Acute tubular necrosis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Serge Korjian, Yazan Daaboul
Overview
Pathophysiology
Phases of Ischemic Acute Tubular Necrosis
Associated Apoptosis
Apoptosis is a programmed cascade occuring secondary to intra- or intercelluar signaling which leads to cell death in the absence of an inflammatory response. Apoptosis has been reported in the initial phase of acute tubular necrosis and during the recovery phase. With initial ischemic or cytotoxic injury, a number of tubular cells may undergo apoptosis. This may be either due to insufficiently cytotoxic insults, or due to associated molecular cascades that release TNF-alpha or Fas (CD95). Classically with prolonged ATP depletion lasting more than 12 hours necrosis of tubular cells becomes more evident. However, both apoptosis and necrosis can be detected in biopsies of patients with ATN. During the recovery phase, apoptosis is thought to be a mechanism involved in the remodeling of the injured renal tubules.
Maladaptive Vascular Reaction
Many studies have demonstrated that following ischemia, the renal vasculature has increased sensitivity to vasoconstrictive stimuli particularly endothelin. Endothelin (ET-1) is a vasoactive substance release by endothelial cells and one of the most potent vasoconstrictors identified. The ET-1 gene has also been shown to be upregulated during ischemic injuries.[1] In parallel, the initial insult following renal ischemia is endothelial dysfunction which contributes to the exacerbation of tissue hypoxia via several mechanisms. Endothelial injury disrupts normal vascular function and impairs reactivity and permeability of renal vessels causing maladaptive vasoconstriction and increased leukocyte recruitment. This is further exacerbated by an increase in vasoconstrictor substances, adhesion molecules, and inflammatory mediators.[2]
Tubular Dysfunction
When exposed to ischemic stress, tubular cells are prone to loss polarity and even detachment of viable cells due to the disruption of key structural anchors. Several important proteins are required for tubular cells to maintain their structure and polarity including the actin cytoskeleton, microvilli, and junctional complexes such as tight junctions and adherens junctions.[3] The initial tubular insult modifies the actin cytoskeleton causing a shift in many major structural and adherence proteins. The earliest finding in ATN is the loss of polarity and brush border membrane.[4] Detachment later occurs mainly due to the displacement of integrins, the main adherence proteins, from a basolateral location to the apex of the cell.[3] Furthermore, necrotic cell debris and apoptotic bodies can be seen in addition to detached viable cells within the tubular lumen. Cells with prolonged ATP depletion undergo necrosis with ensuing inflammation. Apoptosis has also been detected in early phases of renal between 12 and 48 hours after the initial insult.[5] Accumulation of cells and cellular debris along with an overlying immune response within the tubular lumen causes significant obstruction that further aggravates a decreasing GFR.
Other associated dysfunctions include tubular backleak and abnormal tubuloglomerular feedback. With detachment and cell death, loss of the tubular epithelial barrier occurs. This leads to some reabsorption of filtered solutes into the circulation leading to an increase in substances used to estimate GFR including creatinine and inulin. This is known as tubular backleak. However, the tubular backleack phenomenon has not been well substantiated in clinical ATN, and can only account for around 10% of the decrease in GFR. Another important associated dysfunction in ATN is the abnormal tubuloglomerular feedback occuring due to a decrease in the proximal tubular reabsorption of sodium. This leads to an increase in sodium chloride delivery to the macula densa activating the tubuloglomerular feedback. Counter-intuitively, a constriction of the afferent arteriole occurs leading to a decrease in GFR.
References
- ↑ Lameire N, Vanholder R (2001). "Pathophysiologic features and prevention of human and experimental acute tubular necrosis". J Am Soc Nephrol. 12 Suppl 17: S20–32. PMID 11251028.
- ↑ Fogo A, Cohen AH, Colvin RB et al. Fundamentals of Renal Pathology. Springer 2013. Acute Tubular Necrosis. http://dx.doi.org/10.1007/978-3-642-39080-7_15
- ↑ 3.0 3.1 Sutton TA, Molitoris BA (1998). "Mechanisms of cellular injury in ischemic acute renal failure". Semin Nephrol. 18 (5): 490–7. PMID 9754601.
- ↑ Schrier RW, Wang W, Poole B, Mitra A (2004). "Acute renal failure: definitions, diagnosis, pathogenesis, and therapy". J Clin Invest. 114 (1): 5–14. doi:10.1172/JCI22353. PMC 437979. PMID 15232604.
- ↑ Lieberthal W, Koh JS, Levine JS (1998). "Necrosis and apoptosis in acute renal failure". Semin Nephrol. 18 (5): 505–18. PMID 9754603' Check
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