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Pathogenesis and etiology of postischemic (ischemic) acute tubular necrosis

INTRODUCTION

Patients who are hypotensive due to surgery, sepsis, bleeding, or other causes are at risk of developing postischemic (also called ischemic) acute tubular necrosis (ATN) especially if the impairment in renal perfusion is either severe or prolonged in duration. This disorder is characterized by a rising plasma creatinine concentration, a urine volume that may be reduced or normal, and a characteristic set of changes in the urinalysis, including many granular casts and a fractional excretion of sodium above 1 percent and fractional excretion of urea above 35 percent.

The pathogenesis and etiology of postischemic ATN will be reviewed here [1,2]. The diagnosis of ATN, potential therapies for postischemic ATN, and other causes of ATN are discussed separately. (See "Possible prevention and therapy of postischemic (ischemic) acute tubular necrosis" and "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury (acute renal failure)" and "Manifestations of and risk factors for aminoglycoside nephrotoxicity" and "Clinical features and diagnosis of heme pigment-induced acute kidney injury (acute renal failure)" and "Pathogenesis, clinical features, and diagnosis of contrast-induced nephropathy".)

PATHOLOGY AND PATHOGENESIS

The process underlying ischemic ATN occurs in multiple phases, including prerenal (impairment in renal perfusion), initiation of injury, extension of injury, maintenance, and repair [3]. The major histologic changes in ATN are effacement and loss of proximal tubule brush border, patchy loss of tubule cells, focal areas of proximal tubule dilatation, distal tubule casts, and areas of cellular regeneration that appear during the phase of recovery of renal function (picture 1A-B) [4,5].

However, the decline in renal function is usually more prominent than the severity of the histologic changes. In some cases necrotic cell death is not readily apparent and is restricted to the outer medullary regions (including the S3 segment of the proximal tubule and thick ascending limb of the loop of Henle). In addition to observable tubule obstruction and cell death, other factors may contribute to the decline in glomerular filtration rate (GFR) [4,6]:

  • Tubules from multiple nephrons drain into a single collecting tubule. As a result, obstruction in a relatively small number of collecting tubules may lead to failure of filtration in a large number of nephrons.
  • The combination of glomerular filtration and impaired proximal and loop reabsorptive function leads to increased sodium chloride delivery to the macula densa in individual nephrons. This activates the tubuloglomerular feedback mechanism causing afferent arteriolar constriction, which lowers the GFR in an attempt to reduce tubule flow rate [7]. (See "Chapter 2D: Regulation of GFR and renal plasma flow", section on 'Tubuloglomerular feedback'.)
  • Back leak of filtered tubular fluid may occur across the damaged tubule epithelium [8,9].
  • Apoptosis occurs in both proximal and distal tubule cells [10].
  • Peritubular capillaries in the outer medulla may be congested with leukocyte accumulation that impairs local renal blood flow [11].
  • A number of processes contribute to the pathogenesis of ATN, including endothelial and epithelial cell injury, intratubular obstruction, changes in local microvascular blood flow and immunological or inflammatory processes.

              

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Literature review current through: May 2013. | This topic last updated: Apr 26, 2013.
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