INTRODUCTION:

Acute renal failure (ARF) is defined as the cessation of renal excretory function within a period of hours or days, accompanied by a rise in serum urea and creatinine. It is usually, but not always, accompanied by a fall in urine output. This may present as anuria (a complete lack of urine output) or oliguria (low urine output, i.e., less than 15 to 20 ml/hour, or about 500ml/day, in a normal adult) and is usually indicative of failure of both glomerular and tubular function.¹ The incidence of ARF in the general population is estimated to be approximately 70 to 140 cases per million.² around half of these will require dialysis. Some degree of renal impairment is found in around 5 percent of all hospital admissions.³ However, in intensive care units (ICUs) the figure is much higher, with over 15 per cent of patients admitted to hospital having renal impairment. In about half of these cases, the cause is sepsis. The financial implications of renal impairment are considerable. The cost of one survivor leaving ICU with renal failure is 70 times that of a patient without renal impairment. ⁴ ARF is a potentially reversible reduction in the capacity of the kidney to excrete nitrogenous wastes and maintain fluid and electrolyte homoeostasis, which usually occurs over hours to days.

The initial clinical approach is identical in all patients a thorough history and examination with simultaneous treatment of any life threatening features (for example, severe hyperkalaemia). The mortality of ARF approached 100% in World War II, since the development of acute hemodialysis for clinical use had not yet occurred. Acute hemodialysis was first used clinically during the Korean War in 1950 to treat military casualties, and this led to a decrease in mortality of the ARF clinical syndrome from about 90% to about 50% ^5,6. In the half century that has since passed, much has been learned about the pathogenesis of ischemic and nephrotoxic ARF in experimental models, but there has been very little improvement in mortality. This may be explained by changing demographics the age of patients with ARF continues to rise, and comorbid diseases are increasingly common in this population. Both factors may obscure any increased survival related to improved critical care.⁶ Subsequent management should focus on determining the cause, which may demand specific treatment, maintaining the patient’s volume status, and avoiding further nephrotoxic insults. Moreover our review mainly focuses on acute renal failure severity and controls is important in the evaluation of patients and their response to treatment and management of the diseases.

Aetiology:

Pre-renal failure:

Changes in pre-glomerular and post-glomerular arteriolar resistance enable renal blood flow and glomerular filtration rate to remain roughly constant across a wide range of mean arterial pressures. However, below a mean arterial pressure of 70 mmHg auto regulation is impaired and glomerular filtration rate falls proportionately. Renal auto regulation chiefly depends on a combination of pre-glomerular arteriolar vasodilatation, mediated by prostaglandins and nitric oxide, and post-glomerular arteriolar vasoconstriction, mediated by angiotensin II. Drugs that interfere with these mediators namely, non-steroidal anti-inflammatory drugs or selective cyclo-oxygenase 2 inhibitors, and angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists may provoke pre-renal acute renal failure in particular clinical settings.^7-11.It has been shown in the table no : 1

Table No 1: Factors leads to prerenal failure

Hypovolaemia

· Haemorrhage.

· Volume depletion (for example, vomiting, diarrhoea).

· Inappropriate diuresis, and burns.

Renal hypoperfusion

· Non-steroidal anti-inflammatory drugs /selective.

· Cyclo-oxygenase 2 inhibitors.

· Angiotensin converting enzyme inhibitors.

· Angiotensin II receptor antagonists.

· Abdominal aortic aneurysm.

· Renal artery stenosis /occlusion.

· Hepatorenal syndrome.

Hypotension

· Cardiogenic shock.

· Distributive shock (for example, sepsis, anaphylaxis).

· Oedematous states.

· Cardiac failure.

· Hepatic cirrhosis.

· Nephrotic syndrome.

“Intrinsic” renal failure:

Intrinsic acute renal failure may be caused by diseases affecting the glomeruli, renal tubules, interstitium, or vasculature. Overall, the most common cause is acute tubular necrosis, resulting from continuation of the same pathophysiological processes that lead to pre-renal hypo perfusion. Intrinsic acute renal failure is often multifactorial in intensive care the most common cause is sepsis, often accompanied by multi-organ failure.¹² Postoperative acute tubular necrosis accounts for up to 25% of cases of hospital acquired acute renal failure, mostly resulting from prerenal causes.¹³ The third most common cause of hospital acquired acute renal failure is acute radiocontrast nephropathy.¹⁴ It has shown in table no : 2

Post renal failure:

This occurs when there is an obstruction to renal flow anywhere distal to the pelvis. Obstruction is always the most likely diagnosis, when there is anuria. For this to occur both ureters, and the urethra should be obstructed. It is commonly seen in patients with retroperitoneal or pelvic pathology and abdominal ultrasound is a good diagnostic tool. Do remember to check the patency of the Foleys catheter. Although obstruction secondary to prostatic disease is as common in some community studies.¹⁵ Intrinsic disease is most probably attributable to ischaemic ATN (50% of cases of intrinsic ARF), with nephrotoxic ATN, interstitial nephritis, and glomerulonephritis accounting for 35%, 10%, and 5% of cases respectively.¹⁶ The condition is often multifactorial, for example, the septic, hypotensive patient given amino glycosides and intravenous contrast. Elderly patients, diabetic patients, and those with pre-existing renal disease are all at higher risk. It has been show in Table no : 3

Table No 2: Principal causes of intrinsic renal acute renal failure

Glomerular disease

· Inflammatory post-infectious glomerulonephritis.

· Cryoglobulinaemia, Henoch-Schonlein purpura.

· Systemic lupus erythematosus, antineutrophil.

· Cytoplasmic antibody associated glomerulonephritis.

· Anti-glomerular basement membrane disease.

· Thrombotic disseminated intravascular.

· Coagulopathy, thrombotic microangiopathy.

Interstitial nephritis

· Drug induced non-steroidal anti-inflammatory drugs, antibiotics.

· Infiltrative lymphoma.

· Granulomatous sarcoidosis, tuberculosis.

· Infection related post-infective, pyelonephritis.

Tubular injury

· Ischaemia—prolonged renal hypoperfusion.

· Toxins—drugs (such as amino glycosides).

· Radio contrast media, pigments (such as myoglobin).

· Heavy metals (such as cisplatinum).

· Metabolic—hypercalcaemia, immunoglobulin light chains.

· Crystals—urate, oxalate.

Vascular

· Vasculitis (usually associated with antineutrophil cytoplasmic antibody).

· Cryoglobulinaemia.

· Polyarteritis nodosa.

· Thrombotic microangiopathy.

· Cholesterol emboli.

· Renal artery or renal vein thrombosis.

Table No 3: Principal Post-renal causes of acute renal failure

Intrinsic

· Intra-luminal—stone, blood clot, papillary necrosis.

· Intra-mural—urethral stricture, prostatic hypertrophy or malignancy, bladder tumour, radiation fibrosis.

Extrinsic

· Pelvic malignancy.

· Retroperitoneal fibrosis.

PATHOGENESIS:

Renal blood flow is 25% of cardiac output but some areas are particularly sensitive to ischaemic damage. Most of the blood flow supplies the cortex, which contains the glomeruli and convoluted tubules, areas that require good perfusion to achieve filtration and reabsorption, the latter with high energy demands. The outer medulla is comparatively starved of oxygen, its blood supply first traversing the glomerula capillary bed, and losing hydrostatic pressure (in essence, a portal circulation), and then on entering the medulla, losing oxygen by countercurrent exchange with the venous vasa recta. These features are essential to maintain the osmotic gradients within the medulla and thus generate concentrated urine, but render the outer medulla very susceptible to variations in blood flow. This area contains the thick ascending limb of the loop of Henle and S3 segment of the proximal tubule, both with high oxygen requirements. Impaired tubular sodium reabsorption attributable to reduced perfusion causes constriction of the afferent arteriole and a further reduction in glomerular filtration rate (GFR). This compensatory mechanism (tubuloglomerular feedback), designed to protect the downstream nephron, may cause injury if prolonged, or if normal regulation of the arterial tone is blocked (for example, by non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARBs)). Reduced blood flow in the peritubular capillaries produces ischaemic damage in vascular endothelial cells, resulting in cell swelling and the expression of cell adhesion molecules reducing flow further and leading to leucocyte activation. Adherent leucocytes further impede blood flow and produce cytokines and reactive oxygen species that damage endothelial and tubular epithelial cells. Tubular cells swell, lose their brush border, and develop cytoskeletal abnormalities with abnormal localization of cell membrane components (for example, Na⁺/K⁺2ATPase), changes in cellular polarity, and loss of Cell-Cell and cell-basement membrane attachment. These swollen, detached cells obstruct the tubular lumen, and back leak of filtrate occurs through the damaged basement membrane. In the classic histological appearance of ATN, tubules are surrounded by flattened, denuded epithelium, and the lumen filled by cell debris, with congested peritubular capillaries and an extensive inflammatory cell infiltrate. Cell death occurs predominantly by necrosis, although apoptosis also contributes, especially in the thick ascending limb and late in the process. A remarkable feature of the kidney is its ability to regain normal structure and function after such injury. Once renal perfusion and oxygen supply are normalised, viable cells still adherent to the tubular basement membrane can spread to cover denuded areas, and then differentiate to reproduce normal tubular architecture, and function. The return of glomerular filtration aids clearance of tubular debris and relief of obstruction. A period may exist where glomerular filtration has normalised, but tubular function remains deranged, hence the polyuric phase of ATN, where urine output is often excessive without normal homoeostasis. The anuric phase of ATN classically lasts 7–21 days, and recovery to pre-insult levels of renal function can be expected, although some impairment of function may persist, particularly if there is a background of chronic renal insufficiency. ¹⁷

Diagnosis:

A physical examination often helps our physician diagnose acute renal failure. Bladder stones that obstruct urine flow can often be palpated (an examination by touching), as can an enlarged bladder. Diagnosis requires knowledge of the natural history of various causes of ARF and a systematic approach to evaluating renal insufficiency by excluding and correcting both prerenal and postrenal causes. Laboratory studies include blood tests and a urinalysis to determine how well the kidneys are filtering and removing wastes from the blood. Ultrasound, X-rays of the abdomen and biopsies of the kidney help show causes of acute renal failure and help establish a prognosis.¹⁸

Predisposing factors of acute renal failure:

It includes malaria, leptospirosis, tetanus, salmonellosis, shigellosis, and cholera. Schistosomiasis may cause ARF in both haematobium and mansoni infections. Of those, the main infections causing ARF are malaria, leptospirosis and tetanus. ARF associated with salmonellosis, shigellosis and cholera is less common. Hepatitis B and C viruses are associated with chronic renal disease. Dengue hemorrhagic fever can be associated with ARF. In addition to that elderly individual with acute kidney injury, particularly those who previously diagnosed chronic kidney disease (CKD), are at significantly increased risk of end renal disease (ESRD), suggesting episode of acute kidney injury.¹⁹

Malaria:

ARF complicates malaria in 1 – 5% of the natives in endemic areas but in non-immune visitors the figure goes up to 30%. It is mostly due to P. falciparum with P. vivax being the causative species in a minority of cases. The main features are oliguria and hyper catabolism in addition to the systemic effects of malaria. Mild proteinuria, <1gm/day, may occur but almost resolves completely after treatment. The urine sediment is usually negative. Hyperkalaemia is usually striking due to haemolysis, rhabdomyolysis and acidosis. A study of prognosis from Yemen reported that out of 64 children (4.2 – 11.2 years) who required dialysis for ARF secondary to falciparum malaria, 28 (43.8%) died. The group that died had significantly high plasma creatinine and BP and low urine output.²⁰

Leptospirosis:

Leptospirosis is caused by pathogenic spiral bacteria belonging to the genus leptospira. The pathogen enters the body via the skin or mucosa. It multiplies in the blood and spreads to other parts of the body particularly the liver and kidneys.²¹Leptospirosis causes necrotizing vasculitis causing severe glomerulonephritis in some patients while in others there is mild mesangioproliferative glomerulonephritis with IgM immunofluorescence deposit. Interstitial nephritis also occurs with focal or diffuse mononuclear cell infiltration. The organism is rarely seen in the renal biopsy. Treatment is mainly directed towards treating the disease, Penicillin being the drug of choice some patients may require dialysis before recovery of renal function. Plasma exchange is advocated by some workers in patients with severe jaundice.²² Referring of ARF is almost invariable in patients, who recover from the acute illness.

Salmonellosis:

Abnormal renal function is reported in about 16% of patients ²³ with salmonellosis. The main renal lesions are pyelonephritis, acute tubular necrosis and glomerulonephritis.²⁴ which are exudative. During the febrile phase haematuria and proteinuria, usually less than one gram, are common. The renal involvement is usually mild with full recovery within two weeks of typhoid treatment. ²⁵ A more severe illness mimicking post infections glomerulonephritis was reported from South Africa with generalized oedema and hypertension.²⁶ Renal biopsy showed mild to moderate mesangioproliferative glomerulonephritis with IgG and IgM deposits.

Shigellosis:

ATN may occur due to dehydration in severe infections. In a series reported by Bennish et al, out of 2018 patients ARF occurred in 26% of cases. ²⁷ Proliferative glomerulonephritis can occur. Shigellosis may also induce hemolytic uremic syndrome (HUS) especially in children.²⁸ In such cases there may be cortical necrosis and diffuse fibrous deposits in the glomeruli. Mortality may be high in those patients.

Cholera:

ARF occurrence in cholera is similar to that of shigellosis, being due to fluid and electrolytes loss. Hypokalaemia can be severe. In addition to ATN, proximal tubular vacoulation can occur due to hypokalaemia and cortical necrosis was noted in some patients. ²⁹

Dengue Hemorrhagic Fever:³¹

ARF occurs in 5% of patients with Dengue Hemorrhagic Fever. It is mainly due to ATN. Which is associated with interstitial oedema and mononuclear cell infiltration. Mesangioproliferative glomerulonephritis may be seen with IgG, IgM and C3 deposits. It is associated with mild proteinuria and abnormal urinary sediment.

Drug-induced acute renal failure:³²

Renal dysfunction after exposure to a causative drug can occur within a few hours but can be delayed for weeks or months. Recovery of renal function usually occurs over one month to a year following drug withdrawal, but permanent impairment can result. Papillary necrosis is a radiological diagnosis in which the normal cupped shape of the renal papillae is replaced by a clubbed appearance. This indicates that the collecting system architecture has been destroyed. Papillary necrosis can complicate interstitial nephritis, analgesic nephropathy or other systemic conditions, such as diabetes mellitus and sickle cell disease. Analgesic nephropathy is a form of renal disease in which there is often renal papillary necrosis and a history of analgesic administration. It is now much less common in the United Kingdom, where many of the drugs with which it is strongly associated have been withdrawn,²⁸Eg. phenacetin. analgesic combinations, especially those containing salicylates, caffeine or paracetamol, seem to increase the risk of developing chronic tubular interstitial disease and papillary necrosis.Analgesic nephropathy is still under diagnosed, because patients often under-report their use of analgesics. ²⁹

Drug that cause pre-renal disease:

Drugs that compromise the circulation and hence decrease renal perfusion will have an indirect adverse effect on renal function. Volume depletion resulting from aggressive diuretic therapy or from major gastrointestinal losses caused by drug-induced diarrhoea and/or vomiting can compromise renal function. Example: Antihypertensives, Laxatives, Diuretics, NSAIDs and Vasoconstrictors

Drug that cause crystalluria:

Uric acid crystals can form as a result of probenecid therapy or following cancer chemotherapy. In both situations there is an increase in uric acid excretion, for which allopurinol prophylaxis should be used. Some drugs can form crystals within the renal tract, although this is rarely a clinical problem, if the patient is sufficiently hydrated. Eg. Acetazolamide, Nitrofurantoin, Foscarnet, Pentamidine, Indinavir, Sulphonamides, Mercaptopurine, Triamterene, Methotrexate and Vitamin C.

Mannitol:

Mannitol is as osmotic diuretic, it increases RBF secondary to release of intrarenal vasodilating prostaglandins and ANP decreases the production of renin and reduces endothelial cell swelling. As explained in the pathophysiology, it is imperative to know whether mannitol induced increased in RBF occurs in the cortex or in the medulla. Studies in animal or humans have failed to identify whether the medullary or cortical blood flow increases. Mannitol has been extensively used as a prophylactic agent to minimize the risk of ARF in patient with hemodynamic instability. Those with radiocontrast nephropathy and those who have undergone biliary surgery and aortic surgery. Mannitol has been used for longtime in the prophylaxis of rhabdomyolysis induced ARF. Recent study suggest aggressive volume expansions alone is sufficient to prevent ARF. Mannitol when gives in excess of 200g/d (or) a cumulative dose of >400g/48h can cause ARF due to severe renal vasoconstriction. The recommended dose of mannitol in renal transplantation is 250ml mannitol 20% along with adequate volume expansion just before removal of the arterial clamp.

Fruseamide:

Fruseamide a loop diuretic is prescribed by the clinician when they are faced with low urine output, with the hope that inducing diuresis is protective against ARF. Loop diuretic decreases the metabolic demand of the renal tubular cell, reducing its oxygen requirement and thereby increasing its resistance to ischemia. Frusemide combines with albumin in the renal tubules and is actively reabsorbed in the proximal tubule where its exerts its action. Therefore, correction of severe hypoalbuminemia may help, fruseamide administered to patients at risk of developing ARF produced no change in GFR, renal plasma flow, RBF and RBF distribution. Frusemide has not been found to be effective in cardiac surgery or in radio contrast induced neprotoxicity or in combination with dopamine. Frusemide in large doses of 1.5-6mg/kg given every 4hrs intravenously produced good diuresis, but there was no difference in the number of dialysis required or in the mean duration of renal failure. Prospective studies have reported that continuous infusion of frusemide is better than a large bolus dose. However, the number of dialysis, duration of renal failure and mortality were not different in the two groups. Fruseamide induced diuresis without maintenance of volume expansion may be detrimental. The present data don’t provide convincing evidence for the routine use of fruseamide as a prophylactic agent against PO-ARF and its role is limited to producing a non-oliguric state. Which will allow fluid manipulation.

Dopamine:

Low dose dopamine (1 to 3 ¼gkg^-1 per min) increases diuresis and natriuresis in healthy experimental animals and humans. These effects are not seen uniformly in the critically ill. However after extensively reviewing the data available the same authors came to the conclusion that the use of dopamine in renoprotective doses should be abandoned as there was no evidence supporting its effectiveness in preventing ARF and it should not be used as a panacea for oliguria. In addition, dopamine can precipitate serious cardiovascular and metabolic complications such as depression of the respiratory drive, triggering of tachyarrhythmia’s, causing myocardial ischemia, accelerating intestinal ischemia, depression of anterior pituitary hormones and decreased T-cell function.^33-35

Fenoldepam:

Fenoldepam mesylate is a dopamine analogue which stimulates postsynaptic, peripheral dopamine-1 receptor and has no activity on Dopamine 2 receptors or on a and b adrenergic receptors. Fenoldepam has been shown to increase RBF, urine output and natriuresis, Natriuresis and diuresis can occur without vasodilatation, indicating a proximal tubule site of action for fenoldepam. Fenoldepam is 6 time more potent than dopamine in producing renal vasodilatation. The potential advantages of fenoldepam over dopamine include: increase in dopaminergic potency, lack of tachyarrhythmia’s and ability to safely infuse through a peripheral vein. Two studies reported the beneficial role of fenoldepam in the prevention of PO-ARF in patients undergoing abdominal aortic aneurysm repair and coronary artery bypass graft. Further randomized studies are required before one can advocate the use of fenoldepam in the prevention of ARF.

Calcium Channel Blocker:

During ischemia calcium channels open resulting in vasospasm. The calcium blockers exert direct vascular effect with preservation of renal auto regulation and enhanced recovery of RBF, GFR and natriuresis three prospective studies in renal transplantation patients confirm the benefits of calcium channel blocker. However, it has been suggested that there may be factors other than attenuation of ARF in the positive response to calcium antagonists, including increasing plasma cyclosporine and limiting cyclosporin induced renal vasoconstriction as well as modifying T-Cell function. Calcium channel blockers have been tried successfully in the prevention of radio-contrast induced nephropathy, but others have failed to confirm. This critically ill patients may not tolerate high dose of calcium channel antagonists which may further compromise their hemodynamic status. As of now calcium channel blockers cannot be recommended for the preservation of renal function.

Atrial natriuretic peptide:

This hormone it produced in the cardiac atria in response to volume overload. The action of ANP is mediated by cyclic guanosine monophosphate (CGMP).The physiological effects of ANP include.

1. Decreased rennin and aldesterone secretion

2. Decreased sodium reabsorption in the tubule

3.Decreased sodium and chloride uptake in the ascending loop of Henle

4. Redistribution of medullary blood flow

5. Reversal of endothelin induced vasoconstriction

6. Increased GFR

The synthetic ANP analogue anaritide and a renally produced natriuretic peptide ularitide have been tried in preventing or improving renal failure. A preliminary study was promising but in a subsequent large randomized multicenter study in patients with ATN anaritide failed to demonstrate the beneficial effect.Anaritide failed to reduce the overall mortality and dialysis free survival although in a subgroup patients who were oliguric had improved dialysis is free survival while non-oliguric patients had worsened dialysis free survival. This was taught to be due to the hyportensive effect of anaritide. Ularitide analog of ANP which causes less hypotension was found to effective for the treatment of incipient oliguric ARF following surgery. However, large prospective positive studies are required to warrant clinical use of the drug³⁰.

Nor adrenaline:³⁶

It markedly improves mean arterial pressure and glomerular filtration. This is especially seen in high output low resistance septic shock. Urine flow reappears with restoration of systemic hemodynamic and renal function improves without the use of low dose dopamine or frusemide. This fact supports the hypothesis that renal ischemia observed during hyper dynamic septic shock is not worsened by nor adrenaline infusion and even suggests that this drug may effectively optimize renal blood flow and renal vascular resistance

Adrenaline:

In patients who fail to respond to fluid administration and other vasopressin adrenaline can increase arterial pressure primarily by increasing cardiac index and stroke volume. However, adrenaline has detrimental effects on splanchnic blood flow and causes transient decreases in pH and increases the PCO2.³⁶

Dialysis:

Dialysis may be emergent or elective. The indications for dialysis are volume overload, hyperkalemia, severe acidosis, and uremia (with a change in mutations, pericarditis, pleuritis or bleeding). Emergency dialysis is rarely required in hospitalized patient’s. In the ICU set up BUN and creatinine clearance is assessed daily and dialysis is usually started when the BUN level exceeds 100 mgdl-1 or the creatinine clearance is less than15 mlmin-1. There are four contemporary modes of dialysis: - Peritoneal Dialysis (PD, not usually considered in the post operative general surgical patient with abdominal pathology or respiratory compromise). - Hemodialysis (HD, difficult to do especially in the hypotensive post operative or septic patient, requiring vasopressor support). - Continuous Arterio Venous Hemofiltration (CAVH, relies on an adequate pressure head, has no external apparatus to control flow or provide warning and requires the insertion of a wide bore catheter into an artery which may result in bleeding, an aneurysm, thrombosis and clot formation). It has been largely replaced by Continuous Venous Hemofiltration CVVH, is a slow method of solute and fluid removal, results in a largely haemodynamically stable milieu and can remove a large quantity of cytokines, which may reduce the incidence or progression of multi-organ failure. The newer machines have improved safety features such as an air detector and a pressure monitor. They do however require one on one nursing and frequent, 4-6 hourly, and potassium assessment. They are capable of removing up to 10 liters of fluid at one sitting and is often helpful in weaning from mechanical ventilation and shortening ICU stay.³⁷

CONCLUSIONS:

Acute renal failure is a life threatening illness with high mortality despite advances in supportive care. An additional cost exists in terms of morbidity and the high demands placed on healthcare resources. The most commonly used drugs in the ICU, which will require adjustment, include penicillin’s, cephalosporins, vancomycin, amino glycosides, amphotericin, digoxin, and some muscle relaxants thus, a reduction in dose is often necessary for ARF. The pathophysiology is not well understood, therapeutic options are limited, and a considerable proportion of patients progress to dialysis dependent end stage renal disease. The priorities in management of acute renal failure include early recognition, institution of appropriate preventive measures, optimisation of fluid balance, identification and treatment of underlying causes, and timely initiation of renal replacement therapy where appropriate.

ACKNOWLEDGEMENT:

The authors would like to thank Dr .P. K kar, Professor, Department of Pharmacology, and Himalayan pharmacy institute, Sikkim, India who critically review manuscript and offered valuable suggestions.

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Received on 22.11.2009 Modified on 20.01.2010

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 327-332