ATN is a clinicopathologic entity charaterized morphologically by destruction of tubular epithelial cells and clinically by acute suppression of renal function. It is the most common cause of acute renal failure, which signifies acute suppression of renal function and urine flow, falling within 24 hours to less than 400ml. It can be caused by a variety of conditions including:

Organic vascular obstruction caused by diffuse involvement of the intrarenal vesseles such as in polyarteritis nodosa and malignant hypertension and the hemolytic uremic syndrome

Severe glomerular disease, such RPGN

Acute tubulointerstitial nephritis, most commonly occurring as a hypersensitivity to drugs.

Massive infection (pyelonephritis), especially when it is accompanied by papillary necrosis

Disseminated intravascular coagulation

Urinary obstruction by tumors, prostatic hypertrophy or blood clots ( so-called postrenal acute renal failure) Acute tubular necrosis (ATN)

ATN is a reversible renal lesion that arises in a variety of clinical settings. Most of these ranging from sevee trauma to acute pancreatitis, have in common a period of inadequate blood flow to the peripheral organs, usually accompanied by marked hypotension and shock. This patern of ATN is called ischemic ATN. Mismatched blood transfusions and other hemolytic crises causing hemoglobinuria and skeletal muscle injuries causing myoglobinuria also produce a picture resembling ischemic ATN. The second pattern, called nephrotoxic ATN is caused by multitude of drugs, such genetamicin and other antibiotics radiographic contrast agents; poisons, including heavy metals (e.g., mercury); and organic solvents (e.g.,) carbon tetra chloride). In addition to its frequency, the potential reversibility of ATN adds to its clinical importance. Proper management means the difference between full recovery and death.

The critical events in both ischemic and nephrotoxic ATN are believed to be (1) tubular injury and (2) persistent and severe disturbances in blood flow.

Tubule cell injury

Tubular epithelial cells are particularly sensitive to ischemia and are also vulnerable to toxins. Several factors predispose the tubules to toxic injury, including a vast electrically charged surface for tubular reabsorption, active transport systems for ions and organic acids and the capability for effective concentration.

Ischemia causes numerous structural and functional alterations in epithelial cells.

The structural changes include those of reversible injury (such as cellular swelling, loss of brush border, blebbing, loss of polarity and cell detachment) and those associated with lethal injury (necrosis and apoptosis). Biochemically, there is depletion of adenosine triphosphate; accumulation of intracellular calcium; activation of proteases (eg., calpain) which cause cytoskeletal rearrangement and phospholipases, which damage membranes; generations of reactive oxygen species and activation of caspases, which induce apoptotic cell death. One early reversible result of ischemia is loss of cell polarity due to redistrubution of membrane proteins from the basolateral to the luminal surface of the tubular cells, resulting in abnormal ion transport across the cells, and increased sodium delivery to distal tubules. The latter results in tubuloglomerular feedback, which as will be described incites vasoconstriction. In addition , ischemic tubular cells express cytokines and adhesion molecules thus recruiting leukocytes that appear to participate in the subsequent injury. In time detached injured cells cause luminal tubule obstruction , increase intratubular pressure and decrease the GFR. In addition fluid from the damaged tubules could leak into the interstitium, resulting in increased interstitial pressure and collapse of the tubule.

Distrurbances in blood flow

Ischemic renal injury is also charaterized by hemodynamic alterations that cause reduced GFR. The major one is intrarenal vasoconstriction, which results in both reduced glomerular plasma flow and reduced oxygen delivery to the functionally important tubules in the outer medulla. A number of vasoconstrictor pathways have been implicated including the renin angiotension mechanism, stimulated by increased distal sodium delivery and sublethal endothelial injury leading to increased release of the endothelial vasoconstrictor endothelin and decreased production of the vasodilator nitric oxide and PGI. Finally there is also some evidence of a direct effect of ischemia or toxins on the glomerulus causing a reduced glomerular ultrafiltration coefficient possibly due to mesangial contaction.

The patchiness of tubular necrosis and maintenance of the integirity of the basement membrane along many segments allow ready repair of the necrotic foci and recovery of function if the precipitating cause is removed. This repair is dependent on the capacity of reversibly injured epithelial cells to proliferate and differentiate. Re-epithelialization is mediated by a variety of growth factors and cytokines produed locally by the tubular cells themselves or by inflammatory cells in the cinity of necrotic foci.

Clinical course

The clinical course of ATN is highly variable but he classic case may be divided into initiating maintenance and recovery stages. The initiating phase, lasting for about 36 hours is dominated by the inciting medical, surgical, or obsteric event in the ischemic form of ATN. The only indication of renal involvement is a slight decline in urine output with a rise in BUN. At this point oliguria could be explained on the basisi of a transient decrease in blood flow to the kidneys.

The maintenance stage is charaterized by sustained decreases in urine output to between 40 and 400 ml/day , with salt and water overload rising BUN concentrations,, hyperkalemia, metabolic acidosis, and other manifestations of uremia dominating this phase. With appropriate attention to the balance of water and blood electrolytes, including dialysis, the patient can be carried over this oliguric crisis.