Acute tubular necrosis


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Acute tubular necrosis

  1. 1. Tubular and Interstitial Diseases • (1) ischemic or toxic tubular injury, leading to acute kidney injury (AKI) or ATN and acute renal failure, and • (2) inflammatory reactions of the tubules and interstitium (tubulointerstitial nephritis). Acute Kidney Injury Tubulointerstitial Nephritis
  2. 2. Lecture 48 Tubular & Interstitial Diseases AKI ATI ATN The most common cause of RENAL FAILURE
  3. 3. ACUTE KIDNEY INJURY (AKI) (ACUTE TUBULAR NECROSIS, ATN) ATN is a clinicopathologic entity characterized clinically by Acute reduction of renal function and often, but not invariably, morphologic evidence of tubular injury.
  4. 4. AKI / ATI / ATN • It is the most common cause of acute renal failure, which signifies rapid reduction of renal function and urine flow, falling within 24 hours to less than 400 mL per day.
  5. 5. Causes of AKI 1. Ischemia due to decreased or interrupted blood flow, 2. Direct toxic injury to the tubules 3. Acute tubulointerstitial nephritis 4. Urinary obstruction
  6. 6. ISCHEMIA • Examples: • diffuse involvement of the intrarenal blood vessels such as in microscopic polyangiitis, malignant hypertension, microangiopathies • systemic conditions associated with thrombosis (e.g., hemolytic uremic syndrome [HUS], thrombotic thrombocytopenic pupura [TTP], • disseminated intravascular coagulation [DIC]), • decreased effective circulating blood volume
  7. 7. • Direct toxic injury to the tubules (e.g., by drugs, radiocontrast dyes, myoglobin, hemoglobin, radiation) • • Acute tubulointerstitial nephritis, most commonly occurring as a hypersensitivity reaction to drugs • • Urinary obstruction by tumors, prostatic hypertrophy, or blood clots (so-called postrenal acute renal failure))
  8. 8. AKIaccounts for some 50%of cases of acute renal failure in hospitalized patients.
  9. 9. Types of AkI 1. Ischemic 2. Nephrotoxic 3. Mixed
  10. 10. Pathogenesis • The critical events in both ischemic and nephrotoxic AKI are believed to be (1) Tubular injury and (2)Disturbances in blood flow
  11. 11. Pathogenesis-Tubule cell injury • Tubular epithelial cells are particularly •Sensitive to ischemia and are also •Vulnerable to toxins.
  12. 12. Pathogenesis Tubular Injury Ischemia causes numerous structural and functional alterations in epithelial cells. The structural changes include those of reversible injury (such as cellular swelling, loss of brush border and polarity, blebbing, and cell detachment) and those associated with lethal injury (necrosis and apoptosis). TubularInjury
  13. 13. Pathogenesis: Biochemical changes • Depletion of ATP; • Accumulation of intracellular calcium; • Activation of proteases (e.g., calpain). Tubular Injury
  14. 14. Pathogenesis: Biochemical changes cause: • Cytoskeletal disruption; • Activation of phospholipases, which damage membranes; • Generation of reactive oxygen species; and • Activation of caspases, • which induce apoptotic cell death. Tubular Injury
  15. 15. Cell polarity refers to spatial differences in the shape, structure, and function of cells. • One early reversible result of ischemia is loss of cell polarity due to redistribution of membrane proteins (e.g., the enzyme Na+ , K+ -ATPase) from the basolateral to the luminal surface of the tubular cells, resulting in abnormal ion transport across the cells, and • increased sodium delivery to distal tubules. • The latter incites vasoconstriction via tubuloglomerular feedback. Pathogenesis Tubular Injury
  16. 16. Pathogenesis- Cytokines & Adhesion molecules • In addition, ischemic tubular cells express cytokines (such as monocyte chemoattractant protein 1) and adhesion molecules (such as intercellular adhesion molecule 1), thus recruiting leukocytes that appear to participate in the subsequent injury. Tubular Injury
  17. 17. Pathogenesis • In time, injured cells detach from the basement membranes and cause luminal obstruction, increased intratubular pressure, and decreased GFR. Tubular Injury
  18. 18. Pathogenesis • In addition, fluid from the damaged tubules leaks into the interstitium, resulting in interstitial edema, increased interstitial pressure, and further damage to the tubule. All these effects contribute to the decreased GFR. Tubular Injury
  19. 19. Pathogenesis Disturbances in blood flow Ischemic renal injury is also characterized by hemodynamic alterations that cause reduced GFR. •
  20. 20. Pathogenesis Disturbances in blood flow The major one is intrarenal vasoconstriction, which results in both • reduced glomerular blood flow and • reduced oxygen delivery to the functionally important tubules in the outer medulla (thick ascending limb and straight segment of the proximal tubule). Hemodynamic alterations
  21. 21. Several vasoconstrictor pathways have been implicated, including: • The renin-angiotensin system, stimulated by increased distal sodium delivery (via tubuloglomerular feedback), and sublethal endothelial injury, leading to increased release of the vasoconstrictor endothelin and decreased production of the vasodilators nitric oxide and prostacyclin (prostaglandin I2). Pathogenesis- Disturbances in blood flow- vasoconstriction
  22. 22. Pathogenesis • There is also some evidence of • a directeffect of ischemia or toxins on the glomerulus, causing a reduced glomerular ultrafiltration coefficient, possibly due to mesangial contraction.
  23. 23. Pathogenesis • The patchiness of tubular necrosis and maintenance of the integrity of the basement membrane along many segments allow ready repair of the necrotic foci and recovery of function if the precipitating cause is removed. • This repair is dependent on the capacity of reversibly injured epithelial cells to proliferate and differentiate.
  24. 24. Re-epithelialization is mediated by a variety of growth factors and cytokines: 1. Autocrine stimulation: Produced locally by the tubular cells themselves 2. Paracrine stimulation: By inflammatory cells in the vicinity of necrotic foci. Pathogenesis
  25. 25. Pathogenesis Re-epitheliazation by growth factors: 1. Epidermal growth factor, 2. TGF-α, 3. Insulin-like growth factor type 1, and 4. Hepatocyte growth factor are particularly important in renal tubular repair.
  26. 26. Structural & Functional alteration in Epithelial cells:Biochemical Changes From basement membrane Injured cells Luminal Disturbances in blood flow Hemodynamic alterations Vasoconstrictor pathways ↓ATP ↑Ca Act.of caspases Reepithilization by cytokines & growth factors Cytokines + Adhesion Molecules=Leukocytes=Injury In addition, fluid from the damaged tubules leaks into the interstitium, resulting in interstitial edema, increased interstitial pressure, and further damage to the tubule. All these effects contribute to the decreased GFR.
  27. 27. Morphology Ischemic AKI • focal tubular epithelial necrosis at multiple points along the nephron, with large skip areas in between, often accompanied by • rupture of basement membranes (tubulorrhexis) and • occlusion of tubular lumens by casts.
  28. 28. Morphology of Ischemic AKI • The straight portion of the proximal tubule and the ascending thick limb in the renal medulla are especially vulnerable, but focal lesions may also occur in the distal tubule, often in conjunction with casts.
  29. 29. Morphology Ischemic AKI •Eosinophilic hyaline casts, as well as pigmented granular casts, are common, particularly in distal tubules and collecting ducts.
  30. 30. Morphology of Ischemic AKI • These casts consist principally of Tamm-Horsfall protein (a urinary glycoprotein normally secreted by the cells of ascending thick limb and distal tubules) in conjunction with other plasma proteins.
  31. 31. Morphology of Ischemic AKI • Other findings in ischemic AKI are interstitial edemaand accumulations of leukocytes within dilated vasa recta.
  32. 32. There is also evidence of epithelial regeneration: Flattened epithelial cells with hyperchromatic nuclei and mitotic figures are often present. In the course of time this regeneration repopulates the tubules so that, no residual evidence of damage is seen.
  33. 33. Toxic AKI • Toxic AKI is manifested by acute tubular injury, most obvious in the proximal convoluted tubules.
  34. 34. Toxic AKI • On histologic examination • the tubular necrosis may be entirely nonspecific, but it is somewhat distinctive in poisoning with certain agents.
  35. 35. Toxic AKI with Mercuric chloride • Severely injured cells may contain large acidophilic inclusions. Later, these cells become totally necrotic, are desquamated into the lumen, and may undergo calcification.
  36. 36. Toxic AKI Carbon tetrachloride poisoning • is characterized by • the accumulation of neutral lipids in injured cells; followed by necrosis.
  37. 37. Toxic AKI Ethylene glycol • produces marked ballooning and • hydropic or vacuolar degeneration of proximal convoluted tubules. • Calcium oxalate crystals are often found in the tubular lumens in such poisoning.
  38. 38. Clinical Course The clinical course of AKI is highly variable, but the classic case may be divided into 1.initiation, 2. maintenance, and 3.recovery stages.
  39. 39. The initiation phase Lasting for about 36 hours, is dominated by the inciting medical, surgical, or obstetric event in the ischemic form of AKI.
  40. 40. The Initiation Phase • The only indication of renal involvement is a slight decline in urine output with a rise in BUN. • At this point, oliguria could be explained on the basis of a transient decrease in blood flow and declining GFR.
  41. 41. The maintenance phase • is characterized by sustained decreases in urine output to between 40 and 400 mL/day (oliguria), salt and water overload, rising BUN concentrations, hyperkalemia, metabolic acidosis, and other manifestations of uremia.
  42. 42. The recovery phase • a steady increase in urine volume that may reach up to 3 L/day. • The tubules are still damaged, so large amounts of water, sodium, and potassium are lost in the flood of urine.
  43. 43. The recovery phase •Hypokalemia, rather than hyperkalemia, becomes a clinical problem. There is a peculiar increased vulnerability to infectionat this stage.
  44. 44. The recovery phase • Eventually, renal tubular function is restored and concentrating ability improves. At the same time, BUN and creatinine levels begin to return to normal. Subtle tubular functional impairment may persist for months, but most patients who reach this phase eventually recover completely.
  45. 45. Nonoliguric AKI • Up to 50% of patients with AKI do not have oliguria and instead often have increased urine volumes. • This so-called nonoliguric AKI occurs particularly often with nephrotoxins, and it generally tends to follow a more benign clinical course.
  46. 46. Prognosis • With current supportive care, 95% Conversely, in shock related to sepsis, extensive burns, or other causes of multi- organ failure, the mortality rate can rise to more than 50%.