AKI is often caused by more than one etiology, but the pathophysiologic processes can be separated into three separate classifications: prerenal, intrinsic (or “renal”), and postrenal injuries. This is helpful both to determine the underlying etiology and for management (Table 25.2).

1. Prerenal (Kidney Hypoperfusion)
1. Decreased intravascular volume
1. Systemic vasodilation (eg, sepsis): Sepsis is the most common cause of AKI in the ICU (~50% can be attributed) and is associated with a very high mortality.
2. Hypovolemia (eg, hemorrhage, gastrointestinal [GI] losses, burns)
3. Hypotension, decreased cardiac output (congestive heart failure [CHF], arrhythmias)
4. Small vessel (renal) vasoconstriction
1. Nonsteroidal anti-inflammatory drugs (NSAIDs):Prostaglandins have important vasodilatory effects on the afferent arteriolar vessels. Cyclooxygenase inhibitors inhibit the production of prostaglandins, resulting in decreased renal blood flow.
2. Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEis/ARBs): Angiotensin-II is a potent efferent arteriolar vasoconstrictor and the inhibition of its production (ACEis) or the blockage of ARBs results in decreased glomerular perfusion pressure. This is of particular concern when the patient has other risk factors (CKD, renal artery stenosis [RAS], older age) or exposures (diuretics, hypotension, NSAIDs, nephrotoxins).
3. Contrast: Intravenous (IV) contrast is both cytotoxic to renal tubular cells and causes intrarenal vasoconstriction.
4. Hypercalcemia: directly causes vasoconstriction
5. Calcineurin inhibitors (CNIs): Both cyclosporine and tacrolimus, which lead to afferent and efferent arteriolar vasoconstriction, are used as immunosuppressants for patients after renal transplant.
6. Hepatorenal syndrome (HRS): Splanchnic and systemic vasodilation causes an increased neuroendocrine (angiotensin, vasopressin) tone, resulting in renal vasoconstriction. Prognosis is very poor.
7. Intra-abdominal hypertension (IAH; intra-abdominal pressure [IAP] >12 mm Hg) and abdominal compartment syndrome (ACS; IAP >20 mm Hg with new organ failure): The pathophysiology is likely a combination of (initially) intrarenal venous congestion/hypertension (HTN; normally a low-pressure system), followed by decreased cardiac output and elevated catecholamines, neurohormones, and cytokines (inflammation).
8. Cardiorenal syndrome: In addition to decreased cardiac output (acute CHF) resulting in decreased intravascular volume, other pathophysiologic processes are likely involved. Mechanisms likely include a combination of venous congestion (elevated central venous pressure [CVP]) and visceral edema resulting in decreased abdominal perfusion pressure (APP) and elevated neuroendocrine (angiotensin, vasopressin) hormones, resulting in decreased renal perfusion.
5. Large-vessel etiologies
1. Renal artery stenosis (RAS): This usually is in combination with other etiologies (eg, ACEis, hypotension).
2. Aortic or renal artery dissection (or compression)
3. Thrombosis or embolism of the renal vessels
2. Intrinsic Renal Injury
1. Acute tubular necrosis (ATN)
1. Ischemia (prerenal azotemia naturally progresses into ATN): This is the most significant cause of ATN in the ICU.
2. Pigments (hemoglobin, myoglobin): Of note, rhabdomyolysis should be considered with CPK (creatinine phosphokinase) levels greater than 5000 units/L. Injury is secondary to direct tubular toxicity from cast formation, in addition to intrarenal vasoconstriction and hypovolemia (muscle inflammation and third spacing). It is important to remember that CPK levels are a marker for muscle injury and that direct injury is caused by myoglobin.
3. Drugs
1. Aminoglycosides, particularly at high doses, are toxic to proximal tubular cells. Once-daily dosing and vigilant dosing of medications can prevent some, but not all, cases.
2. Amphotericin B can cause AKI because of nephrotoxicity and vasoconstriction. It is also associated with the development of distal renal tubular acidosis (RTA). Liposomal and colloid dispersion may decrease the incidence of severe AKI.
3. Vancomycin has been shown to be associated with ATN; however, the incidence has decreased since the preparation has changed. Higher doses/levels may lead to increased incidence.
4. Hydroxyethyl starches (HES) are associated with significant AKI and increased mortality when used as a volume expander in patients with sepsis who are critically ill. Osmotic nephrosis is seen in the proximal tubules.
5. Contrast-induced AKI (CIAKI) or contrast-induced nephropathy (CIN): Contrast is both directly cytotoxic and decreases renal blood flow by vasoconstriction. This usually is in combination with hypovolemia/hypotension.
4. Proteins (immunoglobulin light chains—multiple myeloma): Notably, intravenous immunoglobulin (IVIG) therapy has been associated with proximal tubular osmotic nephrosis and, possibly, arterial vasoconstriction.
5. Crystals (uric acid, acyclovir, methotrexate)
2. Acute interstitial nephritis
1. Allergic (drug induced): The most common drugs include β-lactam antibiotics and sulfonamides. Others include NSAIDs, proton pump inhibitors (PPIs), fluoroquinolones, vancomycin, and phenytoin.
2. Infection: Bacterial and viral infections can lead to AIN by direct (pyelonephritis) and indirect (legionella) renal involvement.
3. Infiltrative/autoimmune: Sarcoidosis, lupus, lymphoma/leukemia, and other systemic diseases can lead to interstitial inflammation.
3. Glomerulonephritis
1. Intraglomerular inflammation with various timelines of progression and acuity of disease: Progression can be acute or rapidly progressive and severe, requiring early diagnosis. Pulmonary hemorrhage is a rare but feared complication (can be seen with antineutrophil cytoplasmic antibody [ANCA] or anti-glomerular basement membrane [GBM] disease). Typically classified on the basis of pathology, that is, pauci-immune (ANCA vasculitis), anti-GBM, and immune complex (postinfectious, immunoglobulin A [IgA], lupus nephritis, membranoproliferative, cryoglobulinemia, etc)
4. Small vessel disease
1. Thrombosis: various pathophysiologic processes including hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), preeclampsia, antiphospholipid antibody syndrome (APLAS), polyarthritis nodosa (PAN), scleroderma, and disseminated intravascular coagulopathy (DIC)
2. Cholesterol embolism
3. Postrenal (Obstruction and Hydronephrosis)
1. Bilateral ureteral obstruction
1. Malignancy (including lymphadenopathy), aneurysmal compression, nephrolithiasis, or retroperitoneal fibrosis or hematoma
2. Bladder/urethral pathology
1. Prostate enlargement (from benign prostatic hyperplasia or malignancy), Foley catheter or urethral obstruction, anticholinergic medications, and neurogenic bladder can all contribute to urinary obstruction and postrenal kidney dysfunction.