LECTURE SLIDES ON ACUTE TUBULAR NECROSIS #NEPHROLOGY # INTERNAL MEDICINE

1. ACUTE TUBULAR NECROSIS
(ATN)
PRESENTER: DR.SOHAN BISWAS, DNB JR-2,
DEPARTMENT OF INTERNAL MEDICINE,
MAX SUPERSPECIALITY HOSPITAL

2. • Most common intrinsic cause of acute kidney injury
• Renal tubular cell damage and death
• Term ‘tubular necrosis’ is a misnomer, as true cellular necrosis is
usually minimal
• Acute tubular necrosis is precipitated by an acute ischemic or toxic
event or sepsis.

5. Ischemic-Induced Acute Tubular Necrosis:
-Any factor that leads to prerenal azotemia can lead to ischemic acute
tubular necrosis.
-Hypovolemic states such as diarrhoea, vomiting, bleeding, dehydration,
burns, renal losses via diuretics or osmotic diuresis, and third space
sequestration.

6. Ischemic-Induced Acute Tubular Necrosis:
-Oedematous states such as heart failure and cirrhosis cause reduced
kidney perfusion.
-Sepsis or anaphylaxis leads to systemic vasodilation.
-Coagulopathy, such as disseminated intravascular coagulation, can also
cause acute tubular necrosis.

7. Nephrotoxic-Induced Acute Tubular Necrosis:
• ENDOTOXINS MEDIATED:
--Heme pigment-containing proteins such as hemoglobin and myoglobin
--Crystal-induced nephropathy due to high cell turnover such as uric
acid, calcium phosphate crystals in the setting of ongoing malignancy
treatment
--Light chain accumulation in multiple myeloma

8. Nephrotoxic-Induced Acute Tubular Necrosis:
• EXOTOXIN MEDIATED:
• Drugs such as aminoglycoside, amphotericin B, radiocontrast media,
sulpha drugs, acyclovir, cisplatin, calcineurin inhibitors (tacrolimus,
cyclosporine), mTOR inhibitors (everolimus), intravenous
immunoglobulin etc..

9. Sepsis-Induced Acute Tubular Necrosis
• Systemic hypotension and renal hypoperfusion.
• Inflammatory cytokines and reactive oxygen species
• Bacterial toxins

10. HISTOLOGY
• Typical features of ATN include vacuolization and loss of brush border
in proximal tubular cells.
• Sloughing of tubular cells into the lumen leads to cast obstruction,
manifested by tubular dilation.

12. EVALUATION
• The workup is usually to differentiate acute tubular necrosis from
prerenal AKI and other causes of AKI

14. Ratio of Blood Urea Nitrogen to Creatinine
• In prerenal AKI the ratio may exceed 20:1 because of a disproportionate
increase in urea reabsorption resulting from elevated serum vasopressin
levels.
• Upper gastrointestinal tract bleeding, impaired protein anabolism (e.g.,
systemic corticosteroid administration), increased catabolism (e.g., sepsis),
and increased protein intake all raise BUN levels.
• Furthermore, diminished urea production from decreased protein intake
or underlying liver disease are associated with lower BUN levels.

15. Fractional Excretion of Sodium and Urea
• FENa = [U/S] Na / [U/S] Cr × 100%
• Basic premise is that renal tubular cells will reabsorb sodium in the
prerenal setting, whereas tubules damaged by ATN will not.
• FENa less than 1% is consistent with prerenal AKI, and FENa greater
than 3% is typical of ATN

16. • However, FENa may be less than 1% despite ATN in the setting of
sepsis, hemoglobinuria or myoglobinuria, radiocontrast exposure,
heart failure, and advanced cirrhosis
• Underlying CKD, diuretic use, recent intravenous fluid administration,
glycosuria, bicarbonaturia, and salt wasting disorders may be
associated with elevated FENa despite the presence of prerenal AKI

17. • Urea reabsorption, primarily occurring in proximal tubules, is less
affected by loop and thiazide diuretics, and the fractional excretion of
urea (FEUrea) may be an alternative to FENa in patients receiving
diuretics.
• The calculation of FEUrea is identical to that of FENa, and values less
than 35% favor prerenal AKI over ATN.

18. • Urinalysis (UA)
--In prerenal disease, the UA microscopy is normal or may contain hyaline
casts.
--UA of acute tubular necrosis - muddy brown casts
• Urine sodium concentration:
• This test determines whether kidney is trying to conserve sodium or lose
sodium due to tubular injury with values more than 40 to 50 mEq/L
indicating acute tubular necrosis and less than 20 mEq/L suggestive of
prerenal disease

19. URINE – MUDDY BROWN GRANULAR CASTS
• In hospitalized patients with AKI, the presence of more than 10
granular casts per low-power field had a positive predictive value of
100% for a final diagnosis of ATN

20. Kidney Biopsy
• Kidney biopsy is reserved for patients in whom prerenal and postrenal
AKI have been excluded and the cause of intrinsic AKI remains unclear
• Particularly useful when clinical assessment and laboratory
investigations suggest diagnoses other than ischemic or nephrotoxic
injury that may respond to disease specific therapy (e.g., vasculitis,
systemic lupus erythematosus, and AIN).

21. MANAGEMENT
• 1) Treatment of the underlying cause
• 2) Maintain Fluid balance/avoid pre-renal insult
• 3) Diuretics not indicated to convert oliguric AKI to non-oliguric
AKI(only indicated for fluid overload – may need RRT)
• 4) Avoid and stop all nephrotoxic drugs

22. • Indications for urgent dialysis in patients with ATN include the
following:
• Refractory fluid overload
• Severe hyperkalemia
• Signs of uremia (eg, pericarditis, encephalopathy, altered
mental status)
• Severe metabolic acidosis (pH < 7.1)

23. • In patients without an indication for dialysis, initiating renal
replacement therapy (RRT) prophylactically offers no benefit
over performing RRT as and when required. Several trials and
meta-analysis have shown no improvement in outcome with
early versus late RRT for patients with AKI

24. COMPLICATIONS OF ATN
• Volume overload
• Acid-base and electrolyte imbalances, especially Hyperkalemia,
acidosis, hyperphosphatemia, and hypocalcemia
• Uremia, leading to problems such as prolonged bleeding,
altered mental status, and pericardial disease

25. NEW BIOMARKERS

26. Neutrophil Gelatinase-Associated Lipocalin(NGAL)
• Widely expressed in a variety of adult human tissues, including prostate,
salivary gland, stomach, colon, trachea, lung, liver and kidney
• Major renal source of urinary NGAL is from the thick ascending limb and
collecting ducts.
• Non-specific plasma NGAL can be filtered through glomeruli and be absorbed
in the proximal tubules

27. • Thus, urine NGAL elevation could reflect the decreased absorption of filtered
NGAL due to dysfunction or injury in the proximal tubules and/or increased
NGAL release from the thick ascending limb and collecting ducts
• Dramatically upregulated following ischemic or nephrotoxic kidney injury.
• As early as 3h following the injury, elevated NGAL protein is detectable in the
urine

28. Liver-Type Fatty Acid-Binding Protein(L-FABP)
• Expressed in the proximal tubules.
• Urinary L-FABP levels increase almost immediately and peak within 6 h after
tubular injury
• Exact function of L-FABP is yet to be fully elucidated. It is however considered
a renal protective protein in general.
• It binds to and promotes the metabolism of fatty acids and possesses
antioxidant properties

29. Interleukin-18
• Pro-inflammatory cytokine formed in the proximal tubular cells.
• Urinary IL-18 is elevated following renal injury
• AKI patients with high urine IL-18 concentration could potentially benefit from
anti-IL-18 therapy, although its utility is yet to be validated

30. Urinary Insulin-Like Growth Factor-Binding Protein 7 and Tissue
Inhibitor of Metalloproteinase-2
• TIMP-2 and IGFBP-7 are inducers of G1 cell cycle arrest of renal tubular cells,
which occurs during the early period of cell injury caused by ischemic or
inflammatory processes
• Failure to achieve G1 cell cycle arrest can lead to an increased proportion of
renal tubular cells in the G2/M phase, which in the animal model shows to be
correlated with lasting kidney damage, including extensive glomerulosclerosis
and interstitial fibrosis

31. Serum and Urine Kidney Injury Molecule 1
• Very low expression in the normal kidney. Its expression is markedly
upregulated after ischemia-reperfusion injury.
• Reflects the proliferating dedifferentiated epithelial cells of the proximal
tubules and appears to peak at approximately 48 h
• Promotes epithelial regeneration and regulates tubule cell apoptosis.

32. • Persistent KIM-1 elevation in blood, however, indicates ongoing tubular injury,
which would be a risk for the development of CKD/ESRD.
• Urinary KIM-1 shows similar correlation of kidney injury

33. CLINICAL CASE – 1 (SEPSIS INDUCED ATN)
• Mrs. Johnson is brought to the emergency department by ambulance with a one-day
history of high fever, confusion, and decreased urine output. She has a known diabetic
foot ulcer for which she has been receiving outpatient wound care.
• Initial Assessment:
• Vital Signs: Blood pressure 90/60 mmHg, heart rate 120 bpm, respiratory rate 24
breaths/min, temperature 39.5°C.
• Physical Examination: Mrs. Johnson appears acutely ill and disoriented. She has cool
extremities with weak peripheral pulses. Lung examination reveals bilateral crackles. Her
foot ulcer shows signs of cellulitis with surrounding erythema and tenderness.
• Laboratory Investigations:
• Serum Creatinine: 4.0 mg/dL (baseline 1.0 mg/dL)
• Blood Urea Nitrogen (BUN): 50 mg/dL
• Serum Potassium: 5.6 mmol/L
• White Blood Cell Count: 20,000/mm³ with left shift
• Arterial Blood Gas (ABG): pH 7.32, pCO2 30 mmHg, HCO3- 18 mmol/L
• Urinalysis: Proteinuria (3+), muddy brown granular casts, few red blood cells, few white blood cells.

34. CLINICAL CASE – 2(NEPHROTOXIC INDUCED
ATN)
• Mr. Lee presents to the emergency department with complaints of nausea,
vomiting, and decreased urine output for the past two days. He reports recent
use of over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs) for
worsening knee pain.
• Initial Assessment:
• Vital Signs: Blood pressure 140/90 mmHg, heart rate 80 bpm, respiratory rate
16 breaths/min, temperature 37.0°C.
• Physical Examination: Mr. Lee appears dehydrated and mildly lethargic. His
abdomen is soft and non-tender with no rebound tenderness. Lung and heart
examinations are unremarkable.
• Laboratory Investigations:
• Serum Creatinine: 3.5 mg/dL (baseline 1.0 mg/dL)
• Blood Urea Nitrogen (BUN): 45 mg/dL
• Serum Potassium: 5.2 mmol/L
• Urinalysis: Proteinuria (1+), muddy brown granular casts, few red blood cells, few white
blood cells.

35. CLINICAL CASE – 3(ISCHEMIA INDUCED ATN)
• Mr. Johnson is brought to the emergency department by ambulance following a motor
vehicle accident. He was found unconscious at the scene and is now awake but
confused. He complains of severe abdominal pain and has not passed urine since the
accident.
• Initial Assessment:
• Vital Signs: Blood pressure 90/60 mmHg, heart rate 110 bpm, respiratory rate 22
breaths/min, temperature 37.2°C.
• Physical Examination: Mr. Johnson appears lethargic and in distress. His abdomen is
tender on palpation, with guarding and rebound tenderness in the bilateral flanks. There
are no other significant findings on cardiovascular or respiratory examination.
• Laboratory Investigations:
• Serum Creatinine: 6.0 mg/dL (baseline unknown)
• Blood Urea Nitrogen (BUN): 70 mg/dL
• Serum Potassium: 6.2 mmol/L
• Arterial Blood Gas (ABG): pH 7.28, pCO2 30 mmHg, HCO3- 18 mmol/L
• Urinalysis: Proteinuria (3+), muddy brown granular casts, few red blood cells, few white blood cells.

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