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Summary Table

Feature	Detail
Risk Factors	Prolonged hypotension (sepsis, hemorrhage, major surgery), nephrotoxin exposure (aminoglycosides, contrast dye, myoglobin, cisplatin), advanced age, pre-existing CKD, volume depletion, ICU admission
Etiology	Ischemic injury to renal tubular epithelial cells or direct nephrotoxic damage; the two most common causes of intrinsic acute kidney injury
Patient Presentation	Oliguria or anuria developing after a hypotensive episode, major surgery, or nephrotoxin exposure; rising serum creatinine over days; may present with volume overload, uremic symptoms, or electrolyte derangements
Classic Physical Exam	Often noncontributory in isolation; look for signs of the precipitating event (hypotension, sepsis stigmata, rhabdomyolysis with dark urine, recent IV contrast). Peripheral edema, pulmonary crackles if fluid overloaded
Key Diagnostic Results	Urinalysis: muddy brown granular casts and renal tubular epithelial cell casts. $FE_{Na} > 2%$. Urine osmolality $< 350\ \text{mOsm/kg}$. Urine sodium $> 40\ \text{mEq/L}$. BUN:Creatinine ratio $< 20:1$
Management	Supportive: IV fluids for volume optimization, removal of offending nephrotoxins, correction of electrolytes, dialysis if indicated (refractory hyperkalemia, severe metabolic acidosis, volume overload, uremic encephalopathy/pericarditis). Renal recovery expected in 1 to 3 weeks
Keywords	"Muddy brown casts," "post-operative oliguric renal failure," "rising creatinine after aminoglycoside use," "crush injury with dark urine," "contrast-induced nephropathy," "high FENa"

1. Pathophysiology

ATN is the single most common cause of intrinsic acute kidney injury (AKI), and understanding it requires knowing two things: the anatomy of the renal tubule and the concept of a "watershed" blood supply.

The renal tubular epithelial cells, particularly those lining the proximal tubule and the thick ascending limb of the loop of Henle, are metabolically active cells that depend heavily on oxidative phosphorylation. These segments sit in the outer medulla, a zone that operates under physiologically low oxygen tension even under normal conditions. This makes the outer medulla exquisitely vulnerable to any further drop in perfusion. When systemic blood pressure falls (from hemorrhage, sepsis, or cardiac failure), renal blood flow decreases, and these segments are the first to suffer ischemic injury. This is why the classic exam scenario is a patient who develops oliguric AKI after a prolonged hypotensive episode or major surgery.

In the ischemic pathway, the injury progresses through a well-defined sequence. First, ATP depletion causes loss of cell polarity, meaning the $Na^+/K^+$-ATPase pumps redistribute from the basolateral membrane to the apical surface. This disrupts sodium reabsorption, which is why the kidney can no longer concentrate urine and why urinary sodium rises above 40 mEq/L and $FE_{Na}$ exceeds 2%. Damaged cells then slough off into the tubular lumen, forming the characteristic muddy brown granular casts that define ATN on urinalysis. These casts, along with cellular debris, obstruct the tubular lumen and cause a rise in intratubular pressure, which opposes glomerular filtration. Simultaneously, the disrupted tubular basement membrane allows filtrate to leak back into the interstitium ("backleak"), further reducing effective GFR.

In the nephrotoxic pathway, the mechanism is direct cellular toxicity rather than ischemia, but the downstream consequences are identical. Aminoglycosides accumulate in proximal tubular cells via megalin-mediated endocytosis and disrupt mitochondrial function. Contrast dye causes a combination of direct tubular toxicity and medullary vasoconstriction. Myoglobin (from rhabdomyolysis) and hemoglobin (from hemolysis) are freely filtered, precipitate in tubules in acidic conditions, and generate free radicals that damage epithelial cells. Cisplatin, another high-yield nephrotoxin, concentrates in the proximal tubule and causes DNA cross-linking and apoptosis.

The critical clinical concept is the three-phase model of ATN:

The initiation phase (hours to days) is the period of active injury. The insult is occurring, GFR is dropping, and this is the window where early intervention (restoring perfusion, discontinuing the offending agent) can limit damage.
The maintenance phase (1 to 2 weeks) is the oliguric or anuric period. Even after the insult is removed, the kidney remains non-functional because of tubular obstruction, backleak, and ongoing inflammation. Creatinine continues to rise, and this is when complications such as hyperkalemia, metabolic acidosis, and volume overload become dangerous.
The recovery phase begins when tubular cells regenerate. This phase is marked by a polyuric state because the newly regenerated tubular cells are not yet fully functional and cannot properly concentrate urine. During this phase, patients are at risk for volume depletion and electrolyte wasting (hypokalemia, hyponatremia, hypomagnesemia), and careful monitoring with fluid and electrolyte replacement is essential.

2. Classification and Clinical Manifestation

By Etiology

Type	Mechanism	Common Causes	Key Vignette Clues
Ischemic ATN	Sustained hypoperfusion causing tubular epithelial necrosis in the outer medulla	Hemorrhagic shock, septic shock, major cardiac or aortic surgery, severe dehydration, cardiogenic shock	"Blood pressure dropped to 70/40 during surgery," "prolonged ICU stay with vasopressor requirement," "massive GI bleed"
Nephrotoxic ATN	Direct chemical injury to tubular epithelial cells	Aminoglycosides (gentamicin, tobramycin), radiocontrast agents, cisplatin, amphotericin B, vancomycin (at supratherapeutic levels), tenofovir	"Started on gentamicin 5 days ago," "creatinine rise 48 to 72 hours after cardiac catheterization," "receiving cisplatin-based chemotherapy"
Pigment Nephropathy	Myoglobin or hemoglobin precipitation in tubules with free radical injury	Rhabdomyolysis (crush injury, statins, seizures, heat stroke), hemolytic transfusion reactions	"Found unconscious after earthquake," "dark brown urine," "markedly elevated CK," "recent blood transfusion with fever and flank pain"

By Phase

Phase	Duration	Clinical Features	Laboratory Findings
Initiation	Hours to days	Exposure to ischemia or nephrotoxin; urine output begins to fall; patient may still appear clinically stable	Gradual rise in serum creatinine; urine sediment may initially be bland before casts appear
Maintenance (Oliguric)	1 to 2 weeks	Oliguria ($< 400\ \text{mL/day}$) or anuria; volume overload (edema, pulmonary congestion); uremic symptoms (nausea, confusion, pericardial friction rub); electrolyte disturbances	Peak serum creatinine; hyperkalemia, metabolic acidosis (elevated anion gap), hyperphosphatemia, hypocalcemia; muddy brown casts on urinalysis
Recovery (Polyuric)	Days to weeks	Urine output increases dramatically (may exceed 3 to 5 L/day); patient improves clinically but is at risk for dehydration	Creatinine begins to fall; risk of hypokalemia, hyponatremia, and hypomagnesemia due to tubular wasting

Non-oliguric ATN deserves attention because it is frequently tested. Some forms of nephrotoxic ATN (particularly aminoglycoside-induced) present with a rising creatinine but preserved urine output. This is a classic exam trap: students assume AKI always means oliguria. Non-oliguric ATN generally carries a better prognosis.

3. Diagnostic Workup

Test	Finding in ATN	Purpose
Urinalysis with microscopy	Muddy brown granular casts, renal tubular epithelial cell casts	Best initial test; hallmark finding that distinguishes ATN from prerenal azotemia
Fractional excretion of sodium ($FE_{Na}$)	$> 2%$	Differentiates intrinsic renal disease from prerenal azotemia ($FE_{Na} < 1%$)
Fractional excretion of urea ($FE_{Urea}$)	$> 35%$	Used when patient is on diuretics (which falsely elevate $FE_{Na}$); more reliable in this setting
Urine sodium	$> 40\ \text{mEq/L}$	Tubules cannot reabsorb sodium; contrasts with prerenal ($< 20\ \text{mEq/L}$)
Urine osmolality	$< 350\ \text{mOsm/kg}$	Tubules cannot concentrate urine; contrasts with prerenal ($> 500\ \text{mOsm/kg}$)
BUN:Creatinine ratio	$< 20:1$	Both rise proportionally; in prerenal disease, BUN rises disproportionately ($> 20:1$)
Serum creatinine	Rising trend over hours to days	Confirms AKI; serial monitoring required
Basic metabolic panel	Hyperkalemia, metabolic acidosis, hyperphosphatemia, hypocalcemia	Assesses complications of impaired renal function
Creatine kinase (CK)	Markedly elevated ($> 5{,}000\ \text{U/L}$, often $> 10{,}000$)	Ordered when rhabdomyolysis is suspected as the cause
Renal ultrasound	Normal-sized kidneys, no hydronephrosis	Rules out obstructive (postrenal) causes
Renal biopsy	Tubular epithelial necrosis and regeneration	Gold standard but rarely needed; reserved for atypical presentations where clinical diagnosis is uncertain

The workup for ATN is fundamentally an exercise in differential diagnosis. When you encounter a rising creatinine on an exam, the test-writer expects you to systematically categorize the AKI as prerenal, intrinsic, or postrenal before jumping to treatment.

Step 1: Rule out postrenal obstruction. Order a renal ultrasound. If bilateral hydronephrosis is present, the problem is obstructive, and the answer is catheterization or ureteral stent placement. This step is fast and easy, so it comes first.

Step 2: Distinguish prerenal from intrinsic. This is where the exam lives. The key formula is:

$$FE_{Na} = \frac{U_{Na} \times P_{Cr}}{P_{Na} \times U_{Cr}} \times 100$$

A $FE_{Na} < 1%$ suggests the tubules are working properly and avidly reabsorbing sodium in response to decreased perfusion (prerenal). A $FE_{Na} > 2%$ suggests the tubules are damaged and unable to reabsorb sodium (intrinsic, consistent with ATN). However, if the patient is on diuretics, $FE_{Na}$ becomes unreliable because diuretics artificially increase urinary sodium excretion. In this setting, use $FE_{Urea}$: a value $> 35%$ suggests intrinsic disease.

Step 3: Examine the urine sediment. This is the single most discriminating test. Muddy brown granular casts are pathognomonic for ATN and will not appear in prerenal azotemia (which shows a bland sediment or hyaline casts). The vignette will often describe these casts, and that alone should clinch the diagnosis. Other urine sediment findings point to other intrinsic causes: RBC casts suggest glomerulonephritis, WBC casts suggest interstitial nephritis or pyelonephritis, and fatty casts (oval fat bodies) suggest nephrotic syndrome.

Step 4: Identify the precipitant. Once you have confirmed ATN, determine whether the cause is ischemic (look for preceding hypotension, surgery, sepsis), nephrotoxic (look for recent drug exposure), or pigment-related (look for crush injury, elevated CK, dark urine). This determines preventive strategy.

4. Management and Treatment

Phase / Scenario	Intervention	Details
Remove the offending agent	Discontinue nephrotoxins	Stop aminoglycosides, hold contrast dye, switch to less nephrotoxic alternatives; this is always the first step
Volume resuscitation (ischemic ATN)	Isotonic saline (0.9% NaCl)	Restore renal perfusion; target MAP $\geq 65\ \text{mmHg}$; avoid over-resuscitation once euvolemic
Rhabdomyolysis-induced ATN	Aggressive IV normal saline	Target urine output $200\text{--}300\ \text{mL/hr}$; IV fluids at 1 to 1.5 L/hr initially; alkalinization of urine with IV sodium bicarbonate (target urine pH $> 6.5$) is sometimes used but remains debated
Contrast-induced ATN prevention	Pre-procedure IV normal saline hydration	1 mL/kg/hr for 6 to 12 hours before and 6 to 12 hours after contrast exposure; use low-osmolar or iso-osmolar contrast agents; hold metformin (risk of lactic acidosis with concurrent AKI)
Hyperkalemia	Calcium gluconate, insulin + glucose, sodium bicarbonate, kayexalate, loop diuretics, or dialysis	Calcium gluconate stabilizes the cardiac membrane (does not lower potassium); insulin drives potassium intracellularly; dialysis for refractory cases
Metabolic acidosis	IV sodium bicarbonate if pH $< 7.1$; dialysis if refractory	Correct severe acidemia; mild acidosis often resolves with restoration of renal function
Volume overload	Loop diuretics (furosemide 40 to 80 mg IV) or dialysis	Furosemide may convert oliguric to non-oliguric ATN (prognostically favorable) but does not change overall mortality or accelerate recovery
Dialysis indications	Emergent hemodialysis	Indicated for refractory hyperkalemia, severe metabolic acidosis ($pH < 7.1$), refractory volume overload (pulmonary edema), uremic symptoms (encephalopathy, pericarditis, bleeding), and certain toxic ingestions
Recovery (polyuric) phase	Monitor and replace fluids and electrolytes	Watch for hypokalemia, hyponatremia, hypomagnesemia; replace IV fluids to match urine output; frequent electrolyte checks

The first principle of ATN management is that there is no pharmacologic therapy that reverses established ATN. The tubular epithelium must regenerate on its own, and supportive care is the cornerstone of treatment. This concept is tested frequently: dopamine, mannitol, and fenoldopam have all been studied and none have shown benefit. If an exam question offers "low-dose renal dopamine" as a treatment option for ATN, it is a distractor.

Step 1 is always to identify and remove the precipitant. If the patient is on an aminoglycoside, discontinue it. If hypotension caused the injury, restore perfusion with IV fluids and vasopressors as needed. If contrast dye was the trigger, ensure adequate hydration and avoid repeat exposure.

Step 2 is volume management. If the patient is hypovolemic (prerenal component contributing to ischemic ATN), isotonic crystalloid is the fluid of choice. If the patient is euvolemic or hypervolemic with pulmonary edema, loop diuretics or dialysis may be required. Furosemide is frequently tested: it can increase urine output and potentially convert oliguric ATN to non-oliguric ATN, which is associated with a better prognosis and easier fluid management. However, furosemide does not improve mortality or hasten tubular recovery, and it should not be used to "treat" ATN.

Step 3 is managing the complications of renal failure. Hyperkalemia is the most immediately life-threatening complication. The sequence is: (1) ECG to assess for peaked T waves, widened QRS, or sine wave pattern; (2) calcium gluconate if ECG changes are present (membrane stabilizer, buys time); (3) insulin (10 units regular IV) with dextrose (25 g IV) to shift potassium intracellularly; (4) definitive potassium removal via dialysis if refractory.

Step 4 is dialysis decision-making. The classic indications are remembered by the mnemonic AEIOU: Acidosis (refractory), Electrolyte abnormalities (refractory hyperkalemia), Ingestion (of dialyzable toxins), Overload (volume, refractory to diuretics), and Uremia (encephalopathy, pericarditis, bleeding diathesis). On an exam, if a patient with ATN develops any of these complications and medical management has failed, the next best step is hemodialysis.

For rhabdomyolysis-induced ATN, the key preventive and early treatment measure is aggressive IV fluid resuscitation with normal saline, targeting high-volume urine output. Urine alkalinization with sodium bicarbonate (goal urine pH $> 6.5$) is used at some centers to reduce myoglobin precipitation, but evidence remains mixed. Avoid lactated Ringer's in this setting because it contains potassium, and these patients are often already hyperkalemic from muscle breakdown.

For contrast-induced ATN prevention, the evidence-supported strategy is pre- and post-procedure IV normal saline hydration. N-acetylcysteine (NAC) was previously recommended but recent large trials (particularly the PRESERVE trial) showed no benefit, so it is no longer considered standard of care. If an exam offers NAC as the "best" preventive strategy, it is likely a distractor; IV saline hydration is the answer.

5. Differential Diagnosis and Distractors

Differential	Why It Looks Similar	Key Discriminator
Prerenal azotemia	Rising creatinine, oliguria, occurs after hypotension or dehydration; identical clinical scenario to early ischemic ATN	$FE_{Na} < 1%$, urine osmolality $> 500\ \text{mOsm/kg}$, bland urine sediment (hyaline casts or no casts), BUN:Cr $> 20:1$. Creatinine improves rapidly with fluid resuscitation. ATN does not improve with fluids once established
Acute interstitial nephritis (AIN)	Drug-induced AKI with rising creatinine after starting a new medication; can mimic nephrotoxic ATN	Classic triad of fever, rash, and eosinophilia; urinalysis shows WBC casts and eosinophiluria (not muddy brown casts). Common culprits: NSAIDs, penicillins, cephalosporins, proton pump inhibitors, rifampin
Glomerulonephritis (GN)	Intrinsic AKI with abnormal urine sediment; both cause elevated creatinine and may present with oliguria	Urinalysis shows RBC casts and dysmorphic red blood cells (not muddy brown casts). Often accompanied by proteinuria, hypertension, and signs of a systemic disease (lupus, ANCA vasculitis, post-streptococcal infection)
Obstructive uropathy (postrenal AKI)	Rising creatinine with oliguria/anuria; may develop suddenly after surgery or in elderly patients with BPH	Bilateral hydronephrosis on renal ultrasound. History of BPH, pelvic malignancy, nephrolithiasis, or recent instrumentation. Creatinine improves after catheterization or stent placement
Hepatorenal syndrome (HRS)	Rising creatinine with low urine sodium and $FE_{Na} < 1%$ in a hospitalized patient, mimicking prerenal physiology	Occurs exclusively in the setting of advanced liver disease with portal hypertension (cirrhosis, ascites, jaundice). Does not respond to IV fluid challenge. Bland urine sediment. Treatment is albumin + vasopressors (midodrine + octreotide or terlipressin), not just fluids
Atheroembolic renal disease	AKI developing after a vascular procedure (catheterization, vascular surgery), mimicking contrast nephropathy	Onset is delayed (days to weeks after the procedure, not 24 to 72 hours). Physical exam shows blue/purple toes (livedo reticularis) despite palpable pulses. Labs show eosinophilia, low complement, elevated ESR. Urinalysis may show cholesterol clefts on biopsy
Thrombotic microangiopathy (TTP/HUS)	AKI with schistocytes and low platelets; may overlap with pigment nephropathy in terms of dark urine	Microangiopathic hemolytic anemia (schistocytes on smear, elevated LDH, low haptoglobin) with thrombocytopenia. Normal coagulation studies (PT/PTT). TTP features neurologic symptoms; HUS features diarrhea (often bloody, E. coli O157:H7)

6. Traps and High-Yield Pearls

The most common way students lose points on ATN questions is by confusing it with prerenal azotemia. Both conditions can follow hypotension, both cause oliguria, and both produce a rising creatinine. The entire diagnostic strategy hinges on the urine studies: prerenal azotemia shows concentrated urine with low sodium and a bland sediment (the tubules are working and compensating for low perfusion), while ATN shows dilute urine with high sodium and muddy brown casts (the tubules are damaged and unable to do their job). A vignette describing a post-surgical patient with oliguria and a rising creatinine is testing whether you can make this distinction. The answer to "what is the best next step?" is almost always to check urinalysis with microscopy and calculate $FE_{Na}$.

A second common trap involves diuretic use confounding $FE_{Na}$. If the patient is on furosemide or another loop diuretic, $FE_{Na}$ will be falsely elevated even in prerenal azotemia, because the diuretic blocks sodium reabsorption. In this scenario, the correct test is $FE_{Urea}$, which is not affected by diuretics. A $FE_{Urea} > 35%$ confirms intrinsic renal disease; a $FE_{Urea} < 35%$ suggests prerenal physiology. If you see a question where the $FE_{Na}$ is elevated but the patient is on diuretics, do not automatically call it ATN.

A third trap targets the recovery phase. Students focus on the oliguric phase and forget that the polyuric recovery phase carries its own dangers. When the question describes a patient with ATN whose creatinine is now trending down but who suddenly develops weakness, cardiac arrhythmias, or muscle cramps, the answer is hypokalemia from renal potassium wasting during the diuretic recovery phase. The correct management is aggressive potassium monitoring and replacement.

Finally, remember that contrast-induced nephropathy (a form of nephrotoxic ATN) has a predictable timeline: creatinine rises within 24 to 72 hours of contrast exposure and typically peaks at 3 to 5 days. If a vignette describes AKI occurring weeks after a catheterization with livedo reticularis and eosinophilia, that is atheroembolic disease, not contrast nephropathy. This timeline distinction is a favorite exam question.

The core competency being tested with ATN is your ability to correctly localize the cause of AKI (prerenal vs. intrinsic vs. postrenal), use urine studies to confirm the diagnosis, manage complications supportively, and recognize when dialysis is indicated.

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