AKI and ATN

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"acute kidney injury"[MeSH Terms] AND management

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Acute Kidney Injury (AKI) and Acute Tubular Necrosis / Acute Tubular Injury (ATN/ATI)

1. Definition and Overview

Acute Kidney Injury (AKI) is a syndrome of abrupt decline in kidney function over hours to days, resulting in the retention of nitrogenous waste products (urea, creatinine) and disruption of fluid, electrolyte, and acid-base homeostasis.

Acute Tubular Injury/Necrosis (ATI/ATN) is the single most common cause of AKI, accounting for ~50% of all AKI in hospitalized patients and over half of ICU cases. The term "ATI" is now preferred by pathologists over the historical "ATN," because frank necrosis is not always present - injury may manifest as apoptosis or sublethal damage.

Robbins Pathologic Basis of Disease (p. 864); Frameworks for Internal Medicine (p. 454)

2. KDIGO Staging of AKI

The RIFLE and AKIN criteria were harmonized into the KDIGO (Kidney Disease: Improving Global Outcomes) 2012 criteria, now the universal standard:

Stage	Serum Creatinine Criteria	Urine Output Criteria
1	1.5-1.9× baseline, or ≥0.3 mg/dL rise within 48 h	<0.5 mL/kg/h for 6-12 h
2	2.0-2.9× baseline	<0.5 mL/kg/h for ≥12 h
3	≥3.0× baseline, or sCr ≥4.0 mg/dL, or initiation of RRT, or eGFR <35 mL/min (age <18)	<0.3 mL/kg/h for ≥24 h, or anuria for ≥12 h

Brenner and Rector's The Kidney (p. 1156)

Limitation: Serum creatinine is a functional (not damage) biomarker - it can rise in prerenal states without tubular injury, and remain normal with significant tubular injury in patients with high renal reserve. Novel biomarkers (NGAL, KIM-1, IL-18, TIMP-2, IGFBP7) are being studied to supplement creatinine-based definitions.

3. Classification of AKI by Location

Prerenal AKI

Reduced renal perfusion (hypovolemia, cardiogenic shock, septic shock, RAAS activation, renal artery stenosis)
Functional/reversible - no intrinsic tubular damage yet
FENa <1%, BUN:Cr ratio >20, urine specific gravity >1.020

Intrarenal AKI (Intrinsic)

ATI/ATN - ischemic or nephrotoxic (most common)
Glomerulonephritis (rapidly progressive)
Acute interstitial nephritis (drug-induced, infection)
Vascular (TTP/HUS, vasculitis, atheroembolic disease)

Postrenal AKI

Urinary obstruction (BPH, stones, malignancy, papillary necrosis)
Must be bilateral (or unilateral in solitary kidney) to cause AKI

4. Pathogenesis of ATI/ATN

Why the Proximal Tubule is Most Vulnerable

Proximal tubular cells are packed with mitochondria, depend on oxidative phosphorylation, have a large absorptive surface area, and actively concentrate toxins via transport systems. They cannot switch to anaerobic glycolysis effectively. The outer medullary segment (PST = proximal straight tubule and thick ascending limb of Henle) is particularly at risk because it operates in a relative hypoxic environment even under normal conditions.

Two Mechanisms

A. Ischemic ATI

The following cascade occurs (see diagram below):

Loss of cell polarity: Ischemia causes redistribution of Na,K+-ATPase from the basolateral to the luminal membrane → impaired Na+ reabsorption → increased distal Na+ delivery → tubuloglomerular feedback → afferent arteriolar vasoconstriction → ↓ GFR
Cell detachment: Injured tubular epithelial cells slough into the lumen → luminal obstruction → ↑ intratubular pressure → ↓ GFR
Filtrate leak: Disrupted tubular epithelium allows glomerular filtrate to leak back into the interstitium → interstitial edema → ↑ interstitial pressure → further ischemia
Inflammatory amplification: Injured cells release cytokines/chemokines → leukocyte recruitment → additional injury
Intrarenal vasoconstriction: Via renin-angiotensin system, endothelin release ↑, nitric oxide and prostacyclin production ↓

ATN Pathogenesis Diagram - Ischemic and toxic injury → epithelial injury → decreased Na+ resorption → tubuloglomerular feedback → vasoconstriction → decreased GFR; also cell detachment → obstruction and fluid leak → interstitial pressure → decreased urine output

Fig. 20.28 - Postulated sequence in ischemic or toxic ATI. (Robbins Pathologic Basis of Disease)

B. Nephrotoxic ATI

Direct toxicity to tubular epithelial cells
Common nephrotoxins: aminoglycosides (gentamicin), IV contrast (contrast-induced nephropathy), cisplatin, amphotericin B, heavy metals (mercury), organic solvents (carbon tetrachloride), myoglobin (rhabdomyolysis), hemoglobin (hemolytic crises)
In toxic ATI: more extensive necrosis distributed along the proximal convoluted tubule (PCT) segments (vs. patchy PST and thick ascending limb in ischemic ATI)

5. Morphology (Histopathology)

Ischemic vs toxic ATN tubular necrosis patterns - ischemic: patchy PST and HL; toxic: extensive PCT necrosis; both show casts in DCT and CD

Fig. 20.29 - Patterns of tubular damage in ischemic vs toxic ATI. (Robbins, p. 864)

Ischemic ATI:

Patchy necrosis, short segments affected
PST (proximal straight tubule) and ascending limb of Henle loop most vulnerable
Tubulorrhexis (basement membrane rupture)
Interstitial edema, leukocytes in vasa recta
Casts in DCT and collecting ducts

Toxic ATI:

More extensive, confluent necrosis along PCT
Basement membrane intact (key - allows repair/re-epithelialization)
DCT and collecting ducts contain casts

Recovery: Patchy necrosis with intact basement membranes allows re-epithelialization mediated by growth factors. The severity of histologic findings often does NOT correlate with clinical severity.

Robbins Pathologic Basis of Disease (p. 864-865)

6. Clinical Phases of ATN/AKI

Phase	Duration	Features
Initiation	Hours-days	Precipitating insult; sCr begins to rise
Maintenance (Oliguric)	1-2 weeks typically	Oliguria (<400 mL/day) or anuria; sCr peaks; risk of uremic complications
Recovery (Diuretic)	Days-weeks	Polyuria may occur as tubular function recovers before concentrating ability; risk of hypokalemia and hypovolemia

Note: ~50% of ATN cases are non-oliguric (better prognosis).

7. Laboratory Findings

Test	Prerenal AKI	Intrinsic AKI (ATN)
FENa	<1%	>1-2%
BUN:Cr ratio	>20	~10-15
Urine osmolality	>500 mOsm/kg	~300 mOsm/kg (isosthenuria)
Urine Na+	<20 mEq/L	>40 mEq/L
Urine sediment	Hyaline casts (bland)	"Muddy brown" granular casts
FEUrea	<35%	>35-50% (useful when on diuretics)

The "Muddy Brown" Cast - Hallmark of ATN

Muddy brown granular cast - hallmark of ATN on urine microscopy

Fig. 33-6 - "Muddy brown" granular cast in ATN. ATN is highly likely when ≥6 granular casts are seen. (Frameworks for Internal Medicine, p. 455)

These casts are composed of sloughed, pigment-laden tubular epithelial cells. They form in the distal tubule and collecting duct.

Frameworks for Internal Medicine (p. 454-455)

8. Causes of ATN - Clinical Correlation

Clinical Scenario	Cause of ATN
Cardiogenic shock, hypotension	Prerenal spectrum → ischemic ATN
Amphotericin B (immunocompromised patient)	Direct nephrotoxicity
CT contrast + pre-existing CKD/DM	Contrast-induced nephropathy
Crush injury, rhabdomyolysis	Pigment nephropathy (myoglobin)
Hemolytic transfusion reaction	Hemoglobinuria
Myeloma (anemia, ↑protein gap, ↓anion gap)	Light chain (myeloma kidney)

9. Complications of AKI (AEIOU mnemonic)

A - Acidosis (metabolic, high anion gap)
E - Electrolytes (hyperkalemia, hyperphosphatemia, hyponatremia, hypocalcemia)
I - Ingestions/toxins (inability to clear)
O - Overload (fluid - pulmonary edema)
U - Uremia (pericarditis, encephalopathy, platelet dysfunction, nausea/vomiting)

10. Management

General Principles

Identify and remove the cause - stop nephrotoxins, correct hypovolemia, treat sepsis, relieve obstruction
Volume optimization - restore euvolemia with isotonic crystalloids (balanced solutions preferred over normal saline in most settings); avoid fluid overload
Hemodynamic support - target MAP >65 mmHg; vasopressors in septic shock
Avoid nephrotoxins - NSAIDs, ACEi/ARBs, aminoglycosides (or dose-adjust), IV contrast (use iso-osmolar, minimize dose, pre-hydrate)
Monitor electrolytes and acid-base - treat hyperkalemia aggressively
Nutrition - adequate protein (avoid restriction in non-dialyzed patients)
Medication dose adjustment - renally cleared drugs

Renal Replacement Therapy (RRT) - Indications

AEIOU mnemonic above (refractory to medical management):

Refractory hyperkalemia
Severe/refractory metabolic acidosis (pH <7.1)
Pulmonary edema unresponsive to diuretics
Uremic complications (pericarditis, encephalopathy, bleeding)
Stage 3 AKI in appropriate clinical context

No proven pharmacologic therapy exists for established ATN

Dopamine, fenoldopam, NAC for contrast prophylaxis - not proven to reduce established ATN
Diuretics do NOT improve outcomes in ATN (may convert oliguric to non-oliguric but don't shorten course)
Brenner and Rector's The Kidney (pharmacologic therapy for ATN)

11. Prognosis and Recovery

ATI is generally reversible if the underlying cause is corrected and basement membranes remain intact. Recovery depends on:

Severity and duration of the insult
Patient age and baseline kidney function (CKD, diabetes, hypertension lower the threshold for injury)
Whether sepsis is the precipitant (worst prognosis)
Complications during the oliguric phase

Survivors of severe AKI have a significantly increased long-term risk of CKD, ESRD, and cardiovascular events. AKI-to-CKD transition is now a recognized entity.

Key Sources:

Robbins, Cotran & Kumar Pathologic Basis of Disease - ATI pathogenesis and morphology (pp. 863-865)
National Kidney Foundation Primer on Kidney Diseases, 8e - ATI mechanisms (pp. 972+)
Brenner and Rector's The Kidney, 2-Volume Set - KDIGO staging, biomarkers, pharmacologic therapy
Frameworks for Internal Medicine - Clinical features, urine sediment (pp. 454-455)

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