Acute Tubular Necrosis

Acute tubular necrosis (ATN) is common, particularly in hospital practice. It results most often from renal ischaemia but can also be caused by direct renal toxins including drugs such as the aminoglycosides, lithium and platinum derivatives.

Kidneys appear to be particularly vulnerable to ischaemic injury when cholestatic jaundice is present, and more than one ischaemic factor appears to be present in some situations. For example, disseminated intravascular coagulation complicating Gram-negative septicaemia and complications of pregnancy such as placental rupture, pre-eclampsia and eclampsia, may result in occlusion or partial occlusion of intrarenal vessels, exacerbating the ischaemic insult resulting from hypotension associated with the underlying condition.

Myoglobinaemia and haemoglobinaemia consequent upon muscle injury (rhabdomyolysis) complicating trauma, pressure necrosis or heroin use predispose to ATN, perhaps in part owing to occlusion of renal tubules by myoglobin and haemoglobin casts. In liver failure, acute renal failure appears to result from rapidly reversible vasomotor abnormalities within the kidney. A kidney removed from a patient with hepatic cirrhosis and liver failure dying with oliguric renal failure may function normally immediately after transplantation into a normal individual. Efferent glomerular arteriolar dilatation resulting from ACE-inhibitor drug therapy, with consequent lowering of glomerular filtration pressure, may cause acute deterioration in excretory function if renal arterial disease is also present. The effect is compounded by concomitant use of non-steroidal anti-inflammatory agents which reduce prostaglandin production, opposing this effect.

Factors postulated to be involved in the development of ATN include:

(i) entry of calcium into cells with an increase in cytosolic cell calcium concentration;

(ii) induction by hypoxia of nitric oxide synthases with increased production of nitric oxide;

(iii) increased production of intracellular proteases such as calpain (fairly strong evidence exists that this mechanism operates in ciclosporin-induced nephrotoxicity);

(iv) activation of phospholipase A 2 with increased production of free fatty acids and consequent damage to cell membranes;

(v) cell injury resulting from reperfusion with blood after initial ischaemia;

(vi) vasoconstriction;

(vii) liberation of toxic endothelial factors;

(viii) damage from the vasodilator effects of endotoxins;

(ix) reduced prostaglandin production;

(x) tubular obstruction by desquamated cells and casts.

The decline in the supply of oxygen and essential nutrients to tubular cells and the effect of various toxic factors results in patchy tubular cell necrosis with disruption of the cell membrane, denaturation of intracellular protein, lysosomal disruption and cell necrosis. Tubular cells have the capacity to regenerate rapidly and to reform the disrupted tubular basement membrane, which explains the reversibility of ATN. In established ATN renal blood flow is much reduced, particularly blood flow to the renal cortex.

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