ACUTE TUBULAR NECROSIS (ATN)

What is acute renal failure?

-an abrupt decline in renal function over hours to days
-failure of the kidney to excrete waste products leading to a rise in serum urea and creatinine, usually with decreased urine output (<400ml/24h)
-variable other physical and biochemical abnormalities depending on duration of renal insufficiency (esp. electrolytes)
-traditionally divided into 3 etiologies:
prerenal
renal
post renal
-prerenal and ATN can be viewed as part of a continuum and are the most common causes of ARF in a hospitalized patient.

ATN=reversible destruction of tubular epithelial cells associated with acute suppression of renal function

Microscopic features of ISCHEMIC acute tubular necrosis

-patchy, focal tubular epithelial necrosis, with rupture of tubular basement membranes (tubulorrhexis) and luminal occlusion by casts
-PCT and ascending thick limb most susceptible, but focal necrosis with casts can be seen in distal tubules
-epithelial cells show a spectrum of changes depending on severity and evolution of lesion:
-cell swelling, dilatation of proximal tubules, and varying degrees of necrosis and sloughing of epithelium
-eosinophilic hyaline and granular casts seen predominantly in distal tubule and collecting ducts
-consist of Tamm-Horsfall protein (urinary glycoprotein usually secreted by these cells) with Hb, myoglobin, other proteins and cell debris
-with time see evidence of regeneration *
-flattened epithelial cells
-hyperchromatic, large nuclei
-mitotic activity
-interstitial edema and WBC in vasa recta (vascular supply)

Microscopic features of NEPHROTOXIC acute tubular necrosis

-extensive epithelial necrosis predominantly affecting the proximal tubules (classically NOT patchy)
-also see eosinophilic and granular casts in distal tubules and collecting ducts
-“classic” changes associated with different etiologic agents:
-ethylene glycol: ballooning and vacuolar degeneration of PCT with deposition of oxalate crystals in tubular lumina
-lead: dark intranuclear inclusions
-CCl4: lipid accumulation
-hemoglobin/myoglobin: multiple deeply pigmented dark red/brown casts

-tubulitis is NOT a feature of ATN

Acute Tubular Necrosis Critical Events

a)tubular cell injury
b)disturbances in blood flow

-tubule cells sensitive to ischemia →structural (reversible and irreversible) and biochemical (ie. activation of proteases and phospholipases) abnormalities
-loss of cell polarity with redistribution of membrane proteins
→abnormal ion transport across cells and increased Na to distal tubules
→tubuloglomerular feedback and vasoconstriction
-expression of cytokines and adhesion molecules, accumulation of inflam cells
-sloughed, injured cells are incorporated in casts causing luminal obstruction

-ischemic injury incites hemodynamic changes causing decreased GFR
-intrarenal vasoconstriction through various mechanisms:
-direct ischemic injury to glomeruli
-renin/angiotensin activation stimulated by tubuloglomerular feedback
-direct endothelial cell injury with release of vasoconstrictor mediators
-regeneration of tubular epithelial cells possible when and if inciting agent is removed
-dependent on cytokines and growth factors produced by both the tubular cells themselves and inflammatory cells in the vicinity ie. EDGF, TGFα, IGF, HepGF