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Acute Tubular Necrosis (ATN) / Acute Tubular Injury (ATI)

Terminology note: Pathologists now prefer Acute Tubular Injury (ATI) over ATN because frank necrosis is often absent on biopsy; necrosis can be focal or entirely missed in a cortical sample. Clinically and in most texts the term ATN persists.

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1. Overview and Epidemiology

• Robbins Pathologic Basis of Disease, p. 863
• Frameworks for Internal Medicine, p. 454

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2. Causes

• Robbins, p. 863-864
• Frameworks for Internal Medicine, p. 455

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3. Pathophysiology

3a. Tubular Cell Injury

• It depends almost exclusively on fatty acid oxidation (minimal capacity for anaerobic glycolysis)
• It receives primarily venous capillary flow, so medullary perfusion fails to recover even when cortical flow normalizes ("extension phase")

1. Loss of brush border - earliest change; microvilli disruption with bleb formation into the lumen
2. Loss of cell polarity - Na⁺/K⁺-ATPase redistributes from the basolateral to the apical/luminal surface → defective Na⁺ reabsorption → increased distal Na⁺ delivery
3. Tubuloglomerular feedback (TGF) - elevated distal Na⁺ triggers afferent arteriolar vasoconstriction, dropping GFR further
4. Cell detachment - necrotic/apoptotic cells slough from the basement membrane, form casts, and obstruct the tubular lumen → increased intratubular pressure → further GFR reduction
5. Tubular backleak - areas of denuded basement membrane allow filtered urine to leak back into the interstitium → interstitial edema → increased interstitial pressure → worsens tubular obstruction
6. Inflammation - injured cells release cytokines and DAMPs, recruit neutrophils, macrophages, NKT cells, and T lymphocytes → amplify injury

3b. Vascular/Hemodynamic Disturbances

• Decreased synthesis and/or increased consumption of vasodilatory prostaglandins and nitric oxide in the ischemic kidney
• Increased endothelin and angiotensin II-mediated vasoconstriction
• Endothelial swelling, leukocyte adhesion, and platelet aggregation in peritubular capillaries perpetuate medullary ischemia even after the initial insult resolves

• Comprehensive Clinical Nephrology 7e, p. 990
• Brenner and Rector's The Kidney, p. 1205

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4. Morphology / Histology

Pattern of injury (Ischemic vs. Toxic)

• Vacuolation and loss of brush border in proximal tubule cells
• Thinning of epithelium to maintain tubular monolayer integrity
• Intraluminal cast accumulation with cellular debris
• Apoptosis of tubular cells (necrosis may be subtle or focal)
• Regenerative changes: flattened cells, hyperchromatic nuclei, mitotic figures - coexisting with fresh injury in the same biopsy (indicating ongoing ischemic episodes during the maintenance phase)
• Necrosis is focal and often missed on biopsy because the outer medulla is inadequately sampled

• Robbins, p. 864-865
• Comprehensive Nephrology 7e, p. 990-991

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5. Clinical Features - The Three Phases

• ~50% of ATN is non-oliguric (urine output >400 mL/day), especially nephrotoxic ATN; this carries a better prognosis.
• Robbins, p. 864-865

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6. Diagnosis

Urinalysis and Urine Microscopy

Laboratory Indices

• Comprehensive Nephrology 7e, p. 990
• Frameworks for Internal Medicine, p. 454-455

Note: FENa can be falsely low (<1%) in ATN superimposed on: contrast nephropathy, myoglobinuria, early obstruction, or hepatorenal syndrome. FEUrea is more reliable in patients on diuretics.

Novel Biomarkers

• Urine NGAL (neutrophil gelatinase-associated lipocalin), KIM-1 (kidney injury molecule-1), IL-18, TIMP-2 x IGFBP7 (NephroCheck) - can detect ATN before creatinine rises
• No definitive non-invasive test exists; kidney biopsy is the gold standard but rarely needed

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7. Management

Supportive Care

• Treat the underlying cause - optimize hemodynamics, discontinue nephrotoxins, treat sepsis
• Fluid balance - avoid fluid overload; restrict intake to insensible losses + urine output
• Electrolytes - manage hyperkalemia (ECG monitoring, calcium gluconate, insulin/glucose, kayexalate, dialysis if refractory); correct metabolic acidosis
• Nutrition - adequate protein/calorie intake (avoid excessive protein restriction)
• Renal replacement therapy (RRT) - indicated for refractory hyperkalemia, acidosis, fluid overload, uremic symptoms; continuous RRT preferred in hemodynamically unstable patients
• Drug dose adjustment - renally clear drugs must be dosed per reduced GFR

Pharmacologic Interventions - What Does NOT Work

• Loop diuretics (furosemide) - no change in course; may convert oliguric to non-oliguric ATN but does not improve outcomes
• Low-dose ("renal dose") dopamine - does not prevent or shorten ATN (increases renal vascular resistance in patients with AKI)
• Fenoldopam, atrial natriuretic peptide, thyroid hormone, alpha-MSH, erythropoietin, insulin growth factor, prostaglandin A1

Prevention

• Pre-procedure volume expansion (IV saline before contrast administration or nephrotoxic drugs)
• N-acetylcysteine - evidence mixed, but low risk; commonly used before radiocontrast
• Minimize aminoglycoside exposure; use once-daily dosing with therapeutic drug monitoring
• Remote ischemic preconditioning (RIPC) - brief ischemia to a limb triggers HIF-1α, heat shock proteins, and protective signaling; promising but not yet standard of care
• Brenner and Rector's The Kidney, p. 1268-1269

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8. Prognosis

• ATN is generally reversible if the precipitating cause is corrected - recovery depends on intact tubular basement membranes allowing re-epithelialization
• Hospital mortality for ICU-associated ATN requiring dialysis: 50-80%
• Incomplete recovery occurs in ~30% of survivors, leading to CKD or end-stage renal disease
• Patchiness of necrosis and preserved basement membrane segments are the structural basis for recovery

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Summary Diagram - Pathophysiology

1. Afferent vasoconstriction (via TGF from defective Na⁺ reabsorption)
2. Tubular cast obstruction (from sloughed epithelial cells)
3. Tubular backleak (filtrate re-enters interstitium through denuded basement membrane)
4. Interstitial edema and pressure (from backleak, compressing tubules and capillaries)

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• Robbins, Cotran & Kumar - Pathologic Basis of Disease, p. 863-865
• Brenner and Rector's The Kidney (2-Volume Set), p. 1205-1210, 1268-1269
• Comprehensive Clinical Nephrology, 7th Edition, p. 989-991
• Frameworks for Internal Medicine, p. 454-455

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Acute Tubulointerstitial Nephritis (ATIN / AIN)

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1. Definition

• Brenner and Rector's The Kidney, p. 1595
• Harrison's Internal Medicine 22E, p. 1457

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2. Epidemiology

• Accounts for 1-3% of all kidney biopsies and 10-20% of biopsies for unexplained AKI
• Represents 15-27% of biopsies performed for AKI in some series
• Its incidence appears to be rising, in part due to increasing polypharmacy and immune checkpoint inhibitor use
• More common in older individuals (drug-induced) vs. younger individuals (immune-mediated, TINU)
• Medications are now the leading cause in developed countries
• Brenner and Rector's The Kidney, p. 1595-1596
• Comprehensive Clinical Nephrology 7e, p. 889

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3. Etiology and Classification

A. Drug-Induced (Most Common - ~70% of all ATIN)

B. Infectious (Pre-antibiotic era was dominant cause)

• Bacterial: Streptococcal infections (Councilman's nephritis in scarlet fever/diphtheria - historical), Legionella, leptospirosis, Mycobacterium tuberculosis (caseating granulomas first appearing near glomeruli in cortex where O₂ tension is highest)
• Viral: EBV, CMV, hantavirus, HIV
• Other: Mycoplasma, Lyme disease, toxoplasmosis
• Mechanism: indirect immune/hypersensitivity reaction; the pathogen is not cultured from the renal parenchyma (distinguishing it from pyelonephritis)

C. Immune-Mediated / Autoimmune

D. Tubulointerstitial Nephritis and Uveitis Syndrome (TINU)

• Uveitis (painful red eyes, photophobia) - may precede, follow, or occur simultaneously with renal disease
• Systemic features: weight loss, fever, anemia, hyperglobulinemia
• Isolated proximal tubulopathy or Fanconi syndrome as the initial renal manifestation
• Associated infections (EBV, toxoplasmosis, giardiasis) have been reported
• Treatment: steroids for 3-6 months with slow taper; steroid-sparing agents (MMF, methotrexate, cyclosporine) for relapses
• Brenner and Rector's The Kidney, p. 1604-1605

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4. Pathogenesis

• Occurs in only a small fraction of exposed patients (not dose-dependent for most agents)
• Associated with extrarenal manifestations of hypersensitivity
• Recurs with re-exposure to the same or related drug (anamnestic response)
• Interstitial infiltrates contain T lymphocytes and sometimes granulomas (DTH)
• No neutrophilic (purulent) character to the inflammation

Key Antigens Implicated:

1. Tubular basement membrane (TBM) components - glycoproteins 3M-1 and TIN-Ag/TIN1
2. Secreted tubular proteins - uromodulin (Tamm-Horsfall protein)
3. Non-renal ("planted") antigens - drugs/metabolites binding to kidney structures; acting as haptens modifying native proteins; immune complex deposition within the interstitium

Inflammatory Cascade:

• Drug/antigen → processed and presented via MHC class II to Th lymphocytes
• Cell-mediated (dominant): Th1 → cytotoxic CD8+ T cells and macrophages → direct tubular injury
• Antibody-mediated: Th2 → B cells → anti-TBM antibodies → complement activation + eosinophil recruitment
• Interstitial infiltration → inflammatory cytokine release (IL-1, TNF, TGF-β) → fibroblast activation → interstitial fibrosis if untreated
• Comprehensive Clinical Nephrology 7e, p. 889-890

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5. Histopathology

Key Histologic Features:

1. Interstitial inflammatory infiltrate - primarily mononuclear cells; lymphocytes (CD4+ and CD8+ T cells predominant), monocytes/macrophages, plasma cells, B cells
2. Tubulitis - lymphocytes crossing the tubular basement membrane and invading the tubular epithelium (pathognomonic)
3. Interstitial edema - often prominent, especially early
4. Interstitial fibrosis - variable; severity predicts prognosis and likelihood of CKD
5. Eosinophils - more common in drug-induced (especially β-lactam) ATIN; often absent in NSAID-induced
6. Granulomas - noncaseating in sarcoidosis, drug reactions, and some infections; caseating in TB
7. Neutrophils - when prominent, raise concern for pyelonephritis

Biopsy Differential by Infiltrate Composition:

• Brenner and Rector's The Kidney, p. 1599-1600
• NKF Primer on Kidney Diseases 8e

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6. Clinical Features

Renal Manifestations:

• Acute rise in serum creatinine (often the only finding)
• Oliguria (in severe cases)
• Flank pain (due to acute distension of the renal capsule)
• Polyuria and nocturia (tubular dysfunction - nephrogenic DI)
• Signs of tubular dysfunction: renal tubular acidosis, glycosuria with normal blood glucose, hypophosphatemia, hypokalemia or hyperkalemia, Fanconi syndrome (proximal RTA + glycosuria + phosphaturia + aminoaciduria + bicarbonaturia)

Extrarenal Manifestations (drug-induced):

• Fever (common with β-lactams)
• Maculopapular rash
• Peripheral eosinophilia
• Arthralgias (45% in one analysis)
• DRESS syndrome (Drug Rash, Eosinophilia, and Systemic Symptoms) - associated with AIN in up to 40% of cases with prolonged drug exposure

Temporal Pattern:

• Drug reaction: days to weeks after starting the drug; can be months later with NSAIDs, PPIs, or checkpoint inhibitors
• Classic drug reaction setting: febrile patient on antibiotics who defervesces but develops recurrent fever several days later
• Re-exposure: rapid, severe recurrence (anamnestic response)
• Comprehensive Clinical Nephrology 7e, p. 890
• Goldman-Cecil Medicine, p. 3544-3548
• Frameworks for Internal Medicine, p. 456

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7. Diagnosis

Urinalysis and Urine Microscopy

Blood Tests:

• Elevated serum creatinine/BUN
• Peripheral eosinophilia (inconsistent; more common in drug-induced)
• Elevated ESR, CRP (non-specific)
• Elevated IgE (in drug-induced)
• ANA, ANCA, anti-GBM, complement levels (for immune-mediated causes)
• Serum IgG4 (for IgG4-related disease)

Urine Chemistries:

• FENa is not useful for diagnosing ATIN - values can be above or below 1%; it does not distinguish ATIN from ATN reliably
• Low-grade tubular proteinuria and β2-microglobulinuria indicate proximal tubular disease

Novel Biomarkers (research stage):

• Urine TNF-α and IL-9 - promising for distinguishing AIN from ATN (JCI Insight, 2019)
• Urine MCP-1, NGAL, α1-microglobulin, NAG - elevated in ATIN but not yet validated for clinical discrimination

When to Perform Kidney Biopsy:

1. Clinical setting and history do not clearly support ATN or volume depletion
2. Tissue diagnosis needed to determine type of lesion, extent of involvement, or degree of fibrosis
3. Patient is stable enough for biopsy and potential immunosuppressive therapy
4. Choice or duration of therapy is partially determined by biopsy findings

• Goldman-Cecil Medicine, p. 3556-3559

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8. Differential Diagnosis

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9. Management

Step 1: Remove the Offending Cause

Step 2: Treat Underlying Condition

• For infection-related ATIN: treat the primary infection
• For sarcoidosis, SLE, Sjögren: see below

Step 3: Corticosteroids

• Methylprednisolone IV 250-500 mg/day × 3-4 days, then
• Oral prednisone 1 mg/kg/day, tapered over 8-12 weeks

• Sarcoidosis-related ATIN (good evidence)
• TINU syndrome (3-6 months with slow taper)
• IgG4-related kidney disease (excellent response)
• Drug-induced ATIN if no recovery after drug withdrawal (on case-by-case basis)

Important: Given potential serious side effects of steroids, their use must be individualized. Patient must be stable enough to receive immunosuppression.

Step 4: Alternative Immunosuppression (steroid-resistant/dependent)

• Mycophenolate mofetil (MMF) - used in steroid-intolerant patients; small case series show improvement/stabilization in drug-induced AIN; used in Sjögren and SLE-related ATIN
• Azathioprine, cyclophosphamide - used in Sjögren, ANCA vasculitis-related ATIN
• Methotrexate, cyclosporine - steroid-sparing options in TINU

Step 5: Supportive Care

• Standard AKI management: fluid/electrolyte balance, manage hyperkalemia/acidosis
• Renal replacement therapy (RRT) if severe AKI, refractory complications, or uremia
• Drug dose adjustment for renally cleared medications

Immune Checkpoint Inhibitor-Induced AIN (Emerging Issue)

• Occurs in ~3% of patients on PD-1/PD-L1/CTLA-4 inhibitors
• Average latency ~4 months after starting therapy
• Management: hold checkpoint inhibitor, administer corticosteroids; patients who recover renal function may often safely resume checkpoint inhibitor therapy
• PPIs may increase risk of AIN in patients already on checkpoint inhibitors
• Brenner and Rector's The Kidney, p. 1271
• Harrison's 22E, p. 1461

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10. Prognosis

• Majority recover renal function if the offending cause is removed promptly and the disease is recognized early
• Incomplete recovery and progression to CKD is common when:
  • Diagnosis is delayed (sustained injury → fibrosis)
  • Significant interstitial fibrosis present on biopsy at diagnosis
  • Older patients with underlying CKD
• The degree of interstitial fibrosis and tubular atrophy on biopsy is the strongest histologic predictor of long-term renal outcome
• Rifampin-induced ATIN has a particularly severe course (dialysis in ~2/3 of patients)
• TINU syndrome generally has a relatively favorable prognosis with treatment, though uveitis may relapse

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11. Special Entities Summary

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• Brenner and Rector's The Kidney (2-Volume Set), p. 1595-1606
• Harrison's Principles of Internal Medicine 22E (2025), p. 1457-1473
• Comprehensive Clinical Nephrology 7e, p. 889-895
• Goldman-Cecil Medicine International Edition, p. 3539-3568
• NKF Primer on Kidney Diseases 8e, p. 1432-1436
• Frameworks for Internal Medicine, p. 454-456

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Acute Tubular Injury (ATI)

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1. Definition and Terminology

• Sudden GFR decline with elevated serum creatinine
• May produce oliguria (urine output <400 mL/day) or be non-oliguric
• Shedding of granular casts and tubular epithelial cells into urine
• Generally reversible if the precipitating cause is corrected
• Robbins & Kumar Basic Pathology, p. 519
• NKF Primer on Kidney Diseases 8e, p. 972-976

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2. Why the Proximal Tubule is Most Vulnerable

• Robbins & Kumar Basic Pathology, p. 519
• NKF Primer on Kidney Diseases 8e, p. 974

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3. Forms and Causes

A. Ischemic ATI (most common)

Sepsis creates a particularly hostile environment: beyond hypoperfusion, inflammatory cytokines independently cause variation in renal macro- and microcirculation, diffusion limitation, and mitochondrial dysfunction - injury may occur even without overt hypotension.

• Cholesterol atheroembolic disease
• Malignant hypertension
• Small vessel vasculitis
• Thrombotic microangiopathy (TMA)
• Renal artery stenosis / thrombosis
• Renal vein thrombosis

• Mismatched blood transfusions / hemolytic crises → hemoglobinuria
• Rhabdomyolysis → myoglobinuria
• (Detailed below)

B. Nephrotoxic ATI

• Myoglobin (rhabdomyolysis)
• Hemoglobin (intravascular hemolysis)
• Uric acid (tumor lysis syndrome → intratubular crystallization)
• Light chains (multiple myeloma)
• Calcium oxalate (hyperoxaluria - including from high-dose vitamin C)
• Robbins & Kumar Basic Pathology, p. 519
• NKF Primer on Kidney Diseases 8e, p. 988-1000

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4. Pathophysiology

The Four Converging Mechanisms of GFR Decline

1. Tubuloglomerular Feedback → Afferent Vasoconstriction

• Injured proximal tubular cells fail to reabsorb Na⁺ → increased NaCl delivery to macula densa → tubuloglomerular feedback → afferent arteriolar vasoconstriction via the renin-angiotensin pathway → reduced GFR and O₂ delivery to the outer medulla → further ischemic tubular injury (self-perpetuating cycle)

2. Tubular Cast Obstruction

• Necrotic/apoptotic cells detach from the tubular basement membrane and shed into the lumen
• Detached cells + Tamm-Horsfall protein + plasma proteins form granular casts in distal tubules and collecting ducts
• Casts obstruct outflow → increased intratubular pressure → backpressure against glomerular filtration → further GFR decline

3. Tubular Backleak

• Areas of denuded basement membrane allow glomerular filtrate to leak back into the renal interstitium
• Increases interstitial edema and pressure
• Interstitial pressure compresses peritubular capillaries → perpetuates ischemia

4. Vascular Dysfunction / Hemodynamic Disturbances

• Decreased vasodilatory prostaglandins and nitric oxide
• Increased endothelin, angiotensin II, vasopressin
• Endothelial swelling + leukocyte adhesion in peritubular capillaries (especially vasa recta)
• Persists even after cortical blood flow normalizes ("extension phase")
• Robbins & Kumar Basic Pathology, p. 519-521

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5. Special Forms: Pigment Nephropathy

Rhabdomyolysis

• Muscle pain, weakness, dark (cola-colored) urine
• Serum CK >5000 U/L (risk of AKI typically significant when >15,000-20,000 U/L)
• Urine dipstick heme-positive but few/no RBCs on microscopy (myoglobin triggers peroxidase reaction)
• Red-brown pigmented granular casts on urine microscopy
• FENa <1% early (despite intrinsic AKI - due to volume depletion and intense renal vasoconstriction)
• Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia (early; hypercalcemia may occur during recovery), elevated LDH

• Myoglobin → renal vasoconstriction (scavenges NO, elevates endothelin and isoprostanes)
• Tubular cast formation: myoglobin + Tamm-Horsfall protein (especially in acidic urine) → tubular obstruction
• Direct tubular cell injury via free radical formation and lipid peroxidation after prolonged heme protein exposure
• NLRP3 inflammasome activation → IL-1β and IL-18 release → proinflammatory cascade

• Score <5: ~2.3% risk of KRT or death
• Score >10: ~61.2% risk of KRT or death

• Aggressive IV fluid resuscitation: isotonic normal saline targeting urine output >200 mL/hr
• Identify and treat underlying cause; prevent further muscle damage
• Electrolyte correction (hyperkalemia priority)
• Urinary alkalinization (sodium bicarbonate) is theoretically beneficial to reduce cast formation but no clear RCT evidence of superiority

Hemoglobinuria (Intravascular Hemolysis)

• NKF Primer on Kidney Diseases 8e, p. 1073-1295

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6. Morphology / Histology

Key Histologic Features:

• Loss/attenuation of proximal tubular brush border (earliest change)
• Blebbing and sloughing of brush border microvilli
• Vacuolization of tubular cells
• Detachment and sloughing of epithelial cells from basement membranes into the lumen
• Skip lesions: patchy necrosis with large areas of spared tubule between foci - characteristic
• Primary sites: straight segment of proximal tubule (S3) and thick ascending limb of Henle in the outer medulla
• Proteinaceous/granular casts in distal tubules and collecting ducts (Tamm-Horsfall protein + plasma proteins)
• Interstitial edema with mild lymphocytic/neutrophilic/plasma cell infiltrate
• Leukocyte accumulations within dilated vasa recta
• Regenerative changes: flattened epithelium, hyperchromatic nuclei, mitotic figures

• Histologically similar but more overt necrosis in the proximal convoluted tubule (PCT, S1/S2 segments)
• More continuous (less skip areas) than ischemic ATI
• Agent-specific changes:
  • Mercury chloride: Large acidophilic inclusions → necrosis → calcification
  • Ethylene glycol: Marked ballooning/hydropic degeneration of PCT + calcium oxalate crystals in tubular lumens
  • Myoglobinuria/hemoglobinuria: Red-brown pigmented casts

• Regenerating cells: flattened, mitotically active, hyperchromatic
• If basement membrane integrity is maintained → re-epithelialization and recovery of function possible
• Robbins & Kumar Basic Pathology, p. 519-521

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7. Clinical Features and Phases

~50% of ATI is non-oliguric - this carries a better prognosis. It is especially common with nephrotoxic ATI (contrast, aminoglycosides).

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8. Diagnosis

Urine Microscopy (the "liquid biopsy")

Urine Chemistry Indices

Exceptions: FENa may be <1% in ATI caused by radiocontrast, myoglobinuria, or early obstruction due to concurrent intense vasoconstriction.

Novel Biomarkers of Tubular Injury

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9. Special Context: COVID-19-Related ATI

1. Critical illness: hypotension, reduced cardiac output, organ cross-talk from ARDS
2. Nephrotoxin exposure: drugs used in ICU management
3. Positive pressure ventilation: reduces cardiac output and renal perfusion
4. Endogenous tubular obstruction: rhabdomyolysis, hyperoxaluria (from IV vitamin C), hyperuricemia
5. Direct viral toxicity (controversial): ACE2 receptor on tubular cells serves as viral entry domain; viral RNA detected in urine but not consistently in tissue

• NKF Primer on Kidney Diseases 8e, p. 1297-1307

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10. Management

Principles

1. Remove/Treat the Cause

• Restore hemodynamics and adequate renal perfusion (volume resuscitation, vasopressors for shock)
• Discontinue nephrotoxic drugs
• Treat sepsis (antibiotics, source control)
• Treat underlying condition

2. Fluid Management

• Correct volume depletion; avoid fluid overload (associated with increased mortality)
• Target adequate urine output; monitor for pulmonary edema
• During recovery phase: replace electrolytes lost in diuresis

3. Electrolyte and Acid-Base Management

• Hyperkalemia: ECG monitoring; calcium gluconate (membrane stabilization), insulin/glucose, sodium bicarbonate, potassium binders, dialysis if refractory
• Metabolic acidosis: sodium bicarbonate if severe (pH <7.1)
• Hyponatremia/hypernatremia: appropriate fluid adjustment
• Recovery phase: watch for hypokalemia, hyponatremia

4. Nutrition

• Adequate calorie/protein intake; avoid excessive restriction

5. Drug Dose Adjustment

• All renally cleared drugs must be dose-adjusted based on current GFR

6. Renal Replacement Therapy (RRT)

• Refractory hyperkalemia
• Refractory metabolic acidosis
• Fluid overload unresponsive to diuretics
• Uremic symptoms (pericarditis, encephalopathy, bleeding)
• Continuous RRT preferred in hemodynamically unstable patients

What Does NOT Work (failed in clinical trials):

• Low-dose ("renal dose") dopamine - increases renal resistance in AKI patients
• Loop diuretics (furosemide) - converts oliguria to non-oliguria but does not change outcomes
• Fenoldopam, atrial natriuretic peptide, thyroid hormone, erythropoietin, IGF-1, prostaglandin A1

Special: Rhabdomyolysis/Pigment Nephropathy

• Aggressive IV normal saline to maintain UO >200 mL/hr
• Urinary alkalinization (sodium bicarbonate) - theoretical benefit (prevents cast formation at alkaline pH), but no RCT evidence of superiority over NS
• Loop diuretics + mannitol - used in some protocols but not proven

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11. Prognosis

• Generally reversible if precipitating cause is corrected and basement membrane integrity is preserved (allows re-epithelialization)
• Recovery timeline: urine output increases over days; BUN/Cr normalize over 1-3 weeks
• Poor prognostic factors: pre-existing CKD, older age, multiorgan failure, prolonged ATI (leading to fibrosis), delayed treatment
• ~30% of survivors have incomplete recovery → CKD or ESRD
• In ICU-acquired ATI requiring dialysis: hospital mortality 50-80%
• The patchiness of necrosis and maintenance of tubular basement membrane integrity are the structural basis for recovery - distinguishing ATI from the irreversible renal cortical necrosis

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Summary Comparison: ATI vs Renal Cortical Necrosis

• Brenner and Rector's The Kidney, p. 2161-2162

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• Robbins & Kumar Basic Pathology, p. 519-521
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 863-865
• NKF Primer on Kidney Diseases 8e, p. 972-1307
• Comprehensive Clinical Nephrology 7e, p. 393-399
• Brenner and Rector's The Kidney (2-Volume Set), p. 1205-1210, 2161-2162