Intrinsic AKI by Anatomic Compartment
Intrinsic acute kidney injury is best organized by which anatomic compartment of the nephron is damaged: the tubules, the interstitium, the glomeruli, or the vasculature. Each compartment has a characteristic combination of common causes, urine sediment, degree of proteinuria, systemic clues, and clinical course. Mastering these patterns lets you localize the lesion from the urinalysis alone and reason toward the correct diagnosis and management.
Tubular — Acute Tubular Necrosis (ATN)
ATN results from ischemia, nephrotoxins, or pigments (e.g., myoglobin, hemoglobin). Ischemic ATN follows prolonged hypoperfusion—hemorrhagic or septic shock, major (especially cardiac or aortic) surgery, or prolonged hypotension—with the medulla being particularly vulnerable because it operates at low oxygen tension. The hallmark urine sediment is muddy brown granular casts and tubular epithelial cells, and proteinuria is mild (<1 g/day). Look for systemic clues such as recent hypotension, surgery, or nephrotoxin exposure. The clinical course classically evolves through an initiation phase (creatinine rises), a maintenance phase (low GFR lasting 1–2 weeks), and a recovery phase in which tubular regeneration occurs and polyuria may develop as concentrating ability returns last. Recovery typically occurs over 1–3 weeks if the inciting cause is removed.
Interstitial — Acute Interstitial Nephritis (AIN)
AIN is most often a drug reaction—classic culprits include penicillins and cephalosporins (often within days), NSAIDs (can occur after months of use), proton pump inhibitors (delayed, weeks to months), fluoroquinolones, sulfonamides, allopurinol, and rifampin—as well as infection. The urine typically shows WBC casts and sterile pyuria. Eosinophiluria was historically taught as a marker but has poor sensitivity and specificity and is no longer recommended to diagnose or exclude AIN. Proteinuria is usually mild (<1 g/day), but there is one important exception: NSAID-induced AIN can be accompanied by concurrent minimal-change disease, producing nephrotic-range proteinuria—a classic, testable distinguishing feature. The classic triad of fever, rash, and eosinophilia is present in less than 10% of cases overall (the higher ~25–30% figure was specific to historical methicillin-induced AIN); arthralgias may occur. Management centers on stopping the offending drug; steroids may accelerate recovery but the evidence is limited and their use is controversial. Recovery usually occurs over weeks after the drug is stopped but may be incomplete.
Glomerular — Glomerulonephritis (GN)
Glomerular AKI arises from post-infectious GN, ANCA-associated vasculitis, anti-GBM disease, and lupus. The defining urine finding is RBC casts (pathognomonic for glomerular bleeding) with dysmorphic RBCs. In the nephritic pattern, proteinuria is characteristically sub-nephrotic (<3.5 g/day); frank nephrotic-range proteinuria is the exception rather than the rule. Systemic clues include hypertension, edema, hematuria (often gross, 'cola-colored'), and signs of systemic vasculitis. The nephritic picture reflects inflammatory infiltration of the glomerulus that disrupts the filtration barrier (allowing blood into the filtrate) and reduces GFR, causing sodium and water retention with resulting hypertension. The course is variable and often requires immunosuppression. Post-streptococcal GN is the nephritic prototype: it follows group A strep by 1–3 weeks (pharyngitis) or 3–6 weeks (skin infection) with low C3 that normalizes in 6–8 weeks, and carries an excellent renal prognosis in children.
Vascular
Vascular intrinsic AKI includes TTP/HUS, vasculitis, cholesterol (atheroembolic) disease, and malignant hypertension. The urine sediment is variable—it may be bland or contain RBCs—and proteinuria is likewise variable. Systemic clues are key to the diagnosis: microangiopathic hemolytic anemia (MAHA) with thrombocytopenia points to TTP/HUS, while livedo reticularis and blue (cyanotic) toes suggest cholesterol emboli. The clinical course depends entirely on the underlying cause.
The Localizing Approach
Because each compartment 'signs its work' in the urine, the sediment localizes the lesion. Muddy brown granular casts → tubular (ATN). WBC casts and sterile pyuria → interstitial (AIN). RBC casts and dysmorphic RBCs → glomerular (GN). A bland or variable sediment with systemic hematologic or embolic clues → vascular. Layer on proteinuria (mild in ATN and most AIN, sub-nephrotic in nephritic GN, and notably nephrotic-range when NSAID-induced AIN coexists with minimal-change disease) and systemic context (recent hypotension/surgery, drug exposure, rash/fever, hypertension/edema, MAHA/livedo) to reach the diagnosis.
High-yield
- Muddy brown granular casts = ATN; WBC casts + sterile pyuria = AIN; RBC casts = glomerulonephritis (pathognomonic).
- RBC casts are the gold standard/pathognomonic sign of glomerular bleeding; dysmorphic RBCs also suggest glomerular origin.
- Nephritic GN produces sub-nephrotic proteinuria (<3.5 g/day); ATN and most AIN cause mild proteinuria (<1 g/day).
- NSAID-induced AIN is the classic exception—it can be accompanied by concurrent minimal-change disease with nephrotic-range proteinuria.
- Eosinophiluria has poor sensitivity and specificity and is no longer recommended to diagnose or exclude AIN.
- The AIN triad of fever, rash, and eosinophilia appears in less than 10% of cases overall—its absence does not rule out AIN.
- Classic AIN timing: penicillins act within days; NSAIDs and PPIs may be delayed weeks to months.
- Ischemic ATN spares no shock state—hemorrhagic/septic shock, major surgery, prolonged hypotension; the medulla is most vulnerable due to low oxygen tension.
- ATN course: initiation → maintenance (low GFR, 1–2 weeks) → recovery with polyuria as concentrating ability returns last.
- MAHA + thrombocytopenia → TTP/HUS; livedo reticularis + blue toes → cholesterol emboli.
- PSGN: follows strep by 1–3 weeks (pharyngitis), low C3 normalizing in 6–8 weeks, excellent renal prognosis in children.
Pitfalls
- Assuming AIN requires the full triad of fever, rash, and eosinophilia—it appears in fewer than 10% of patients overall.
- Relying on eosinophiluria to diagnose or exclude AIN—it has poor test performance and is no longer recommended.
- Confusing WBC casts (interstitial/AIN) with RBC casts (glomerular/GN)—they localize to entirely different compartments.
- Expecting nephrotic-range proteinuria in typical nephritic GN—the nephritic pattern is characteristically sub-nephrotic (<3.5 g/day).
- Applying the mild-proteinuria rule for AIN too absolutely—NSAID-induced AIN can cause nephrotic-range proteinuria via concurrent minimal-change disease.
- Forgetting that NSAIDs and PPIs can cause AIN after months of use—not just the classic within-days penicillin reaction.
- Overlooking the recovery-phase polyuria of ATN and attributing new polyuria to a separate process.
- Assuming vascular AKI always has an active sediment—it may be bland; the diagnosis often rests on systemic clues (MAHA, thrombocytopenia, livedo, blue toes).
- Giving antibiotics to prevent PSGN—antibiotics treat active strep but do not prevent the glomerulonephritis.
Clinical pearls
- Read the urine sediment first—it localizes intrinsic AKI to the compartment before any other test.
- Stop the offending drug in AIN; recovery follows over weeks and steroids are only an adjunct of uncertain benefit.
- Remove the insult in ATN and expect recovery in 1–3 weeks.
- AIN with unexpectedly heavy proteinuria should prompt suspicion of NSAID-associated minimal-change disease.
- Cola-colored urine plus RBC casts and hypertension = nephritic/glomerular disease until proven otherwise.
- In post-streptococcal GN, if C3 has not normalized by 8 weeks, reconsider the diagnosis.
Frequently asked
How do I distinguish ATN from AIN when both usually cause mild proteinuria?
The urine sediment and history separate them: ATN shows muddy brown granular casts and tubular epithelial cells after ischemia or nephrotoxin exposure, while AIN shows WBC casts and sterile pyuria—often after a new drug and sometimes with rash, fever, or arthralgias. Note that NSAID-induced AIN can be an exception, producing nephrotic-range proteinuria from concurrent minimal-change disease.
What urine finding is pathognomonic for glomerular AKI?
RBC casts (with dysmorphic RBCs) are pathognomonic for glomerular bleeding and localize the injury to the glomerulus, distinguishing GN from tubular, interstitial, and vascular causes.
Which drugs classically cause AIN and how does timing differ?
Penicillins and cephalosporins are the classic causes, often within days. NSAIDs can cause it after months of use, PPIs are typically delayed (weeks to months), and fluoroquinolones, sulfonamides, allopurinol, and rifampin are also culprits.
Is eosinophiluria useful for diagnosing AIN?
No—eosinophiluria has poor sensitivity and specificity and is no longer recommended to diagnose or exclude AIN. Base the diagnosis on drug history, WBC casts/sterile pyuria, and the overall clinical picture rather than urine eosinophils.
What proteinuria level is expected in glomerulonephritis versus AIN?
Nephritic GN characteristically produces sub-nephrotic proteinuria (<3.5 g/day); nephrotic-range values are the exception. ATN and most AIN cause mild proteinuria (<1 g/day), with the important exception of NSAID-induced AIN, which can reach nephrotic-range proteinuria through concurrent minimal-change disease.
How reliable is the fever-rash-eosinophilia triad for AIN?
Not reliable—the full triad appears in fewer than 10% of AIN cases overall (the higher ~25–30% figure historically applied to methicillin-induced AIN). Its absence should not dissuade you when WBC casts, sterile pyuria, and a compatible drug history are present.
What is the expected clinical course of ATN?
ATN progresses through an initiation phase (creatinine begins rising), a maintenance phase with low GFR lasting 1–2 weeks, and a recovery phase with tubular regeneration; polyuria may develop as concentrating ability returns last. Overall recovery takes 1–3 weeks if the cause is removed.
What is the first management step in drug-induced AIN?
Stop the offending drug immediately; recovery usually occurs over weeks. Steroids may accelerate recovery if there is no spontaneous improvement, but the evidence is limited and their use is controversial.
Turn this into reasoning you can use on exam day — practice Intrinsic AKI by Anatomic Compartment on branching cases where your decisions shape the patient.