to decrease undesired exposure of nonsmokers to others’ tobacco smoke26. Emissions from automobiles, factories, and power plants also pose potential risks.
Eastern Europe has the highest lung cancer mortality among men, while northern Europe and the U.S. have the highest mortality among women30. Lung cancer incidence is currently less common in developing countries. With increased smoking in developing countries, the incidence is expected to increase in the next few years, notably in China and India.
Lung cancer incidence (by country) has an inverse correlation with sunlight and UVB exposure. One possible explanation is a preventative effect of vitamin D (which is produced in the skin on exposure to sunlight)26.
From the 1950s, the incidence of lung adenocarcinoma started to rise relative to other types of lung cancer. This is partly due to the introduction of filter cigarettes. The use of filters removes larger particles from tobacco smoke, thus reducing deposition in larger airways28. However the smoker has to inhale more deeply to receive the same amount of nicotine, increasing particle deposition in small airways where adenocarcinoma tends to arise30. The incidence of lung adenocarcinoma in the U.S. has fallen since 1999. This may be due to reduction in environmental air pollution.

Bronchogenic carcinoma, which has its origin the bronchial or bronchiolar epithelium, constitutes 90% to 90% of all lung cancers.1 Bronchogenic carcinomas are aggressive, locally invasive, and widely metastatic tumors that arise from the epithelial lining of the major bronchi. These tumors begin as small mucosal lesions that may follow one of several patterns of growth. They may form masses within the lumen of the bronchi that invade the mucosal layer and surrounding connective tissue layer, or they may form large, bulky masses that extend into the adjacent lung tissue. Some large tumors undergo central necrosis and acquire local areas of hemorrhage, and some invade the pleural cavity and chest wall and spread to adjacent.
This is the most common malignant tumour in the west and is the third most common cause of death in the UK after heart diseases and pneumonia. Mortality rates world. Wide are highest in Scotland, closely flowed by England and wales. In the UK 32,000 people die each year from bronchial carcinoma, with a male to female ratio of 3:1 although the mortality rate from this disease has leveled off in men, it continues to rise in women, accounting for 1 in 8 of all deaths from malignant disease in women, second only to carcinoma of breast.2

Morphology
Most tumours arise from bronchi close to the hilum usually an upper lobe or main bronchus is involved.3 Ulceration is common, so the sputum may be bloodstained and contain malignant cells which can be detected cytologically distally, the lung may be consolidated with foamy macrophages, the usual result of proximal bronchial obstruction.
Some adenocarcinomas may arise peripherally. Small peripheral tumours are most amenable to surgery if detected before the development of metastases.

Classification
Histological classification
There are four major types of lung cancer, classified according to their appearance on light microscopy their approximate incidences are:
• Squamous cell carcinoma (SqCC): 20-30%
• Small cell lung carcinoma (SCLC) (including oat cell carcinoma) and bronchial carcinoids: 15-20%
• Adenocarcinoma (AC) 30-40%
• Large cell undifferentiated carcinoma (LCUC): 10-15%
The lung cancers are discussed below according to this classification, but it should be noted that LCUC probably represents a group of squamous and adenocarcinomas that are too poorly differentiated to categorise as such by light microscopy. In fact, using electron microscopy it can be seen that many SqCC and AC are mixtures, composed of glandular and squamous cells; sometimes, a few cells with neuro-endocrine granules characteristics of SCLC are also seen. This is not entirely surprising as it is now thought that all lung cancers arise from a primitive stem cell that gives rise to the numerous varied cells seen in the mature respiratory tree.
Squamous cell carcinoma: this is the type of lung cancer most closely associated with cigarette smoking. The tumours are almost always hilar, and are thought to arise from squamous metaplasia through grades of dysplasia. There is often haemorrhage and necrosis with cavitation. Tumours may be well, moderately or poorly differentiated. sqCC tends to metastasis locally to hilar lymph nodes; distant metastases are a later feature.
Small cell lung carcinomas. Also known as ‘oat cell’ carcinoma because the small nuclei are thought to resemble oat grains, SCLC usually arise in a hilar bronchus. Unlike SqCC, they metastasise very early, producing widespread bulky secondary deposits, sometimes, the primary tumour can be small and difficult to find. The histology is of a highly cellular tumour composed of small cells with hyperchromatic nuclei and indistinct nucleoli. This form is very strongly linked to smoking as a causative factor.4
Adenocarcinomas,
These are usually peripheral. There is a siginificant association with diffuse pulmonary fibrosis and honeycomb lung, especially if due to asbestosis. There is a suspicion that Ac may arise in discrete areas of scaring such as old infarcts or fibrotic tuberculous foci, but it is also likely that the scar is product of adenocarcinoma. A few cases, show multifocal and bilateral diffuse tumour, so called bronchio-alveolar cell carcinoma.
In the latter case, the tumour cells creep along alveolar walls. It is not clear whether the multifocal nature of the disease is due to multiple pulmonary tumours or spread by the movement of air or through intrapulmonary lymphatics. Against the latter explanation is the fact that hilar lymph nodes are often uninvolved. Adenocarcinomas arise from glandular cells, such as mucous goblet cells, Clara cells and type II penumocytes. AC, forming glands and tubules, or of an AC without significant mucus production. A premalignant stage of pulmonary adenosis is recognized.
Large cell undifferentiated carcinomas. Usually central, these are highly aggressive and destructive lesions with necrosis and haemorrhage. Histologically, there is gross nuclear pleomorphism with numerous bizarre mitoses. No squamous or glandular differentiation is seen on light microscopy, although such evidence is often found ultrastructurally.

Causes
1. The strength of the association between cigarettes smoking and bronchial carcinoma overshadows any other aetiological factors.2 (table 1) but there is a higher incidence of bronchial carcinoma in urban compared with rural areas, even when allowance is made for cigarette smoking.
Table 01 Heath rates from using cancer (age standardized) per 100 000 according to smoking habits in male British Doctors
Heath rate number of cigarettes per day Death rate
_________________________________________________________
Non smokers 10 1-14 78
Smokers 43 15-24 127
Continuing smokers 25 or more 251
Any tobacco 104
Pipe/cigar 58
Cigarettes 140
There are progressive changes in the bronchial mucosa associated with smoking. Carcinoma is preceded by squamous metaplasia and, subsequently, dysplasia. Squamous metaplastic and dysplastic cells are seen far more commonly in the sputum of smokers than in that of non-smokers. The number of shed abnormal cells is also in proportion to the number of cigarettes smoked daily.3
2. Passive smoking (the frequent inhalation of other people’s smoke by non smokers) increase the risk of bronchial carcinoma.
3. Occupational factors include,
Exposure to asbestos
And an association is also claimed for workers in contact with arsenic, chromium, iron oxide, petroleum products and oils, coal tar, products of coal combustion and radition.
Tumours associated with occupational factors are mostly adenocarcinomas and appear to be less related to cigarette smoking.
4. Other inhaled dusts.
5. Radioactive gases.
In the 19th century, the scheneeberg mines in Saxony produced rock rich not only in numerous metals but also in radon; many of the workers died from lung cancer. Survivors of the atomic bombs dropped on Japan in 1945 showed an increased incidence of lung cancer. Presumably related to radiation.3

Genetics of bronchial carcinoma
Similar to other many carcinomas, lung cancer is initiated by activation of oncogenes or inactivation of tumour suppressor genes. Oncogenes are genes that are believe to make people more susceptible to cancer. Proto-oncogenes, are believed to turn into oncogenes when exposed to particular carcinogens.
Mutations in the k-ras proto-oncogenes are responsible for 10-30% of lung adenocarcinomas. The epidermal growth factor receptor regulates cell proliferation, apoptosis, angiogenesis and tumour invasion. Mutations and amplification of epidermal growth factor receptor are common in non-small cell lung cancer and provide the basis for treatment with epidermal growthfactor inhibitors. Chromosomal damage can lead to loss of heterozygisity. This can cause inactivation of tomour suppressor genes.
Damage to chromosomes 3p, 5q, 13q, and 17 p are particularly common in small cell lung carcinoma.
The tumour suppressor gene, located on chromosome 17p, is affected in 60-75% of cases. A recent study suggested that the MDMM2 309 G allele is a low-penetrant risk factor for developing lung cancer in Asians.5

Clinical features.
The frequencies of the common symptoms of lung cancer on presentation are shown in table.2 chest pain and discomfort are often described as fullness and pressure in the chest. Sometimes the pain may be pleuritic owing to invasion of the pleura or ribs.
Often there are no abnormal physical signs. Enlarged supraclavicular lymph nodes can be found with small cell carcinoma. There may be signs of a pleural effusion or of labar collapse. Signs of an unresolved pneumonia or of associated underlying disease. (e.g. diffuse pulmonary fibrosis in asbestosis) may be present.
Table 02 The frequency of the common presenting symptoms of bronchial carcinoma. 2
Symptom Frequency (%)
Cough 41
Chest pain 15
Cough and pain 7
Coughing blood <5
Chest infection <5
Malaise <5
Weight loss <5
Shortness of breath <5
Hoarseness <5
No symptoms <5
Weight loss, cough and haemoptysis are common presenting features. Weight loss is often severe and may be due to humoral factors from the tumour. Dyspnoea and chest pain are also common; the latter is often pleuritic and due to obstructive changes. Patients may present with, or ultimately develop, metastases; common sites include lymph nodes, bone, brain, liver and adrenals. Paraneoplastic effects are common and are due to ectopic hormones: ACTH and ADH from small cell lung carcinomas, PTH from squamous cell carcinomas. Finger-clubbing and hypertrophic pulmonary osteoarthropathy are common.
Table 3
Non-metastatic extrapulmonary manifestations of bronchial carcinoma
(percentage of all cases)2
Metabolic (universal at some stage)
Loss of weight
Lassitude
Anorexia
Endocrine (10%)(usually small-cell carcinoma)
Ectopic adernocorticotrophin syndrome
Syndrome of inappropriate hormone (SIADH)
Hypercalcaemia (usually squamous cell carcinoma)
Rarer: hypoglycaemia, thyrotoxicosis, gynaecomastia
Neurological (2-16%)
Encephalopathies – including subacute cerebellar egeneration
Myelopathies – motor neurone disease
Neuropathies – peripheral sensorimotor neuropathy
Muscular disorders – polymyopathy, myasthenic syndrome (Eaton-Lambert syndrome)
Vascular and haematological (rare)
Thrombophlebitis migrans
Non-bacterial thrombotic endocarditis
Microcytic and normocytic anaemia
Disseminated intravascular coagulopathy
Thrombotic thrombocytopenic purpura
Haemolytic anameia
Skeletal
Clubbing (30%)
Hypertrophic osteoarthropathy (+gynaecomastia) (3%)
Cutaneous (rare)
Dermatomyositis
Acanthosis nigricans
Herpes zoster
Bronchorrhea may occur in either bronchioloalveolar cancer or in metastic cancer that is growing in a bronchioalveolar pattern. Where, there is a production of more than 100ml of watery sputum per day.6
Direct spread
The tumour may directly involve the pleura and ribs. Carcinoma in the apex of the lung can erode the ribs and involve the lower part of the brachial plexus (C8, T1 and T2), causing severe pain in the shoulders and down the inner surface of the arm (Pancoast’s tumour). The sympathetic ganglion can also be involved, producing Horner’s syndrome. Further extension may involve the recurrent laryngeal nerve as is passes down the aortic arch, causing unilateral vocal cord paresis with hoarseness and a bovine cough, and rarely the tumour causes spinal cord compression.2
Bronchial carcinoma can also directly invade the phrenic nerve, causing paralysis of the ipsilateral hemideaphragm. It can involve the oesophagus, producing progressive dysphagia, and the pericardium, producing pericardial effusion and malignant dysrhythmias. Superior vena caval obstruction causes early morning headache, facial congestion and oedema involving the upper limbs; the jugular veins are distended, as are the veins on the chest that form a collateral circulation with veins arising from the abdomen.

Complications
Metastatic complications
Bony metastases are common, giving rise to severe pain and pathological fractures. There is frequent involvement of the liver. Secondary deposits in the brain present as a change in personality, epilepsy or as a focal neurological lesion. Secondary deposits in the adrenal gland are a very frequent post-mortem finding but may often be asymptomatic.
Non-metastatic extrapulmonary manifestations
Although approximately 10% of small-cell tumours are thought to produce ectopic hormones at some stage, clinically important extrapulmonary manifestations are relatively rare aprt from finger clubbing.
Hypertrophic pulmonary osteoarthroapathy (HPOA) occurs in approximately 3% of all bronchial carcinomas, particularly squamous-cell carcinomas and adenocarcinomas. Symptoms include joint stiffness and severe pain in the wrists and ankles, sometimes associated with gynaecomastia. X-rays show a characteristic proliferative periostitis at the distal ends of long bones, which have an onion-skin appearance. HPOA is invariably associated with clubbing of the fingers. It may regress after resection of the lung tumour or as a result of vagotomy at thoracotmy.2

Investigation
The aims of investigations are to confirm the diagnosis.
Common redialogical presentation of bronchial carcinoma.7

Bilateral hilar enlargement
Central tumour. Hilar glandular involvement. Beware-peripheral tumour in apical segment of a lower lobe can look like an enlarged hilar shadow on the PA X ray
Peripheral pulmonary opacity
Usually irregular but well circumscribed. May have irregular cavitation within it. Can be very large.
Lung, lobe or segmental collapse
Usually caused by tumour within the bronchus causing occlusion. Lung collapse can be produced by compression of the main bronchus by enlarged lymph glands.
Pleural effusion
Usually indicates tumour invasion of pleural space; very rarely a manifestation of infection in collapsed lung tissue distal to a bronchial carcinoma
Broadening of mediastinum, enlarged cardiac shadow, salvation of a hemidiaphragm
Paratracheal lymphadenopathy may cause widening of the upper mediastinum. A malignant pericardial effusion will cause enlargement of the cardiac shadow. If a raised hemidiaphagm is caused by phrenic nerve palsy, screening will show it to move paradoxically upwards when patient sniffs
Rib destruction
Direct invasion of the chest wall or blood-borne metastatic spread can cause osteolytic lesions of the ribs
CT is useful for evaluating the infiltration, and construction of the lesion8
Fibre – optic bronchoscopy9
Fibre-optic bronchoscopy is an essential tool in the investigation of many forms of respiratory disease. For discrete abnormalities, such as a mass seen on chest X ray and suspected to bea carcinoma, bronchoscopy is usually indicated to investigate its nature. Under local anaesthesia, the flexible bronchoscope is passed through the nose, pharynx and larynx, down the trachea, and the bronchial tree is then inspected. Figure 5.14 shows a carcinoma of the bronchus seen down the bronchoscope. Flexibile biopsy forceps are passed down a channel inside the bronchoscope, and are used to obtain tissue samples for histological examination. Similarly, aspirated bronchial secretions and brushings of any endobronchial abnormality can be sent to the laboratory for cytological examination.
At bronchoscopy, specimens are also taken for microbilogical examination in order to determine the nature of any infecting organisms. In diffuse interstitial lung disease, such as sarcoidosis or pulmonary fibrosis, the technique of transbronchial biopsy can be used to obtain small specimens of lung parenchyma for histological examination and confirmation of the diagnosis.
Broncoscopy enables the physician to examine the interior of the trachea, it’s bifurcation, and the main bronchi.10
Chest X-ray
By the time the lung cancer is causing symptoms, it will almost always be visible on chest X-rays. Asymptomatic tumours may be seen on chest X-ray if they are more than I cm in diameter. CT scanning will detect smaller masses but is not suitable for screening purposes. A minority of tumours are confined to the central airways and mediastinum without obvious change on the plain chest X-ray. These will be readily seen at bronchoscopy or on CT scanning. In general, investigation of isolated haemoptysis with a normal chest X-ray is unrewarding but a normal chest X-ray should not deter from further investigation if there are other symptoms suggestive of bronchial carcinoma. About 70% of all primary lung cancers arise in the hilar region including virtually all small-cell lung cancers and most squamous cell carcinomas.

Management
Surgical resection carries the best hope of long-term survival; however, some patients treated with radical radiotherapy also achieve prolonged remission or cure. Unfortunately, in the majority of cases (over 85%) surgery is not possible or is inappropriate due to extensive spread or co-morbidity, and such patients can only be offered palliative therapy. Radiotherapy, and in some cases chemotherapy, can relieve distressing symptoms.6

Surgical treatment
Careful staging and assessment of the patient’s respiratory reserve and cardiac status are essential prerequisites to surgery. This, coupled with improvements in surgical and post-operative care, now offers 5-year survival rates of over 75% in stage I disease (No, tumour confined within visceral pleura) and 55% in stage II disease, which includes resection in patients with ipsilateral, peribronchial or hilar node involvement.6

Radiotherapy
While much less effective than surgery, radical radiotherapy can offer long-term survival in selected patients with localized diseases in whom comorbidity precludes surgery. The greatest value of radiotherapy, however, is in the palliation of distressing complications such as superior vena caval obstruction, recurrent haemoptysis, and pain caused by chest wall invasion or by skeletal metastatic deposits. Obstruction of the trachea and main bronchi can also be relived temporarily. Radiotherapy can be used in conjunction with chemotherapy in the treatment of small cell carcinoma and is particularly efficient at preventing the development of brain metastases in patients who have had a complete response to chemotherapy. (CHART), in which a similar total dose is given in smaller but more frequent fractions, may offer better survival prospects than conventional schedules.
Chemotherapy
Small-cell cancer. Single or combination chemotherapy has resulted in a fivefold increase in median survival from 2 to 10 months. A small number of patients enjoy several years of remission. Good results have been achieved with the combination of etoposide and cisplatin. The unwanted effects are greater than with single-agent chemotherapy with etoposide and those with additional medical or physical disabilities.2
Non-small-cell cancer (NSCLC). Treatment regiments change frequently and such treatment is best supervised by a specialized oncologist. Response rates with single-agent treatment with newly introduced drugs exceed 20%. Gemcitabine, a pyrimidine antimetabolite, has less toxicity but equivalent antitumour effect to ifosfamide, vindesine and mitomycin C. combination chemotherapy including cisplatin leads to a better response rate in non-operable NSCLC with median survival of 6 months and 10-12 months in responding patients. Most patients achieve their best response after two or three courses of treatment. Adjuvant chemotherapy with radiotherapy improves response rate and extends median survival. Preoperative (neoadjuvant) chemotherapy increases by half the number of previously inoperable NSCLC patients who can undergo surgical resection with 30% survival at 3 years.
Laser therapy, endobronchial irradiation and tracheobronchial stents
These techniques are used in the palliation of inoperable lung cancer in selected patients with tracheobroncheal narrowing from intraluminal tumour or extrinsic compression causing disabling breathlessness, intractable cough and complications, including infection, haemoptysis and respiratory failure.
A neodymium-Yag (Nd-Yag) laser passed through a fiberoptic bronchoscope can be sued to vaporize inoperable fungating intraluminal carcinoma involving short segments of trachea or main bronchus. Benign tumours, strictures and vascular lesions can also be treated effectively with immediate relief of symptoms.
Endobronchial irradiation (brachytherapy) is useful for the treatment of both intraluminal tumour and malignant extrinsic compression. A readioactive source is afterloaded into a catherter placed adjacent to the carcinoma under fibreoptic with distance from the soruce, minimizing damage to adjacent normal tissue. Reduction in endoscopically assessed tumour size occurs in 70-95% of cases.
Tracheobronchial stents made of silicone or as expandable metal springs are available for insertion into strictures caused by tumour or from external compression or when there is weakening and collapse of the tracheobronchial wall.2
Terminal care
Patients dying of cancer of the lung need attention to their overall well-being. Palliative care must not be ignored simply because they cannot be cured. Much can be done to make the patient’s remaining life symptom free and as active as possible. As compared to patients with fatal cancers at other sites, patients with lung cancer tend to remain relatively independent and pain-free, but die more rapidly once they reach the terminal phase.
Daily treatment with prednisolone (up to 15 mg daily) may improve appetite. Morphine or diamorphine must be given regularly for pain, either in the form of a sustained-release morphine sulphate table twice daily or else as regular elixirs or injections. Many patients benefit from a continuous subscutaneous injection of opiates given by a pump. Candidiasis and other infections in the mouth are common and must be looked for and treated, so regular laxatives should be prescribed. Short courses of palliative radiotherapy are helpful for bone pain, serve cough or haemoptysis.
Both the patient and the relatives may require counseling, a task that should be shared between the respiratory teams, the primary care team and the nurses, social workers, hospital chaplains and doctors, who make up the palliative care team.