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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
Lecture 48
Tubular
&
Interstitial
Diseases
AKI
ATI
ATN
The most common cause of RENAL FAILURE
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.
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.
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
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
• 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))
AKIaccounts for some
50%of cases of acute
renal failure
in hospitalized patients.
Types of AkI
1. Ischemic
2. Nephrotoxic
3. Mixed
Pathogenesis
• The critical events in both ischemic and
nephrotoxic AKI are believed to be
(1) Tubular injury and
(2)Disturbances in blood flow
Pathogenesis-Tubule cell injury
• Tubular epithelial cells are
particularly
•Sensitive to ischemia
and are also
•Vulnerable to toxins.
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
Pathogenesis: Biochemical changes
• Depletion of ATP;
• Accumulation of intracellular calcium;
• Activation of proteases (e.g., calpain).
Tubular Injury
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
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
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
Pathogenesis
• In time, injured cells detach from the
basement membranes and cause luminal
obstruction, increased intratubular
pressure, and decreased GFR.
Tubular Injury
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
Pathogenesis Disturbances in blood flow
Ischemic renal injury is also characterized by
hemodynamic alterations
that cause reduced GFR.
•
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
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
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.
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.
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
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.
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.
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.
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.
Morphology Ischemic AKI
•Eosinophilic hyaline casts,
as well as pigmented granular casts,
are common, particularly in
distal tubules and
collecting ducts.
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.
Morphology of Ischemic AKI
• Other findings in ischemic AKI are
interstitial edemaand
accumulations of leukocytes within
dilated vasa recta.
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.
Toxic AKI
• Toxic AKI is manifested by
acute tubular injury,
most obvious in the proximal convoluted
tubules.
Toxic AKI
• On histologic examination
• the tubular necrosis
may be entirely nonspecific, but it is
somewhat distinctive in poisoning with
certain agents.
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.
Toxic AKI Carbon tetrachloride poisoning
• is characterized by
• the accumulation of neutral lipids in injured
cells; followed by necrosis.
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.
Acute tubular necrosis
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.
The initiation phase
Lasting for about 36 hours, is dominated
by the inciting medical, surgical, or obstetric
event in the ischemic form of AKI.
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.
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.
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.
The recovery phase
•Hypokalemia, rather than
hyperkalemia, becomes a clinical problem.
There is a peculiar increased vulnerability to
infectionat this stage.
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.
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.
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%.
Acute tubular necrosis

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Acute tubular necrosis

  • 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
  • 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. 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. 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. 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. • 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. AKIaccounts for some 50%of cases of acute renal failure in hospitalized patients.
  • 9. Types of AkI 1. Ischemic 2. Nephrotoxic 3. Mixed
  • 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. Pathogenesis-Tubule cell injury • Tubular epithelial cells are particularly •Sensitive to ischemia and are also •Vulnerable to toxins.
  • 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. Pathogenesis: Biochemical changes • Depletion of ATP; • Accumulation of intracellular calcium; • Activation of proteases (e.g., calpain). Tubular Injury
  • 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. 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. 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. Pathogenesis • In time, injured cells detach from the basement membranes and cause luminal obstruction, increased intratubular pressure, and decreased GFR. Tubular Injury
  • 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. Pathogenesis Disturbances in blood flow Ischemic renal injury is also characterized by hemodynamic alterations that cause reduced GFR. •
  • 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. 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. 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. 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. 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. 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. 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. 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. 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. Morphology Ischemic AKI •Eosinophilic hyaline casts, as well as pigmented granular casts, are common, particularly in distal tubules and collecting ducts.
  • 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. Morphology of Ischemic AKI • Other findings in ischemic AKI are interstitial edemaand accumulations of leukocytes within dilated vasa recta.
  • 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. Toxic AKI • Toxic AKI is manifested by acute tubular injury, most obvious in the proximal convoluted tubules.
  • 34. Toxic AKI • On histologic examination • the tubular necrosis may be entirely nonspecific, but it is somewhat distinctive in poisoning with certain agents.
  • 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. Toxic AKI Carbon tetrachloride poisoning • is characterized by • the accumulation of neutral lipids in injured cells; followed by necrosis.
  • 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.
  • 39. 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.
  • 40. The initiation phase Lasting for about 36 hours, is dominated by the inciting medical, surgical, or obstetric event in the ischemic form of AKI.
  • 41. 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.
  • 42. 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.
  • 43. 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.
  • 44. The recovery phase •Hypokalemia, rather than hyperkalemia, becomes a clinical problem. There is a peculiar increased vulnerability to infectionat this stage.
  • 45. 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.
  • 46. 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.
  • 47. 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%.