Acute renal failure

The two major mechanisms may participate in association between intratubular hemorrage and nephron damage in acute renal failure. The first mechanism is direct nephrotoxicity from hemoglobin, because intratubular degradation of erythrocytes releases heme and iron which are toxic to cells. The second mechanism is hypoxic damage induced by regional vasoconstriction because heme avidly binds the potent vasodilator nitric oxide.

Intratubular degradation of hemoglobin releases heme containing molecules and eventually free iron. These breakdown products, also elaborated from myoglobin, probably play an important role in the pathogenesis of acute tubular necrosis. Endocytic reabsorption from the tubular him en of filtered free hemoglobin or myoglobin may be a major pathway to proximal tubular damage in pigment nephropathy. In addition, free iron promotes the formation of oxygen free radicals, lipid peroxidation and cell death Another source of toxic iron is from the breakdown of intracellular cytochrom P-450 under hypoxic condition. One of the most potent intrarenal vasodilator system is nitric oxide, produced from L-arginine in vascular endothelium. smooth muscle and tubular calls, causing Vascular smooth muscle relaxation through the induction of intracellular cyclic GMP. Blocking nitric oxide synthesis causes profound vascular constriction, systemic hypertension and a marked decline in renal blood flow. Endothelial dysfunction with reduced nitric oxid production may underlie the defective regional vasodilation in diabetes and atherosclerosis, predisposing to renal ischemia and nephrotoxic insult.

Hemoglobin avidly binds nitric oxide and ingibits nitrovasodilation. The presence of large pool of hemoglobin in the tubular lumen could therefore affect the vasomotor balance of kidney circulation: intrarenal vasoconstriction is likely to be most pronounced and most significant in the medulla., because the ratio of tubular mass to vessels surface may be particularly high in this region. The medulla normally functions at low oxygen tension, because of limited medulla blood flow and counter-current exchange of oxygen. Inhibinion of nitric oxide synthesis induces severe and prolonged outer medullary hypoxia and predisposes to tubular necrosis Unfortunately, biopsy specimens of glomerulonephritis associated with acute tubular necrosis do not provide the precise distribution of the tubular lesions.

In chronic glomerulonephritis tubulo-interstitiaJ damage has often been reported as correlate of kidney function and also its best prognostic marker. Glomerular obsolescence deprives the renal parenchyma from nutritional blood flow, leading to tubule-interstitial fibrosis in medullary rays and outer medulla. Proteinuria imposes to the proximal tubules a constant burden of reabsorption and catabolism of albumin and other proteins from the tubular lumen, which have been suggested to cause cellular injury.