Acute Kidney Injury

Etiology

The driving force for glomerular filtration is the pressure difference between the glomerulus and the Bowman space. This pressure gradient is influenced by renal blood flow and is directly governed by the combined resistances of the afferent and efferent vascular pathways. In most causes of AKI, reduced renal blood flow is a common pathologic pathway leading to a decline in GFR. The pathophysiology of AKI has traditionally been divided into 3 categories: prerenal, intrinsic renal (ie, intrarenal), and postrenal. Each of these categories has many different associated causes, and some causative factors of AKI have overlapping mechanisms of injury.[8][9]

The prerenal form of AKI is due to any cause of reduced blood flow to the kidney. This may be part of systemic hypoperfusion resulting from hypovolemia or due to selective hypoperfusion of the kidneys, such as resulting from renal artery stenosis or aortic dissection. However, tubular and glomerular function tends to be initially normal. A few examples of prerenal AKI mechanisms are listed below:

• Hypovolemia: hemorrhage, severe burns, gastrointestinal fluid losses such as diarrhea, vomiting, and high ostomy output.
• Hypotension from decreased cardiac output: cardiogenic shock, massive pulmonary embolism, acute coronary syndrome.
• Hypotension from systemic vasodilation: septic shock, anaphylaxis, anesthesia administration.
• Renal vasoconstriction: nonsteroidal anti-inflammatory drugs (NSAIDs), iodinated contrast, amphotericin B, calcineurin inhibitors, hepatorenal syndrome.
• Glomerular efferent arteriolar vasodilation (causing intraglomerular hypotension): ACE inhibitors, angiotensin receptor blockers.

Intrinsic renal causes include conditions affecting the glomerulus or tubules, such as acute tubular necrosis and acute interstitial nephritis. This underlying glomerular or tubular injury is associated with the release of vasoconstrictors from the renal efferent pathways. Prolonged renal ischemia, sepsis, and nephrotoxins are the most common causes. Prerenal injury can convert into a renal injury if the offending factor's exposure is prolonged enough to cause cellular damage. A few examples of this mechanism are listed below:

• Acute tubular necrosis (ATN): ischemia from prolonged prerenal injury; drugs such as aminoglycosides, vancomycin, amphotericin B, and pentamidine; iodinated contrast; rhabdomyolysis; intravascular hemolysis
• Acute interstitial nephritis (AIN): Drugs such as beta-lactam antibiotics, penicillins, NSAIDs, proton pump inhibitors (PPIs), and 5-ASA; infection; autoimmune conditions (systemic lupus erythematosus [SLE], immunoglobulin [Ig] G-related disease); and hereditary AIN.
• Glomerulonephritis: anti-glomerular basement membrane disease, immune complex-mediated diseases (such as SLE, post-infectious glomerulonephritis, cryoglobulinemia, IgA nephropathy, IgA vasculitis).
• Intratubular obstruction: monoclonal gammopathy (such as in multiple myeloma), tumor lysis syndrome, hemolytic anemia, and toxins such as ethylene glycol. 

Postrenal etiology of AKI includes obstructive causes that lead to congestion and urinary backflow in the filtration system, shifting the filtration driving forces. Notably, a unilateral obstruction may not always present with AKI, especially if the obstruction is gradual, as the contralateral kidney may compensate for the affected kidney. Pathological disturbances can occur within 2 hours of obstruction, beginning with decreased glomerular filtration due to increased pressure in the upper urinary tract. This results in decreased renal perfusion, inflammation, tubular atrophy, and interstitial fibrosis.

Eventually, bladder atony, periglomerular fibrosis, chronic interstitial nephritis, and secondary focal segmental glomerulosclerosis can develop. Weeks or months of obstruction can lead to ESRD. Once obstruction is released, post-obstructive diuresis occurs in up to 50% of patients and should be monitored for severe complications of hypovolemia and electrolyte abnormalities. The most common etiology of postrenal AKI is bladder outlet obstruction, which is often due to prostatic hypertrophy in older men, pelvic masses in older women, and nephrolithiasis in younger patients.[10]

• Renal/ureteral calculi can present in the renal calyces, renal pelvis, bladder, or urethra. Size and location are the determining factors of AKI, and this is a significant etiology in those with a solitary kidney. Struvite and cystine stones grow especially rapidly and commonly cause obstruction.
• Tumors, blood clots, and neurogenic bladder cause mechanical ureteral outlet obstruction. Blood clots can result from bladder or urinary tract malignancy.
• Prostate enlargement is the most common cause of urethral obstruction in older men.
• The obstruction can also be caused by retroperitoneal fibrosis, pregnancy, fecal impaction, pelvic organ prolapse, pelvic masses/malignancy, or phimosis. 

Perioperative Acute Kidney Injury 

Perioperative acute kidney injury deserves special consideration as it is a common condition associated with significant morbidity. Perioperative AKI is an abrupt decline in renal function within hours to days of surgery.[11] Populations with increased AKI risk include patients undergoing gastric bypass surgery, patients getting liver transplant surgery, individuals with preexisting CKD, advanced age, Black race, preexisting hypertension, active congestive heart failure, pulmonary disease, insulin-dependent diabetes, peripheral vascular disease, presence of ascites, and high body mass index.[12][13]

One study's results showed that 6.8% of patients sustained perioperative AKI, causing a 13.3% in-hospital mortality rate as opposed to 0.9% without perioperative AKI.[14] Another meta-analysis found the incidence of perioperative AKI in cardiac surgery patients to be between 25% and 30%.[15][16] In addition to the etiologies listed above (in the prerenal, intrinsic renal, and postrenal categories), systemic inflammation and cytokine production caused by trauma and surgical stress induce tubular injury and activate inflammatory cellular pathways.[17]

Epidemiology

AKI is commonly seen in hospitalized individuals. While historical reports estimated the incidence of AKI in approximately 1% of hospital admissions and 2% to 5% of hospitalizations, more recent data from 2021 to 2025 indicate that AKI now occurs in roughly 20% to 34% of hospitalized adults.[18][19] The incidence is significantly higher in critical care settings, where 40% to 77% of patients in the intensive care unit develop AKI depending on the clinical context, with particularly high rates observed during the COVID-19 pandemic.[19][20][21]

Pediatric populations also face a substantial burden, with a global meta-analysis reporting an AKI incidence of 26% among hospitalized children.[22] Sepsis remains a major driver, with sepsis-associated AKI incidence reported as high as 48.1% in certain regional cohorts.[23] AKI thus remains an important contributor to more extended hospital stays and patient morbidity.[24][25][26]

Pathophysiology

The pathogenesis of AKI is etiology-driven. The common endpoint in acute tubular necrosis is a cellular insult secondary to ischemia or direct toxins, resulting in brush border effacement, cell death, and decreased tubular cell function. One intrarenal cause is intratubular obstruction—such as by pigments (eg, myoglobin), crystals (eg, uric acid in tumor lysis syndrome), or immunoglobulin light chains, as seen in monoclonal gammopathy—which can also lead to the same result. Other intrarenal mechanisms of injury include glomerulonephritis and acute interstitial nephritis, which can result from immune-mediated vascular injury, inflammatory responses, and immune complex deposition, leading to glomerular and tubular damage. Postrenal pathophysiology is usually related to urinary reflux, causing decreased renal perfusion, tubular atrophy, and interstitial inflammation. 

Histopathology

Histopathology can reliably differentiate the intrinsic renal pattern of AKI from other causes; however, it may not reliably identify a specific cause in every case. Renal biopsy is an invasive procedure and is usually pursued only when a significant impact on management is expected, such as in suspected glomerulonephritis or when multiple etiologies are possible. Immunofluorescence patterns, electron microscopy, and staining for fibrosis and inflammatory cells can help differentiate various causes in such cases.

History and Physical

The history and physical exam should focus on determining the etiology of AKI and the progression timeline. If the history points towards hypovolemia or hypotension, then the treatment is guided towards volume repletion. Clinicians should look for inciting events such as diarrhea, nausea, vomiting, which may have caused volume loss, or any over-the-counter drugs such as NSAIDs.

Differentiating between AKI and CKD is essential, as CKD itself is not an uncommon risk factor for AKI. A history suggestive of CKD can include symptoms such as chronic fatigue, anorexia, nocturia, disturbed sleep-wake cycle, polyuria, and pruritus. Moreover, a careful review of past medical history may reveal comorbid conditions that can help narrow down the etiology of AKI, such as cirrhosis, congestive heart failure, or a history of blood clots requiring anticoagulation. History and physical examination are essential in AKI because labs often cannot provide a clear answer regarding its etiology.

The most common causes of AKI in hospitalized patients are as follows:

• ATN, 45%
• Prerenal disease, 21%
• AKI superimposed on CKD, 13%
• Urinary tract obstruction, 10% 
• Glomerulonephritis or vasculitis, 4%
• AIN, 2%
• Atheroemboli, 1% [7]

A history of urine output may give clues as to the cause of AKI. The following are some associations:

• Oliguria favors AKI.
• Sudden anuria suggests acute urinary tract obstruction, acute glomerulonephritis, or vascular blockage.
• Polyuria suggests either a concentrating tubular defect, such as acute interstitial nephritis, or postobstructive nephropathy.

A detailed physical exam can provide extremely valuable information in establishing the etiology of AKI. A crucial part of the physical exam should be orthostatic vital signs, which may signify hypovolemia. Several organ systems can provide clues regarding the cause of AKI. Some of them are:

• Skin: Livedo reticularis, digital ischemia, butterfly rash, and purpuras to suggest vasculitis. A maculopapular rash may indicate drug-induced AIN. Needle marks may suggest intravenous drug use, which can cause endocarditis. Livedo reticularis and skin infarcts are also seen with cholesterol emboli disease. Decreased skin turgor suggests hypovolemia.
• Eyes and ears: Jaundice is present in liver disease, band keratopathy is present in multiple myeloma, diabetes mellitus can show microscopic retinopathy, and blood vessel narrowing is associated with hypertension. Keratitis, iritis, and uveitis may be present in autoimmune vasculitis. Hearing loss is associated with Alport disease. 
• Cardiovascular system: Pulse rate, blood pressure, and jugular venous pulse can indicate volume status. An irregular rhythm may indicate electrolyte-imbalance-related arrhythmias. Pericardial friction rub may be heard in uremic pericarditis, and a heart murmur is often heard in the case of endocarditis. Embolic disease can present as cyanotic extremities.

Evaluation

Evaluation of AKI should include a thorough search for all possible etiologies of AKI, including prerenal, intrarenal, and postrenal disease. Noting the time of onset of AKI can be useful when dealing with hospitalized patients. For example, if a sudden rise in creatinine is noted, an inciting factor usually occurs within the 24 to 48 hours preceding this rise. It is imperative to review any radiologic studies involving iodinated contrast agents, a common cause of AKI. Reviewing the medications the patient is receiving and determining if the doses need to be modified is important. ACE inhibitors and ARBs are often the co-contributors to AKI. 

All patients presenting with AKI warrant a comprehensive metabolic panel. Urine electrolytes can also help suggest an etiology of the AKI. Urine studies should include testing for electrolytes, protein, osmolality, and albumin-to-creatinine ratio. Older individuals may warrant serum and urine protein electrophoresis (SPEP and UPEP) to rule out monoclonal gammopathy and multiple myeloma.

Renal ultrasound can be helpful if obstructive causes are suspected. CT scans are another important radiographic modality and can be used to look for nephrolithiasis or urolithiasis. Urine microscopy can also provide important clues about the etiology, such as muddy brown casts seen in ATN or white blood cell casts sometimes seen in AIN. Sterile pyuria is the most specific sign of acute interstitial nephritis.[27][28]

Although creatinine is the most commonly used serum chemistry to evaluate for AKI, there is evidence that other biomarkers may be more sensitive and may be elevated earlier in the course of AKI compared to creatinine. Some of these include neutrophil gelatinase–associated lipocalin (NGAL), which can be measured in plasma and urine; kidney injury marker-1 (KIM-1); retinol-binding protein; α- and β-microglobulin; proenkephalin; and urine uromodulin. The use of these biomarkers is not widely available and has not yet been validated in wide-scale studies.[29][30][31]

There is a trend toward using cystatin C to measure GFR, as cystatin C is an earlier marker and is becoming more widely available. The Chronic Kidney Disease Epidemiology Collaboration has even updated its equation to incorporate cystatin C as an alternative to creatinine.[32][33] CKD-EPI using cystatin C. Many groups suggest using both creatinine and cystatin as a way of obtaining the most accurate GFR.

A kidney biopsy is an excellent but infrequently utilized tool, and is usually indicated in patients with rapidly declining renal function without apparent cause or when multiple etiologies of AKI are possible. This is a test with some associated risks, such as bleeding, and should be used cautiously if a solitary kidney or coagulopathy is present. There are markers of tubular function that can be calculated to help distinguish between prerenal, intrarenal, and postrenal causes, such as the fractional excretion of sodium and urea and urine osmolality; however, these parameters are affected by many drugs commonly used in clinical practice, such as diuretics, and are not always diagnostic. No single marker can be reliably used in isolation to distinguish among the causes of AKI, and clinical presentation must be considered.

Treatment / Management

Many cases overlap between prerenal and ATN types of AKI.[34][35] In patients with suspected hypovolemia and no contraindication to volume expansion, a carefully monitored fluid challenge can help determine whether reduced kidney perfusion is contributing to AKI. During the fluid challenge, urine output, serum creatinine, and the patient's volume status should be closely monitored.(B2)

Improvement in renal function after fluid administration supports a prerenal (volume-responsive) component, although many patients have mixed prerenal and intrinsic kidney injury. Acute tubular necrosis and other intrarenal causes are often slow to recover, taking weeks to months for complete restoration of renal function. Diuretics may be required during the oliguric phase of ATN if significant volume overload develops. Avoiding further kidney insults, such as nephrotoxic drugs, is important. In addition, many medications must be renally adjusted once a patient develops AKI. Dietary ingestion of potassium and phosphorus should also be monitored.

If hyperkalemia develops, it needs to be managed expeditiously. Approaches to lower potassium in the body include:

• Dietary restriction
• Insulin, intravenous dextrose, and beta-agonists
• Potassium-binding resins
• Calcium gluconate to stabilize the cardiac membrane if EKG changes are present
• Dialysis for nonresponsive hyperkalemia

Some AKI patients tend to develop volume overload, which should be corrected as early as possible to avoid pulmonary and cardiac complications. A euvolemic state can be achieved with diuretics, which are a cornerstone in managing such patients. Usually, high doses of intravenous loop diuretics are needed to correct volume overload in AKI patients; however, they play no role in converting oliguric AKI to nonoliguric AKI.

In some cases, short-term renal replacement therapy is needed for AKI until the kidney function recovers. Some indications for renal replacement therapy are severe and nonresponsive hyperkalemia, uremic pericarditis, and pulmonary edema. This is especially seen in the oliguric phase of acute tubular necrosis, when the patient is prone to develop multiple electrolyte and acid-base abnormalities, as well as fluid overload.[36] 

Dialysis in this setting is usually performed via a temporary venous catheter as needed. Continuous renal replacement therapy (RRT) can also be utilized in patients who cannot tolerate intermittent hemodialysis due to hemodynamic instablity; it is a much slower, continuous type of dialysis. Correction of some of the metabolic abnormalities, along with dialysis, may be required.

Metabolic acidosis is one such instance in which systemic administration of bicarbonate is often required to maintain an appropriate blood pH. The requirement for renal replacement therapy should be reevaluated daily. Renal replacement therapy is usually required for short periods, ranging from a few days to a few weeks; however, in some cases, recovery can take months and may require intermittent RRT support.

Other treatments are directed at the etiology of the AKI. Examples include administering vasoactive medications and colloids for the treatment of hepatorenal syndrome, cautious diuresis in cardiorenal syndrome, immunosuppressive medication for various glomerulonephritides or vasculitides, or steroids for AIN. Postrenal obstruction may require operative relief in certain situations. For example, benign prostatic hypertrophy may require surgical intervention, and obstructive calculi may require stenting and lithotripsy. 

Differential Diagnosis

Differential diagnoses to be considered in AKI include renal calculi, acute or chronic kidney disease, hypovolemia, gastrointestinal bleeding, decreased cardiac output, urinary tract infection, and urinary obstruction. Rarely, ingesting excessive protein or dietary supplements can cause elevated creatinine levels unrelated to kidney disease.[37]

Prognosis

Most prerenal AKI cases recover completely with correction of the underlying insult if treated early; however, the persistence of the underlying insult may lead to ATN, in which case the damage may not be completely reversible. Another consideration is that although recovery from individual episodes may be complete or partial, repeated AKI can lead to a cumulative worsening of renal function. Therefore, it is essential to monitor these patients closely to normalize renal function or until a new baseline is established. The in-hospital mortality rate for AKI is 40% to 50%, and the mortality for those in the intensive care unit is more than 50%. Other prognostic factors include:

• Older age
• Duration of illness
• Fluid balance
• Diuretic use
• Oliguria
• Hypotension
• Inotropic support
• Multiorgan involvement
• Sepsis
• Number of transfusions

Over the long term, at least 12% to 15% of patients with AKI may require permanent dialysis. Mortality is increased in patients with high APACHE III scores, advanced age, and persistent creatinine elevation.[38][39] 

Complications

Several complications are associated with AKI and mortality. Some of these complications are directly associated with AKI and can easily be gauged (hyperkalemia, volume overload, metabolic acidosis, hyponatremia); however, the effect of other complications on AKI-related mortality, such as inflammation and infection, is more difficult to assess. The most common complications include metabolic derangements such as:

• Hyperkalemia can lead to arrhythmias and, if severe, is considered a medical emergency.
• Metabolic acidosis may necessitate systemic administration of bicarbonate or citrate buffers.
• Hyperphosphatemia can usually be prevented by decreasing dietary ingestion or using phosphate binders.
• Other adverse effects include pulmonary edema from volume overload and peripheral edema from impaired excretion of body water. This is especially common in the oliguric phase of ATN; it may necessitate diuretics or renal replacement therapy.

The other organ-related complications include: 

• Cardiovascular: Heart failure secondary to fluid overload is attributable to oliguric AKI. Arrhythmias can be secondary to acidosis and electrolyte abnormalities. Cardiac arrest can result from metabolic derangements. Myocardial infarction and pericarditis are also rare complications.
• Gastrointestinal: Nausea, vomiting, gastrointestinal bleeding, and anorexia can be associated with AKI. Amylase may be elevated in AKI, so serum lipase should be measured to diagnose pancreatitis if clinical suspicion is present. 
• Neurologic: Central nervous system-related signs of uremia include lethargy, somnolence, disturbed sleep-wake cycle, and cognitive impairment.