Medical School · Year 3 · Internal Medicine · includes a quiz and discussion video

Seminar 9: Acute Kidney Injury

Year 3: Internal Medicine Clerkship

Learning Objectives

By the end of this seminar, students will be able to:

1. Define acute kidney injury using KDIGO criteria
2. Classify AKI by prerenal, intrinsic, and postrenal causes
3. Describe diagnostic workup including urinalysis and urine studies
4. Apply management principles for different AKI etiologies
5. Recognize indications for renal replacement therapy
6. Describe prevention strategies for hospital-acquired AKI

Seminar Outline

I. Definition and Classification

Acute kidney injury represents a sudden decline in kidney function occurring over hours to days, characterized by the accumulation of nitrogenous waste products including creatinine and urea, dysregulation of fluid and electrolyte homeostasis, and reduction in urine output in many cases. The Kidney Disease Improving Global Outcomes (KDIGO) consensus definition establishes AKI as an increase in serum creatinine by 0.3 mg/dL or more within 48 hours, an increase in serum creatinine to 1.5 times or more of baseline known or presumed to have occurred within the prior 7 days, or a urine volume less than 0.5 mL/kg/hour for 6 hours. This standardized definition enables consistent identification, staging, and communication about AKI across clinical settings and research studies. The recognition that even small changes in serum creatinine are associated with increased morbidity and mortality has led to adoption of these sensitive criteria, though clinicians should recognize that creatinine is an imperfect marker that may lag behind true changes in glomerular filtration rate.

The KDIGO staging system stratifies AKI severity into three stages based on the degree of creatinine elevation and urine output reduction, with higher stages associated with worse outcomes. Stage 1 AKI encompasses creatinine increases of 1.5 to 1.9 times baseline or an absolute increase of 0.3 mg/dL or more, or urine output less than 0.5 mL/kg/hour for 6 to 12 hours. Stage 2 AKI is defined by creatinine elevation of 2.0 to 2.9 times baseline or urine output less than 0.5 mL/kg/hour for 12 hours or longer. Stage 3 AKI, the most severe category, includes creatinine elevation of 3 times or more baseline, an absolute creatinine value of 4.0 mg/dL or higher, initiation of renal replacement therapy, urine output less than 0.3 mL/kg/hour for 24 hours or longer, or anuria for 12 hours or more. Staging helps predict prognosis, guide management intensity, and facilitate communication among the healthcare team.

The classification of AKI by anatomic location provides a practical framework for differential diagnosis and guides the diagnostic workup and therapeutic approach. Prerenal AKI, the most common category accounting for 40-70% of cases in most series, results from decreased renal perfusion with structurally intact nephrons and is potentially rapidly reversible if perfusion is restored promptly. Intrinsic AKI involves direct damage to the renal parenchyma, whether the tubules, glomeruli, interstitium, or vasculature, and typically requires longer recovery periods. Postrenal AKI results from obstruction of urine flow anywhere from the renal pelvis to the urethra, requiring bilateral obstruction or unilateral obstruction of a solitary functioning kidney to cause significant creatinine elevation. In clinical practice, these categories may overlap, such as when prolonged prerenal hypoperfusion progresses to intrinsic tubular necrosis.

Distinguishing acute kidney injury from chronic kidney disease has important implications for prognosis, management, and patient counseling. AKI is characterized by rapid onset over days to weeks, typically with previously known normal renal function or a documented recent baseline creatinine, normal or enlarged kidney size on imaging, absence of chronic complications such as renal osteodystrophy or secondary hyperparathyroidism, and potential for recovery of function. CKD is defined by structural or functional kidney abnormalities persisting for 3 months or more, often with chronically elevated creatinine, small kidney size on ultrasound, anemia of chronic disease, hyperphosphatemia with secondary hyperparathyroidism, and irreversible progression. However, AKI and CKD are interconnected: AKI can occur superimposed on pre-existing CKD (acute on chronic kidney injury), and AKI is now recognized as a major risk factor for developing or accelerating CKD. Establishing baseline renal function from prior laboratory results, when available, is essential for accurate diagnosis and staging.

<image>Panel A: KDIGO AKI definition criteria showing the three diagnostic criteria (creatinine rise of 0.3 mg/dL in 48 hours, creatinine 1.5 times baseline in 7 days, or oliguria) with example values. Panel B: KDIGO staging diagram showing Stages 1, 2, and 3 with corresponding creatinine and urine output thresholds and associated mortality risk. Panel C: Anatomic classification schematic showing prerenal (before the kidney), intrinsic (within the kidney subdivided into tubular, glomerular, interstitial, and vascular), and postrenal (obstruction) causes with their relative prevalence. Panel D: AKI versus CKD comparison showing distinguishing features including duration, kidney size, anemia, bone disease, and prognosis.</image>

II. Prerenal AKI

Prerenal azotemia occurs when decreased renal perfusion reduces glomerular filtration while the renal parenchyma remains structurally intact, representing a physiologic response to inadequate blood flow rather than intrinsic kidney damage. True hypovolemia from hemorrhage, gastrointestinal losses through vomiting or diarrhea, renal losses from excessive diuresis, or third-spacing from burns or pancreatitis represents the most straightforward cause of prerenal AKI, as the kidneys appropriately reduce filtration in response to decreased circulating volume. Decreased effective circulating volume despite total body fluid excess, as seen in heart failure with reduced cardiac output, advanced cirrhosis with splanchnic vasodilation, or sepsis with distributive vasodilation, also produces prerenal physiology despite the patient appearing volume overloaded on examination. Medications that impair renal autoregulation, including NSAIDs that block afferent arteriolar prostaglandin-mediated vasodilation and ACE inhibitors or ARBs that prevent angiotensin-mediated efferent arteriolar vasoconstriction, can precipitate prerenal AKI particularly in patients with pre-existing renal hypoperfusion.

The pathophysiology of prerenal AKI involves compensatory mechanisms that initially maintain glomerular filtration rate despite reduced renal blood flow, but eventually fail when perfusion pressure drops below the autoregulatory threshold. The kidneys normally maintain stable GFR across a range of mean arterial pressures through autoregulation involving myogenic responses, tubuloglomerular feedback, and neurohormonal mechanisms including the renin-angiotensin-aldosterone system. When renal perfusion falls, prostaglandin-mediated afferent arteriolar dilation increases blood flow into the glomerulus, while angiotensin II-mediated efferent arteriolar constriction maintains intraglomerular pressure and filtration fraction. These compensatory mechanisms explain why patients on NSAIDs or ACE inhibitors are particularly susceptible to prerenal AKI, as these drugs block the kidney's ability to maintain GFR during hypoperfusion. When autoregulation fails or hypoperfusion is prolonged beyond 24-48 hours, ischemic injury to tubular epithelial cells occurs, and prerenal azotemia transitions to established acute tubular necrosis.

Laboratory findings in prerenal AKI reflect the kidney's appropriate response to hypoperfusion: avid sodium and water retention to restore circulating volume and concentrated urine to conserve fluid. The blood urea nitrogen to creatinine ratio is typically elevated above 20:1 in prerenal states because urea reabsorption in the proximal tubule is enhanced by slow tubular flow rates, while creatinine is neither reabsorbed nor secreted to the same extent. Urine sodium concentration is characteristically low, typically less than 20 mEq/L, reflecting intense sodium reabsorption, and urine osmolality is elevated above 500 mOsm/kg indicating preserved concentrating ability. Urine specific gravity is correspondingly high, generally above 1.020. The urinary sediment in prerenal AKI is characteristically bland, with few cells or casts, as the tubular epithelium remains intact. These laboratory findings help distinguish prerenal from intrinsic causes of AKI, though they may be confounded by concurrent diuretic use, glycosuria, contrast administration, or underlying chronic kidney disease.

The fractional excretion of sodium (FENa) is the most useful calculated index for distinguishing prerenal from intrinsic AKI, representing the percentage of filtered sodium that is excreted in the urine. FENa is calculated as (urine sodium times plasma creatinine) divided by (plasma sodium times urine creatinine), multiplied by 100, with values below 1% suggesting prerenal etiology and values above 2% suggesting intrinsic renal disease, particularly acute tubular necrosis. However, several important caveats limit FENa interpretation: diuretic use increases sodium excretion even in prerenal states, making FENa unreliable; in these cases, fractional excretion of urea (FEUrea) less than 35% better identifies prerenal physiology because urea handling is less affected by diuretics. FENa may also be falsely low in certain intrinsic diseases including contrast nephropathy, pigment-induced nephropathy from myoglobin or hemoglobin, early obstruction, acute glomerulonephritis, and sepsis-associated AKI. Despite these limitations, FENa remains a valuable diagnostic tool when interpreted in clinical context.

<image>Panel A: Causes of prerenal AKI organized by mechanism (true hypovolemia, decreased effective circulating volume, and medications affecting autoregulation) with specific examples for each category. Panel B: Renal autoregulation diagram showing afferent arteriole, glomerulus, and efferent arteriole with prostaglandin and angiotensin II effects, and how NSAIDs and ACE inhibitors disrupt these mechanisms. Panel C: Laboratory comparison table showing characteristic values for BUN:Cr ratio, urine sodium, FENa, urine osmolality, and specific gravity in prerenal versus intrinsic AKI. Panel D: FENa calculation worksheet with the formula, example calculation, interpretation thresholds, and list of conditions causing false low or false high values.</image>

III. Intrinsic AKI

Intrinsic acute kidney injury involves direct structural damage to the renal parenchyma and is classified by the primary anatomic compartment affected: tubules, glomeruli, interstitium, or vasculature. Acute tubular necrosis is by far the most common form of intrinsic AKI, accounting for approximately 85% of cases, resulting from ischemic injury following prolonged prerenal hypoperfusion or direct nephrotoxic injury from medications, contrast agents, or endogenous substances. Glomerular diseases including rapidly progressive glomerulonephritis and thrombotic microangiopathies present with AKI accompanied by active urinary sediment with dysmorphic red blood cells and red cell casts, often with significant proteinuria. Acute interstitial nephritis, typically drug-induced, and acute pyelonephritis represent interstitial causes characterized by sterile pyuria and white blood cell casts. Vascular causes including renal artery thrombosis, cholesterol embolization, and malignant hypertension produce AKI through ischemic injury to the renal parenchyma.

Acute tubular necrosis develops through either ischemic or nephrotoxic mechanisms and follows a characteristic clinical course of injury, maintenance, and recovery phases. Ischemic ATN occurs when renal hypoperfusion exceeds the duration or severity that the kidney can compensate for, leading to tubular epithelial cell injury and death, particularly in the metabolically active proximal tubule S3 segment and thick ascending limb where oxygen delivery may be inadequate to meet metabolic demands. Nephrotoxic ATN results from direct tubular toxicity from substances including aminoglycoside antibiotics, amphotericin B, cisplatin chemotherapy, iodinated contrast media, and endogenous pigments such as myoglobin from rhabdomyolysis or hemoglobin from hemolysis. The injury phase involves cellular damage and cast formation obstructing tubular lumens, followed by a maintenance phase of established AKI lasting days to weeks, and eventually a recovery phase as tubular epithelium regenerates. The urinary sediment in ATN characteristically shows muddy brown granular casts composed of degenerating tubular cells, which is highly specific for this diagnosis.

A wide variety of nephrotoxins can cause acute tubular necrosis or other forms of intrinsic AKI, and medication review is essential in any patient presenting with unexplained kidney injury. Aminoglycoside antibiotics cause dose-dependent tubular toxicity with peak concentrations correlating with risk, typically manifesting after 5-7 days of therapy with nonoliguric AKI. Iodinated contrast agents cause contrast-induced nephropathy through direct tubular toxicity and renal vasoconstriction, with risk factors including pre-existing CKD, diabetes, volume depletion, and large contrast volumes. Vancomycin, particularly at high trough levels, has been increasingly recognized as a cause of AKI, sometimes in combination with other nephrotoxins. Pigment-induced nephropathy from myoglobin in rhabdomyolysis or hemoglobin in severe hemolysis causes tubular injury through oxidative stress and cast formation. Crystal nephropathy can result from medications including acyclovir, methotrexate, and sulfadiazine, as well as from endogenous substances such as uric acid in tumor lysis syndrome or calcium oxalate in ethylene glycol poisoning.

Acute interstitial nephritis is an inflammatory condition affecting the renal interstitium, most commonly caused by medications, though infections, autoimmune diseases, and idiopathic causes also occur. Drug-induced AIN accounts for over 70% of cases, with common offending agents including beta-lactam antibiotics (particularly penicillins and cephalosporins), proton pump inhibitors, NSAIDs, sulfonamides, and allopurinol. The classic triad of fever, rash, and eosinophilia is present in only 10-30% of cases, making clinical diagnosis challenging and requiring a high index of suspicion in patients with unexplained AKI and recent medication exposure. Urinary findings in AIN include sterile pyuria, white blood cell casts, and eosinophiluria, though the latter has low sensitivity and is present in other conditions as well. Diagnosis is often made clinically based on temporal relationship to medication exposure and supported by urine findings, with renal biopsy reserved for uncertain cases, lack of improvement after drug discontinuation, or when immunosuppressive therapy is considered. Treatment involves discontinuation of the offending agent, with systemic corticosteroids considered in severe cases or when recovery does not occur within 5-7 days of drug withdrawal, though evidence for steroid benefit remains limited.

<image>Panel A: Classification of intrinsic AKI by compartment showing tubular (ATN), glomerular (GN, TMA), interstitial (AIN, pyelonephritis), and vascular (arterial thrombosis, cholesterol emboli) causes with their relative frequencies. Panel B: Phases of acute tubular necrosis diagram showing injury phase with falling GFR, maintenance phase of established AKI, and recovery phase with gradual return of function, with typical time course. Panel C: Common nephrotoxins organized by mechanism including antibiotics, contrast, chemotherapy, pigments, and crystals with specific examples and characteristic features of each. Panel D: Acute interstitial nephritis clinical features showing the classic triad (with percentage of patients affected), common causative medications, urine findings, and treatment approach.</image>

IV. Postrenal AKI

Postrenal acute kidney injury results from obstruction to urinary outflow at any level from the renal pelvis to the urethra, and requires bilateral obstruction or unilateral obstruction of a solitary functioning kidney to cause significant azotemia. Bladder outlet obstruction from benign prostatic hyperplasia is the most common cause in older men, while other lower tract causes include prostate cancer, bladder cancer invading the bladder neck, urethral strictures, and neurogenic bladder with detrusor dysfunction. Ureteral obstruction is less common and may result from nephrolithiasis (though typically unilateral and not causing AKI unless the contralateral kidney is absent or non-functional), ureteral tumors, extrinsic compression from retroperitoneal malignancy or fibrosis, or surgical injury. Upper tract obstruction at the ureteropelvic junction may be congenital or acquired. Postrenal AKI accounts for approximately 5-10% of AKI cases in hospitalized patients but is important to recognize promptly as it is often reversible with relief of obstruction.

The clinical features of urinary tract obstruction depend on the level, duration, and completeness of obstruction, as well as the acuity of onset. Patients with bladder outlet obstruction from BPH typically report lower urinary tract symptoms including urinary hesitancy, weak stream, incomplete emptying, nocturia, and dribbling, developing over weeks to months. Acute complete obstruction may present with sudden anuria, which should always raise suspicion for obstruction and prompt immediate evaluation. Incomplete or fluctuating obstruction may cause varying urine output, with periods of oliguria followed by polyuria. Physical examination may reveal a distended, palpable bladder in lower tract obstruction, and digital rectal examination may identify an enlarged prostate or rectal mass. Flank pain suggests upper tract obstruction, particularly with nephrolithiasis, though chronic obstruction may be painless. Importantly, obstruction can be present even without hydronephrosis on early imaging, particularly in volume-depleted patients or when obstruction is acute.

Diagnostic evaluation for suspected postrenal AKI begins with assessment of bladder volume and proceeds to imaging of the upper urinary tract. Bedside bladder ultrasound or bladder scan provides rapid, non-invasive assessment of bladder volume, with post-void residual volumes exceeding 300-400 mL suggesting bladder outlet obstruction. Placement of a urinary catheter serves both diagnostic and therapeutic purposes: return of large volumes of urine confirms bladder outlet obstruction, and decompression initiates treatment. Renal ultrasound is the initial imaging modality of choice for detecting hydronephrosis, as it is non-invasive, widely available, and does not require contrast administration; however, it may miss early or mild obstruction and cannot always identify the level or cause of obstruction. Non-contrast CT scan provides superior anatomic detail and is particularly useful for identifying ureteral stones, tumors, or retroperitoneal pathology causing extrinsic compression. Laboratory findings in postrenal AKI are variable and may initially mimic prerenal physiology; prolonged obstruction can lead to tubular dysfunction with an ATN-like picture.

Management of postrenal AKI centers on prompt relief of obstruction followed by monitoring for post-obstructive diuresis and definitive treatment of the underlying cause. Urinary catheter placement is the first-line intervention for suspected bladder outlet obstruction and should not be delayed pending imaging if clinical suspicion is high. For ureteral obstruction, intervention by urology or interventional radiology is required: options include retrograde ureteral stent placement via cystoscopy or antegrade percutaneous nephrostomy tube placement, with the choice depending on the cause and level of obstruction and institutional expertise. Post-obstructive diuresis is a physiologic response to relief of obstruction that can lead to significant fluid and electrolyte losses, particularly after relief of bilateral obstruction or obstruction of a solitary kidney; it results from accumulated solute causing an osmotic diuresis, natriuretic factors, and impaired tubular concentrating ability. Patients should have close monitoring of urine output, daily weights, serum electrolytes, and volume status, with IV fluid replacement guided by the degree of polyuria and the patient's volume status. Nephrology and urology consultation should be obtained for ongoing management and to address the underlying etiology.

<image>Panel A: Anatomic diagram of the urinary tract showing potential sites of obstruction including ureteropelvic junction, ureter (stones, tumors, extrinsic compression), bladder (outlet obstruction), and urethra (stricture) with common causes at each level. Panel B: Clinical features of bladder outlet obstruction showing lower urinary tract symptoms, physical examination findings, and relationship between symptom duration and severity. Panel C: Diagnostic algorithm for suspected postrenal AKI starting with bladder scan or catheterization, proceeding to renal ultrasound, and CT scan if needed, with decision points for each step. Panel D: Post-obstructive diuresis management protocol showing monitoring parameters (urine output, electrolytes, weight), fluid replacement strategy, and warning signs requiring intervention.</image>

V. Diagnostic Workup

The diagnostic evaluation of acute kidney injury begins with a thorough history focusing on potential etiologies and risk factors across prerenal, intrinsic, and postrenal categories. Volume status history should address recent fluid intake and losses including vomiting, diarrhea, bleeding, sweating, and urine output, as well as changes in body weight, orthostatic symptoms, and peripheral edema. Medication history is critical and should include all prescription medications with attention to nephrotoxins including NSAIDs, aminoglycosides, vancomycin, ACE inhibitors, ARBs, and diuretics, as well as over-the-counter medications, herbal supplements, and any recent contrast administration or new medications started within the prior weeks. Systemic symptoms such as fever, rash, joint pain, or weight loss suggest underlying infection, autoimmune disease, or malignancy. Urinary symptoms including dysuria, frequency, urgency, hesitancy, weak stream, and gross hematuria help distinguish infectious and obstructive etiologies. Past medical history should address pre-existing kidney disease, diabetes, hypertension, heart failure, liver disease, and any prior AKI episodes.

Physical examination provides essential information for determining the etiology and guiding initial management of AKI. Volume status assessment is paramount and includes evaluation of mucous membranes, skin turgor, capillary refill, jugular venous pressure, presence of orthostatic vital sign changes, and examination for peripheral edema, pulmonary crackles, and third heart sounds that might indicate volume overload or cardiac dysfunction. Abdominal examination should assess for palpable bladder distension indicating outlet obstruction, abdominal masses, or tenderness suggesting underlying pathology. Skin examination may reveal rashes associated with allergic interstitial nephritis, vasculitis, or endocarditis, while livedo reticularis in a patient with recent arterial catheterization suggests cholesterol embolization. Fundoscopic examination can reveal hypertensive or diabetic retinopathy or Roth spots of endocarditis. Joint examination assessing for arthritis may suggest systemic lupus erythematosus, vasculitis, or crystal arthropathy. Cardiovascular examination evaluates for murmurs that might indicate endocarditis as a source of emboli or severe valvular disease contributing to prerenal hypoperfusion.

Laboratory evaluation of AKI extends beyond serum creatinine to include electrolytes, blood counts, and specialized tests guided by clinical suspicion. The basic metabolic panel assesses for hyperkalemia, acidosis, hyponatremia, hyperphosphatemia, and hypocalcemia that may accompany AKI and influence management urgency. Complete blood count may reveal anemia suggesting hemolysis or chronic kidney disease, thrombocytopenia indicating thrombotic microangiopathy or disseminated intravascular coagulation, or eosinophilia suggesting allergic interstitial nephritis or cholesterol embolization. Creatine kinase should be measured when rhabdomyolysis is suspected based on history of trauma, prolonged immobilization, seizures, drug intoxication, or exertional injury. Urine studies including urinalysis, urine sodium and creatinine for FENa calculation, and microscopic examination of sediment are essential components of the workup. When glomerulonephritis is suspected based on active sediment with dysmorphic RBCs, RBC casts, and significant proteinuria, serologic evaluation should include complement levels (C3, C4), ANA, anti-dsDNA, ANCA, anti-GBM antibodies, hepatitis B and C serologies, HIV testing, and serum and urine protein electrophoresis.

Urinalysis and microscopic examination of urine sediment provide critical diagnostic information and should be performed promptly in all patients with AKI. A bland sediment with few cells and no casts is characteristic of prerenal azotemia and uncomplicated postrenal obstruction. Muddy brown granular casts, composed of degenerating tubular epithelial cells and debris, are highly specific for acute tubular necrosis and represent the hallmark finding. Red blood cell casts, appearing as cylindrical structures containing intact RBCs in a protein matrix, are pathognomonic for glomerulonephritis and indicate bleeding from within the glomerular capillaries. White blood cell casts suggest pyelonephritis or acute interstitial nephritis, while the presence of eosinophils in the urine (eosinophiluria) may support AIN diagnosis though with limited sensitivity. Crystalluria may indicate crystal nephropathy from uric acid, calcium oxalate, or medications. Proteinuria exceeding 1-2 grams per day suggests glomerular pathology, while lesser amounts may be seen in tubular or interstitial disease. The combination of urinary findings helps narrow the differential diagnosis and guides further workup including the decision regarding renal biopsy.

<image>Panel A: History checklist for AKI evaluation organized by domain (volume status, medications, systemic symptoms, urinary symptoms, and past medical history) with key questions for each. Panel B: Physical examination findings in AKI showing correlation between findings (orthostatic hypotension, edema/JVD, palpable bladder, rash, livedo reticularis) and likely etiology. Panel C: Laboratory workup algorithm showing initial tests (BMP, CBC, UA, urine chemistries) and additional tests based on clinical scenario (CK for rhabdomyolysis, serologies for GN). Panel D: Urine sediment interpretation guide with images and descriptions of bland sediment, muddy brown casts, RBC casts, WBC casts, and crystals with their associated diagnoses.</image>

VI. Specific Etiologies

Contrast-induced acute kidney injury, also termed contrast-induced nephropathy (CIN) or post-contrast AKI, occurs following intravascular administration of iodinated contrast media and represents a common cause of hospital-acquired AKI. The pathophysiology involves direct tubular toxicity from contrast-induced oxidative stress and renal vasoconstriction mediated by endothelin and adenosine, leading to outer medullary ischemia. Serum creatinine typically begins to rise within 24-48 hours of contrast exposure, peaks at 3-5 days, and returns to baseline within 7-14 days in uncomplicated cases, though some patients develop persistent injury or require dialysis. Risk factors include pre-existing chronic kidney disease (the strongest predictor), diabetes mellitus, heart failure, advanced age, hypovolemia, large contrast volume, and concurrent use of nephrotoxic medications. Prevention strategies center on risk stratification, volume expansion with isotonic saline or sodium bicarbonate before and after contrast administration, use of low-osmolar or iso-osmolar contrast agents, minimizing contrast volume, and avoiding nephrotoxic medications. The previously recommended use of N-acetylcysteine is no longer supported by recent large trials showing no benefit.

Rhabdomyolysis is a syndrome of skeletal muscle breakdown with release of intracellular contents including myoglobin, creatine kinase, potassium, and phosphorus into the circulation, frequently complicated by AKI. Common causes include trauma and crush injuries, prolonged immobilization, seizures, strenuous exertion, drug toxicity from statins, cocaine, or alcohol, electrolyte abnormalities including hypokalemia and hypophosphatemia, infections, and inflammatory myopathies. The diagnosis is established by marked elevation of serum creatine kinase, typically exceeding 10,000 U/L, though AKI can occur with lower levels. Characteristic laboratory findings include hyperkalemia, hyperphosphatemia, hypocalcemia in early stages followed by hypercalcemia during recovery, elevated uric acid, and metabolic acidosis. Urinalysis shows pigmented urine that tests positive for blood on dipstick but has few or no red blood cells on microscopy, reflecting myoglobin rather than hemoglobin. Treatment requires aggressive intravenous fluid resuscitation with isotonic saline targeting urine output of 200-300 mL/hour to prevent myoglobin precipitation in renal tubules, with monitoring and treatment of hyperkalemia and other electrolyte disturbances. Renal replacement therapy may be necessary for refractory hyperkalemia, volume overload, or severe acidosis.

Tumor lysis syndrome is an oncologic emergency occurring when rapid destruction of malignant cells releases intracellular contents into the bloodstream, typically following initiation of cytotoxic chemotherapy for high-grade, rapidly proliferating malignancies. The classic metabolic derangements include hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia, with AKI resulting from uric acid crystal deposition in renal tubules (uric acid nephropathy) and possibly calcium phosphate precipitation. High-risk malignancies include acute lymphoblastic leukemia, Burkitt lymphoma, diffuse large B-cell lymphoma with high tumor burden, and acute myeloid leukemia with elevated white blood cell counts. Prevention in high-risk patients includes aggressive intravenous hydration to maintain urine output exceeding 2 mL/kg/hour, allopurinol to inhibit uric acid production, and rasburicase, a recombinant urate oxidase that rapidly converts uric acid to the more soluble allantoin, for patients at highest risk. Treatment of established TLS involves continued aggressive hydration, rasburicase for hyperuricemia, standard management of hyperkalemia, and dialysis when indicated for refractory electrolyte abnormalities or severe AKI.

Hepatorenal syndrome is a form of functional AKI occurring in patients with advanced cirrhosis and portal hypertension, characterized by intense renal vasoconstriction in the absence of intrinsic renal disease. The pathophysiology involves splanchnic arterial vasodilation triggering compensatory activation of the renin-angiotensin-aldosterone system, sympathetic nervous system, and vasopressin, ultimately causing profound renal vasoconstriction and reduced glomerular filtration despite preserved tubular function. Type 1 HRS is characterized by rapid deterioration of kidney function with doubling of creatinine to above 2.5 mg/dL within 2 weeks, often precipitated by spontaneous bacterial peritonitis or other infections, and carries a median survival of approximately 2 weeks without treatment. Type 2 HRS has a more gradual course and is typically associated with refractory ascites rather than acute decompensation. Diagnosis requires exclusion of other causes of AKI including hypovolemia (no improvement after albumin challenge), nephrotoxic drug exposure, and structural kidney disease. Treatment involves systemic vasoconstrictors, specifically the combination of midodrine and octreotide or terlipressin where available, combined with intravenous albumin to increase effective circulating volume. Liver transplantation remains the only definitive treatment, with simultaneous liver-kidney transplant considered for prolonged dialysis dependence.

<image>Panel A: Contrast-induced nephropathy timeline showing creatinine trajectory from baseline through peak at 3-5 days and recovery, with risk factors listed and prevention strategies. Panel B: Rhabdomyolysis pathophysiology diagram showing muscle breakdown, myoglobin release, tubular injury and cast formation, with characteristic laboratory findings and treatment goals. Panel C: Tumor lysis syndrome metabolic cascade showing cell lysis releasing potassium, phosphorus, nucleic acids (metabolized to uric acid), with resulting hypocalcemia and uric acid nephropathy. Panel D: Hepatorenal syndrome pathophysiology showing portal hypertension leading to splanchnic vasodilation, reduced effective circulating volume, neurohormonal activation, and renal vasoconstriction, with diagnostic criteria and treatment approach.</image>

VII. Management Principles

The management of acute kidney injury follows several core principles applicable across etiologies: identifying and treating the underlying cause, optimizing volume status and hemodynamics, avoiding further nephrotoxic insults, and monitoring for complications that may require urgent intervention. The initial priority is to establish the diagnosis and classify AKI as prerenal, intrinsic, or postrenal, as management differs substantially: prerenal AKI requires restoration of renal perfusion, postrenal AKI requires relief of obstruction, and intrinsic AKI management is primarily supportive while addressing the underlying cause. Simultaneously, the medication list should be thoroughly reviewed to identify and discontinue nephrotoxins including NSAIDs, aminoglycosides, and other potentially offending agents. ACE inhibitors and ARBs should generally be held during acute kidney injury given their effects on glomerular hemodynamics, though this recommendation is based on physiologic rationale rather than randomized trial evidence. Serum creatinine and urine output should be monitored at least daily, with more frequent assessment in critically ill patients or those with rapidly changing renal function.

Volume management in AKI requires careful assessment of the patient's current volume status and underlying etiology, as the optimal approach varies significantly across clinical scenarios. In hypovolemic prerenal AKI from true volume depletion, intravenous fluid resuscitation with balanced crystalloid solutions is the primary treatment, with monitoring of clinical response including urine output, blood pressure, and subsequent creatinine measurements. In contrast, patients with cardiorenal syndrome have decreased effective circulating volume despite total body fluid excess, and diuretic therapy with loop diuretics is the appropriate intervention to reduce congestion and may paradoxically improve renal function by decreasing venous congestion and intra-abdominal pressure. Patients with established AKI and oliguria may develop volume overload requiring diuretic therapy or ultrafiltration; diuretic resistance is common in AKI and may require high doses, continuous infusion, or addition of a thiazide diuretic for sequential nephron blockade. The goal of volume management is euvolemia, avoiding both hypoperfusion that perpetuates prerenal injury and hypervolemia that causes pulmonary edema and tissue edema impairing oxygen delivery.

Medication adjustments are essential in patients with AKI given altered drug pharmacokinetics and the potential for further nephrotoxic injury. All medications should be reviewed for renal dosing requirements, and doses should be adjusted or held based on estimated current kidney function, recognizing that creatinine-based GFR estimates may significantly overestimate function during acute changes. Nephrotoxic medications including aminoglycosides, NSAIDs, and iodinated contrast should be avoided when possible; if essential, drug levels should be monitored closely and exposure minimized. Metformin should be held given the risk of lactic acidosis with impaired renal clearance. Renally cleared medications including gabapentin, morphine (which accumulates active metabolites), and many antibiotics require dose reduction or extended intervals. ACE inhibitors and ARBs are typically held during AKI, with reinitiation considered once renal function has stabilized, as these medications provide important long-term nephroprotection and cardiovascular benefit in appropriate patients. Drug-drug interactions that may be exacerbated by reduced clearance should be evaluated, and serum drug levels should be monitored for medications with narrow therapeutic windows.

Nutritional support in AKI aims to provide adequate calories to prevent catabolism while managing the metabolic consequences of reduced kidney function. Protein restriction, historically recommended to reduce urea generation and delay need for dialysis, is no longer advocated in most situations, as AKI is a catabolic state and inadequate protein intake worsens outcomes; most patients should receive 0.8-1.0 g/kg/day of protein, with higher amounts for patients on continuous renal replacement therapy due to amino acid losses. Potassium restriction is necessary in patients with hyperkalemia or oliguria, with avoidance of high-potassium foods and potassium-containing salt substitutes, IV fluids, and medications. Phosphorus restriction may be needed if hyperphosphatemia develops, particularly in rhabdomyolysis or tumor lysis syndrome. Caloric intake should be adequate to meet metabolic demands, typically 25-30 kcal/kg/day, to prevent muscle catabolism and further nitrogen waste generation. Enteral nutrition is preferred over parenteral when the gastrointestinal tract is functional. Dietary modifications should be individualized based on the patient's metabolic status, expected duration of AKI, and whether renal replacement therapy is anticipated or ongoing.

<image>Panel A: Core AKI management principles flowchart showing simultaneous assessment of cause, volume status, medications, and monitoring, with action items for each domain. Panel B: Volume management algorithm stratified by volume status (hypovolemic, euvolemic, hypervolemic) and underlying condition with appropriate interventions (fluids versus diuretics). Panel C: Medication adjustment checklist showing categories of drugs requiring attention (nephrotoxins to stop, renally cleared drugs requiring dose adjustment, drugs with active metabolites to avoid). Panel D: Nutrition goals in AKI showing recommended protein, calorie, potassium, and phosphorus targets with rationale for each.</image>

VIII. Complications

Hyperkalemia is one of the most dangerous complications of AKI, as severe elevations can cause life-threatening cardiac arrhythmias including ventricular fibrillation and asystole. Potassium accumulates in AKI due to decreased renal excretion, often compounded by tissue breakdown, metabolic acidosis causing transcellular shift of potassium out of cells, and medications including ACE inhibitors, ARBs, potassium-sparing diuretics, and trimethoprim. Severity is classified by serum potassium level and presence of ECG changes: mild hyperkalemia (5.5-6.0 mEq/L) may be managed with dietary restriction, loop diuretics if urine output is adequate, and sodium polystyrene sulfonate or patiromer for intestinal potassium binding; moderate hyperkalemia (6.0-6.5 mEq/L without ECG changes) requires more aggressive intervention including insulin with glucose to shift potassium intracellularly, sodium bicarbonate if acidotic, and potassium binders; severe hyperkalemia (above 6.5 mEq/L or any level with ECG changes) is a medical emergency requiring immediate treatment with intravenous calcium to stabilize the cardiac membrane, insulin/glucose and bicarbonate for temporary intracellular shift, and urgent preparation for dialysis which is the only treatment providing true potassium removal in anuric patients. ECG changes progress from peaked T waves to flattening of P waves, PR prolongation, QRS widening, and ultimately a sinusoidal pattern preceding arrest.

Metabolic acidosis commonly accompanies AKI as the kidney loses its ability to excrete daily acid production and regenerate bicarbonate. The acidosis is typically a high anion gap metabolic acidosis due to accumulation of uremic acids including phosphoric acid, sulfuric acid, and organic acids that cannot be excreted. The severity correlates with the degree of kidney function loss and may be exacerbated by concurrent conditions producing additional acid, such as lactic acidosis from tissue hypoperfusion or ketoacidosis. Respiratory compensation through hyperventilation (Kussmaul breathing) reduces PaCO2 and partially mitigates the pH decline. Treatment of mild to moderate acidosis focuses on treating the underlying AKI and avoiding further acid loads; severe acidosis with pH below 7.1-7.2 or bicarbonate below 10-12 mEq/L may warrant intravenous sodium bicarbonate administration, though this provides temporary benefit and comes with risks of volume overload, paradoxical intracellular acidosis, and possible worsening of ionized calcium. Refractory metabolic acidosis is an indication for renal replacement therapy, which effectively removes acid and provides bicarbonate or bicarbonate-equivalent buffer.

Volume overload is a common and serious complication of oliguric or anuric AKI, as patients cannot excrete administered fluids and may have ongoing volume input from IV medications, nutrition, and blood products. Manifestations include peripheral edema, pulmonary edema with dyspnea and hypoxemia, pleural effusions, ascites, and elevated jugular venous pressure. Pulmonary edema is particularly concerning and may require urgent intervention to prevent respiratory failure. Initial management involves diuretic therapy with high-dose loop diuretics; furosemide in doses of 80-200 mg IV or higher may be needed in AKI, and continuous infusion may be more effective than bolus dosing. If diuretic response is inadequate (diuretic resistance), addition of a thiazide diuretic such as metolazone can enhance natriuresis through sequential nephron blockade. Sodium and fluid restriction should be implemented to minimize ongoing accumulation. When volume overload is refractory to diuretic therapy or when the patient develops respiratory distress from pulmonary edema, urgent renal replacement therapy with ultrafiltration is indicated. Close monitoring of intake, output, and daily weights is essential for managing fluid balance in AKI patients.

Uremic syndrome encompasses the multisystem manifestations of severe azotemia when accumulated uremic toxins reach symptomatic levels, representing an indication for urgent renal replacement therapy. Uremic encephalopathy presents with altered mental status ranging from subtle cognitive impairment and difficulty concentrating to confusion, lethargy, asterixis, seizures, and coma, resulting from accumulation of neurotoxic waste products. Uremic pericarditis is characterized by chest pain, friction rub, and ECG changes showing diffuse ST elevation; it is an indication for urgent dialysis as it can progress to hemorrhagic pericardial effusion and tamponade. Uremic bleeding results from platelet dysfunction caused by uremic toxins interfering with von Willebrand factor and platelet adhesion, presenting as prolonged bleeding time, ecchymoses, and mucosal bleeding; treatment includes dialysis to remove uremic toxins, desmopressin (DDAVP) which releases von Willebrand factor from endothelial cells, and correction of anemia to improve platelet-endothelium interactions. Other uremic manifestations include nausea, vomiting, anorexia, pruritus, and restless legs syndrome. The presence of uremic symptoms indicates the need for dialysis regardless of specific laboratory values.

<image>Panel A: Hyperkalemia management algorithm showing potassium level thresholds, ECG progression (peaked T waves through sinusoidal pattern), and treatment at each severity level including membrane stabilization, transcellular shift, and elimination. Panel B: Metabolic acidosis in AKI showing anion gap calculation, compensation through hyperventilation, bicarbonate thresholds for treatment, and indications for dialysis. Panel C: Volume overload management ladder progressing from fluid restriction through diuretics (bolus and continuous infusion), sequential nephron blockade, and ultimately dialysis/ultrafiltration. Panel D: Uremic syndrome manifestations by organ system (CNS, cardiac, hematologic, GI) with clinical features and specific treatments for each.</image>

IX. Renal Replacement Therapy

The indications for initiating renal replacement therapy in AKI are summarized by the mnemonic AEIOU, representing acidosis, electrolytes, intoxication, overload, and uremia, each of which can be life-threatening and unresponsive to medical management. Refractory metabolic acidosis with pH below 7.1-7.2 despite bicarbonate administration, or severe acidosis causing hemodynamic instability or limiting administration of necessary therapies, warrants dialysis. Severe hyperkalemia above 6.5 mEq/L with ECG changes or refractory to medical management is an urgent indication, as is hyperkalemia in anuric patients where temporizing measures provide only transient benefit. Certain toxic ingestions are amenable to extracorporeal removal, particularly lithium, salicylates, methanol, and ethylene glycol, and toxicology consultation can help determine dialysis indication. Refractory pulmonary edema not responding to diuretics requires ultrafiltration for fluid removal to prevent respiratory failure. Symptomatic uremia manifesting as encephalopathy or uremic pericarditis is an indication for urgent dialysis. The decision to initiate RRT also considers the trajectory of kidney function, expected duration of AKI, and overall clinical status; earlier initiation has not been shown to improve outcomes over a strategy of watchful waiting with initiation for specific indications.

Several modalities of renal replacement therapy are available for AKI, with selection based on patient hemodynamic stability, clinical setting, and specific treatment goals. Intermittent hemodialysis uses a high blood flow rate and dialysate flow rate over a 3-4 hour session, providing rapid correction of electrolyte and acid-base abnormalities and efficient solute clearance. Continuous renal replacement therapy, including continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), runs continuously over 24 hours with slower blood and dialysate flow rates, providing gradual fluid and solute removal with better hemodynamic tolerance. Sustained low-efficiency dialysis (SLED) or prolonged intermittent renal replacement therapy (PIRRT) represents a hybrid approach with extended sessions of 6-12 hours providing intermediate intensity. Peritoneal dialysis uses the peritoneal membrane for solute and fluid exchange and is occasionally used in AKI but is less common than extracorporeal modalities due to slower clearance and potential complications in critically ill patients. The choice between modalities often depends on institutional availability and expertise, patient hemodynamic stability, and specific treatment goals.

Continuous renal replacement therapy offers several advantages over intermittent hemodialysis in hemodynamically unstable critically ill patients. The gradual, continuous nature of solute and fluid removal avoids the rapid osmotic shifts and volume changes that can cause hypotension during intermittent dialysis, making CRRT better tolerated in patients requiring vasopressor support. CRRT allows for tight fluid balance control with precise hourly adjustments in net ultrafiltration, valuable in managing complex ICU patients with ongoing fluid requirements from medications and nutrition. Continuous therapy may also provide more effective control of uremia in severely catabolic patients with high urea generation rates. However, CRRT requires continuous anticoagulation of the extracorporeal circuit, typically with regional citrate anticoagulation or systemic heparin, adding complexity and potential complications. CRRT also requires specialized equipment and nursing expertise, limiting its availability to intensive care units. Clinical trials comparing CRRT to intermittent hemodialysis have not demonstrated mortality benefit for either approach, so modality selection should be individualized based on patient stability, clinical setting, and institutional factors.

Vascular access for renal replacement therapy in AKI is typically achieved with temporary hemodialysis catheters, with site selection balancing adequacy of blood flow, risk of complications, and patient factors. The internal jugular vein is the preferred site for temporary dialysis catheter placement, providing adequate blood flow for dialysis while avoiding the higher infection risk of femoral access and the risk of central venous stenosis associated with subclavian access. The right internal jugular vein is preferred over the left due to the straighter path to the right atrium, though either side can be used. Femoral vein access provides rapid access in emergency situations and may be preferred when coagulopathy makes neck access riskier, but is associated with higher rates of catheter-related infection and should generally be limited to short-term use or replaced with internal jugular access when feasible. Subclavian access should be avoided when possible due to the high rate of subclavian vein stenosis, which can compromise future permanent dialysis access options in patients who may develop CKD. If AKI is prolonged and the patient requires ongoing dialysis beyond 2-3 weeks, consideration should be given to placement of a tunneled dialysis catheter, which has lower infection rates than non-tunneled temporary catheters for extended use.

<image>Panel A: AEIOU indications for dialysis with specific thresholds and clinical examples for acidosis, electrolytes, intoxication, overload, and uremia. Panel B: RRT modality comparison showing intermittent HD, CRRT, and SLED with their characteristics including duration, flow rates, hemodynamic impact, and typical settings. Panel C: CRRT versus IHD decision algorithm based on hemodynamic stability, ICU versus ward setting, and specific clinical scenarios. Panel D: Vascular access options diagram showing internal jugular, femoral, and subclavian sites with their advantages, disadvantages, and relative preference ranking.</image>

X. Prevention and Prognosis

Prevention of acute kidney injury, particularly in hospitalized patients at high risk, requires proactive identification of risk factors and implementation of nephroprotective strategies. Volume optimization is fundamental: patients undergoing surgery, receiving contrast media, or at risk for AKI from other causes should be euvolemic before and during the exposure period, with adequate hydration to maintain urine output. Nephrotoxin exposure should be minimized through medication review, avoiding unnecessary nephrotoxic drugs, using the lowest effective doses when nephrotoxins are necessary, and monitoring drug levels for aminoglycosides and vancomycin. Contrast-associated AKI prevention includes risk stratification, hydration with isotonic saline before and after contrast administration, use of low-osmolar or iso-osmolar contrast agents, minimizing contrast volume, and staging procedures when large contrast loads are anticipated. Hemodynamic support to maintain adequate renal perfusion, including prompt treatment of hypotension and judicious use of vasopressors when needed, helps prevent ischemic AKI in critically ill patients. Electronic health record alerts identifying nephrotoxin prescriptions, declining kidney function, or drug interactions can facilitate early intervention.

Identification of high-risk patients allows for intensified monitoring and preventive measures. Pre-existing chronic kidney disease is the strongest risk factor for developing AKI, as these patients have reduced nephron mass and limited renal reserve; any additional insult can precipitate acute-on-chronic kidney injury. Diabetic patients have heightened susceptibility to contrast nephropathy and other forms of AKI due to underlying nephropathy, impaired vascular reactivity, and frequently present comorbidities. Heart failure patients are at risk for cardiorenal syndrome and are particularly vulnerable to AKI from volume depletion, RAAS blockade, and diuretic-induced prerenal azotemia. Sepsis causes AKI through complex mechanisms including hypotension, endothelial dysfunction, and direct cellular injury, making early recognition and resuscitation critical. Patients undergoing major surgery, particularly cardiac surgery with cardiopulmonary bypass, vascular surgery, and major abdominal procedures, have elevated AKI risk from hypoperfusion, ischemia-reperfusion injury, and nephrotoxin exposure. These high-risk patients should have close monitoring of kidney function, judicious medication management, and prompt attention to volume status and hemodynamics.

The prognosis of acute kidney injury varies widely depending on the underlying cause, severity of injury, patient comorbidities, and development of complications. The majority of patients with prerenal AKI experience complete recovery of kidney function when perfusion is promptly restored, while ATN may require weeks for tubular regeneration before function normalizes. In-hospital mortality rates for AKI range from 10-40% depending on severity, with dialysis-requiring AKI carrying the highest mortality, though death is often due to the underlying critical illness rather than kidney failure itself. Among survivors, incomplete recovery of kidney function is common: approximately 20-30% of patients surviving severe AKI have persistent renal impairment, and AKI has been increasingly recognized as an important risk factor for subsequent development or progression of chronic kidney disease. Even patients whose creatinine returns to baseline have increased long-term mortality and cardiovascular risk compared to those who never experienced AKI. These observations underscore the importance of preventing AKI when possible and optimizing recovery when it occurs.

Follow-up care after an episode of AKI is essential to identify persistent kidney injury, manage complications, and address modifiable risk factors for progressive CKD. Serum creatinine should be measured approximately 3 months after the AKI episode to assess for recovery; the development of CKD is defined by persistent kidney function abnormalities or structural damage beyond this timeframe. Patients who do not recover to baseline kidney function, or who experienced severe AKI requiring dialysis, should be referred to nephrology for ongoing management and consideration of interventions to slow CKD progression. All patients surviving AKI should have careful medication management including reassessment of RAAS blockade indication and dosing, avoidance of nephrotoxins, and renal dose adjustment of chronic medications. Blood pressure control and proteinuria reduction with ACE inhibitors or ARBs, when appropriate, provide renoprotection in patients with established CKD following AKI. Given the increased cardiovascular risk following AKI, aggressive management of cardiovascular risk factors including hypertension, diabetes, dyslipidemia, and smoking cessation is warranted. Patient education about the episode of AKI, increased risk for future AKI, medications to avoid, and importance of hydration during illness empowers patients to participate in their ongoing care and prevention.

<image>Panel A: AKI prevention strategies organized by intervention type (volume optimization, nephrotoxin avoidance, contrast protocols, hemodynamic support) with specific actions for each. Panel B: High-risk patient identification checklist showing CKD, diabetes, heart failure, sepsis, and major surgery with recommended monitoring and prevention measures. Panel C: AKI outcomes diagram showing short-term (in-hospital mortality by severity) and long-term (CKD progression, cardiovascular risk) prognosis with percentages. Panel D: Post-AKI follow-up timeline showing recommended evaluations at discharge, 1 month, and 3 months including creatinine monitoring, medication review, nephrology referral criteria, and cardiovascular risk management.</image>

Summary

• AKI is defined by KDIGO criteria: creatinine rise of 0.3 mg/dL or more in 48 hours, creatinine increase to 1.5 times or more baseline in 7 days, or urine output less than 0.5 mL/kg/hour for 6 hours
• Classification by location (prerenal, intrinsic, postrenal) guides diagnostic workup and management approach
• Prerenal AKI shows FENa less than 1%, BUN:Cr ratio greater than 20:1, concentrated urine, and bland sediment
• Intrinsic causes include ATN (muddy brown casts), AIN (WBC casts, eosinophiluria), and glomerulonephritis (RBC casts)
• Postrenal AKI requires imaging to identify obstruction and prompt relief through catheterization or urology intervention
• Management principles include treating the underlying cause, optimizing volume status, and stopping nephrotoxins
• Major complications include hyperkalemia, metabolic acidosis, volume overload, and uremia, each requiring specific management
• RRT indications follow the AEIOU mnemonic: Acidosis, Electrolytes, Intoxication, Overload, Uremia
• Prevention focuses on maintaining euvolemia, avoiding nephrotoxins, and using contrast protocols in high-risk patients
• AKI increases long-term risk for CKD and cardiovascular disease, making follow-up care essential

Key Terms

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