Acute Renal Tubular Necrosis

Etiology

Acute tubular necrosis is categorized into ischemic, nephrotoxic, or mixed (elements of both) causes. Ischemic causes are the most common; results from one study of patients in the intensive care unit found that 51% had ischemic ATN, 38% had mixed, and 11% had nephrotoxic causes of ATN.[3] Ischemic reperfusion injury is another subcategory categorized under ischemic-induced acute tubular necrosis.[4]

Ischemic-Induced Acute Tubular Necrosis

Prerenal azotemia and ischemic acute tubular necrosis share a similar spectrum of causes. Any factor that leads to prerenal azotemia can also lead to ischemic acute tubular necrosis if the insult is severe or prolonged. Some common causes include hypovolemic states: diarrhea, vomiting, bleeding, dehydration, burns, renal losses via diuretics or osmotic diuresis, and third fluid sequestration, eg, sepsis. Edematous states, such as heart failure and cirrhosis, cause reduced kidney perfusion. Coagulopathy, eg, disseminated intravascular coagulation, can cause acute tubular necrosis.[5]

Sepsis or anaphylaxis leads to systemic vasodilation. Sepsis also plays a role in causing acute tubular necrosis because of systemic hypotension and renal hypoperfusion. Other incompletely understood mechanisms include endotoxemia, which can lead to AKI through renal vasoconstriction and the release of inflammatory cytokines. This results in the enhanced secretion of reactive oxygen species and subsequent renal injury.[6]

Ischemic reperfusion injury (IRI) is thought to cause renal damage primarily through oxidative stress. Reactive oxygen species production by the mitochondria is a crucial step in contributing to IRI and may be a factor in the reversibility of renal injury. Inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1, IL-6) and chemokines produced by kidney epithelial and parenchymal cells also contribute to IRI.[4][7] 

Nephrotoxic-Induced Acute Tubular Necrosis

The kidney clears and metabolizes many drugs. Some of these drugs behave as exogenous toxins and can cause direct renal tubular injury or crystal-induced acute kidney injury, leading to acute tubular necrosis. Drugs, such as vancomycin, aminoglycosides, amphotericin B, radiocontrast media, sulfa drugs, acyclovir, cidofovir, cisplatin, calcineurin inhibitors (tacrolimus, cyclosporine), mammalian target of rapamycin inhibitors (everolimus, temsirolimus), and ifosfamide, are some of the drugs that can cause acute tubular necrosis.[8][9][10] Rarely, intravenous immunoglobulin (IVIg) can cause damage to the tubular epithelium caused by osmotic injury secondary to stabilizers used in the IVIg preparation (sucrose, maltose, glucose).[11]

In ongoing malignancy treatment, crystal-induced nephropathy, such as uric acid and calcium phosphate crystals, can cause direct nephrotoxicity due to high cell turnover. Light chain accumulation in multiple myeloma directly harms the renal proximal and distal tubules. Please see StatPearls' companion reference, "Calcium Deposition and Other Renal Crystal Diseases."[12]

Mixed Forms of Acute Tubular Necrosis

Heme pigment-containing proteins, such as hemoglobin and myoglobin, can cause both ischemic and nephrotoxic ATN. Often, this is considered in the setting of rhabdomyolysis; please see StatPearls' companion reference, "Rhabdomyolysis," but other mechanisms also exist. Free heme, released by myoglobin and hemoglobin, causes vasoconstriction by depleting nitrous oxide, imposing oxidative stress (further causing vasoconstriction via isoprostanes, endothelin-1, and thromboxanes), and potentiating the vasoconstrictive effects of angiotensin II.[13] In addition to direct nephrotoxic effects, heme pigments also cause renal ischemia, reducing adenosine triphosphate, nicotinamide adenine dinucleotide, and glutathione levels.[13][14] 

The proximal tubule is particularly susceptible to heme pigment–induced injury, as these pigments are endocytosed by megalin and cubilin receptors on the apical membrane, leading to inflammation, mitochondrial dysfunction, and ultimately, apoptosis.[15] Results from one large review of biopsies showed that 92% involved the proximal tubule.[16] The thick ascending loop of Henle is also prone to cast formation due to the large amounts of uromodulin (Tamm-Horsfall protein) produced. These can combine with heme proteins to form obstructive casts, potentiated by proximal cellular debris from cell death.[13][17]

Another example of mixed ATN is the use of the drug methamphetamine. Methamphetamine causes decreased blood flow to the kidneys through hypovolemia, hyperthermia, vasoconstriction, and rhabdomyolysis. Myoglobinuria is thought to be the predominant mechanism of ATN.[18][19] However, vasculitis, prerenal azotemia, hypovolemia, and hypertensive nephropathy also contribute to nephrotoxicity. Methamphetamine use is also associated with the rare condition of acute cortical necrosis, which is a condition involving patchy or diffuse ischemia to the renal cortex. This disorder can also occur in the setting of sepsis, hemodynamic instability, and obstetric complications. Often, it is caused by severe and sustained constriction of the small renal blood vessels.[18][20]

Epidemiology

The landmark PICARD (Program to Improve Care In Acute Renal Disease) study was conducted in 5 United States medical institutions and included a cohort of 618 patients in the intensive care unit with acute kidney injury (AKI). The reported etiology of 50% of those patients with acute renal failure was found to be acute tubular necrosis from ischemic causes, and the other 25% were nephrotoxic acute tubular necrosis leading to renal failure. Results from a Spanish multicenter study in 13 tertiary care hospitals in Madrid showed that the most frequent cause of AKI was acute tubular necrosis in 45% of the patients who were hospitalized.[21]

There is difficulty in estimating the number of patients with ATN who develop end-stage renal disease (ESRD) or chronic kidney disease (CKD) because the vast majority of ATN is diagnosed clinically, and the only cases that are biopsied are the indeterminate and most serious cases, leading to selection bias. The United States Renal Data System compiled from 2001 to 2010 showed an annual incidence of ESRD attributed to ATN of 2% to 3%. Progression to ESRD was associated with older age, lower glomerular filtration rates, and higher levels of proteinuria.[22][23] One review of patients with biopsy-proven ATN showed that ATN significantly increased the risk of CKD. Finders were that at a little over 6 years, about 22% of patients had ESRD compared to about 3% of control patients.[23]

Pathophysiology

A decreased glomerular filtration rate (GFR) is associated with acute tubular necrosis, leading to 3 possible mechanisms of injury to the renal tubular epithelial cells:

1. Afferent arteriolar vasoconstriction in response to tubuloglomerular feedback
2. Backleak of glomerular filtrate
3. Tubular obstruction

Clinical Phases

There is no definitive consensus on the stages of ATN, but it is often classified into 4 phases: early injury, later injury, recovery, and long-term outcomes.

Early injury

The initiation phase is characterized by an acute decrease in GFR and a sudden increase in serum creatinine and blood urea nitrogen (BUN) concentrations. However, the rise in creatinine/BUN often lags behind the actual tubular injury and is considered relatively insensitive.[16] As tubular cells are damaged, they release damage-associated proteins (DAMPs), which are recognized by toll-like receptors and membrane-bound pattern recognition receptors on innate immune cells. This initiates a cycle of necroinflammation described below.[24][25]

Later injury

The extension phase consists of 2 major events:

1. Ongoing hypoxia following the ischemic event
2. An inflammatory response

These events are more pronounced in the corticomedullary junction of the kidney. In this phase, damage to the renal vascular endothelial cell is responsible for the ischemia of the renal tubular epithelial cell. The cells in the outer medulla continue to undergo injury and death with the combination of both necrosis and apoptosis. Apoptosis is the default mechanism to remove senescent cells and does not involve an inflammatory cascade. On the other hand, ferroptosis and necroptosis are the likely mechanisms underlying ATN, creating the characteristic "muddy brown casts" seen on urine microscopy.[26] 

Macrophages absorb apoptotic cells, and the plasma membranes of apoptotic cells remain largely intact. Apoptotic cells also do not release DAMPs. On the other hand, ferroptosis is thought to be an important mediator of AKI. This iron-dependent process involves a glutathione metabolizing selenoenzymes which oxidizes lipids to inactivated alcohols.[26][27] Other factors critical to this process are regulation of the intracellular iron pool, control of H2O2_, and lipid synthesis enzymes. This process is thought to be largely mediated by neutrophils and macrophages.[26][28][29] 

Necroinflammation is another process by which ATN can occur. In necroinflammation, necrotic cells release DAMPs and expose cell antigens to cytotoxic T-cells, mediating an adaptive immune response and inflammation. Therefore, the necrotic death of tubular cells reduces kidney function, and the inflammation results in further damage. Necroptosis may cause fibroblast proliferation and irreversible fibrosis.[26] Most models favor ferroptosis as the most dominant process in ATN, which may partially explain the reversibility or improvement of most ATN cases.[26][29][30] Klotho is a transmembrane protein that functions as an obligate co-receptor for fibroblast growth factor 23; this may be renoprotective, and lower expression is associated with a higher degree of ATN.[31] Klotho is thought to reduce oxidative stress and is found to be low in both ischemic and nephrotoxic forms of ATN.[10]

Recovery

The recovery phase is established by cellular repair, migration, and proliferation to maintain cellular and tubule integrity. The cellular function improves slowly as the cells repair and reorganize. Although the toll-like rececptors and macrophages mediate initial necroinflammation, once the inflammatory phase subsides a subset of macrophages, toll-like receptors, and remaining tubular epithelial cells secrete cytokines which help modulate epithelial cell repair.[24][25] The blood flow returns to the normal range, and the cells establish intracellular homeostasis. As noted above, since ferroptosis is thought to be the dominant process and does not involve fibroblasts, regeneration of tubular cells is possible. 

Long term

ATN is associated with a significantly increased risk of CKD, ESRD, and mortality in both hospitalized and nonhospitalized individuals of all ages.[16] Noninflammatory macrophages and bone marrow–derived fibroblasts can release transforming growth factor β and collagen, contributing to renal fibrosis. The secretion of TGF-β and other fibrotic mediators is also associated with the compensatory hypertrophy of the remaining tubular cells, and all these maladaptive responses can contribute to the development of CKD.[24][32]

Histopathology

Acute tubular necrosis is usually diagnosed on a clinical basis. A biopsy is only performed when an entity other than acute tubular necrosis is suspected of causing AKI. Patients with crescents or decreased arteriolar lumen diameters indicate a poor prognosis. Tubular atrophy, interstitial fibrosis, and endocapillary lesions are poor prognostic indicators.[2][23]

A large review of over 2000 renal biopsy samples of patients with acute tubular injury (both ischemic and nephrotoxic) revealed the following:

• Proximal tubules were affected in over 90% of the time.
• Tubular cell sloughing was the second most common finding.
• The next most common findings, in descending order, are tubular epithelial flattening, tubular dilatation, tubular cell necrosis, regenerative changes, tubular cell vacuolization, and loss of the brush border.
• About 42% of studies reported structural changes seen on electron microscopy, including changes in tubular cytoplasm, nucleus, mitochondria, endoplasmic reticulum, and other organelles.
• None of the studies found positive immunofluorescence studies.
• The authors note that there may be selection bias, as when the cause of ATN is very obvious, such as sepsis or drug exposure, a renal biopsy is often not performed, so this review likely includes the more complex cases.[16]

Ischemic Acute Tubular Necrosis

Ischemic ATN is characterized by autophagy.[16] 

Nephrotoxic Acute Tubular Necrosis

Nephrotoxic ATN is usually characterized by necrosis, endoplasmic reticulum dilatation, and mitochondrial swelling.[16] 

Specific nephrotoxic agents that lead to acute tubular necrosis can manifest as different features of histological damage, including the following:

• Ethylene glycol: Calcium oxalate crystals in the urine and renal parenchyma [33]
• Hemoglobin/myoglobin: Deeply pigmented, red-brown casts in the distal and collecting tubules
• Carbon tetrachloride: Neutral lipid accumulation in injured cells followed by necrosis
• Indinavir: Clear intraluminal crystals with mononuclear reaction
• Lead: Intranuclear, dark inclusions, and necrosis
• Mercury: Large acidophilic inclusions
• Tenofovir: Proximal tubular eosinophilic inclusions that represent giant mitochondria
• Vancomycin: Acute interstitial nephritis with eosinophilic and lymphocytic infiltrate and acute tubular necrosis [34]

History and Physical

The history and physical examination offer many clues in identifying an individual with prerenal disease and acute tubular necrosis caused by decreased renal perfusion. Events such as diarrhea, vomiting, sepsis, dehydration, or bleeding that leads to tissue hypoxia can indicate a risk of acute tubular necrosis. Hospitalized individuals with events such as hypotension, sepsis, intraoperative events, use of nephrotoxic agents such as radiocontrast media or nephrotoxic antibiotics, help in identifying the clinical picture causing AKI and acute tubular necrosis. 

Physical findings such as tachycardia, dry mucous membrane, decreased skin turgor, and cool extremities can be present in patients with volume depletion and hypotension. Fever and hypotension are common manifestations of sepsis. Muscle tenderness is present in the setting of rhabdomyolysis. Intraabdominal hypertension that causes abdominal distension due to abdominal compartment syndrome also impedes renal perfusion and raises the concern for acute tubular necrosis.

Evaluation

The workup usually differentiates acute tubular necrosis from prerenal AKI and other causes of AKI, such as acute interstitial nephritis. Common tests that help differentiate include urinalysis, response to fluid repletion, urinary sodium concentration, fractional excretion of sodium, and fractional excretion of urea in patients who receive diuretics and novel biomarkers.

Urinalysis 

The urinalysis microscopy is normal in prerenal disease or may contain hyaline casts. On the other hand, the urinalysis of acute tubular necrosis often shows muddy brown casts or renal tubular epithelial cells secondary to the sloughing of tubular cells into the lumen due to ischemia or toxic injury.

Fractional excretion of sodium

This is a good test to differentiate between acute tubular necrosis and prerenal disease, with a value of less than 1% favoring prerenal disease and more than 2% acute tubular necrosis. However, these values are not always accurate, as in chronic prerenal states such as congestive heart failure and cirrhosis, in which there is an overlap between both (ATN and prerenal AKI), having a value of less than 1%.[35]

Urine sodium concentration

This test determines that the kidney is sodium avid in hypovolemic states (prerenal) where kidneys try to conserve sodium or lose sodium due to tubular injury with values more than 40 to 50 mEq/L indicating acute tubular necrosis and less than 20 mEq/L suggestive of prerenal disease.[36]

Novel biomarkers

Numerous biomarkers have evolved to detect AKI/acute tubular necrosis earlier than serum creatinine. These biomarkers include serum cystatin C as an early and reliable marker of renal injury compared to a rise in serum creatinine, which is often witnessed 48 to 72 hours after the initial insult.[10][18] Other markers include urinary α-one microglobulin, β-2 microglobulin, hemoxygenase-1, osteopontin, and kidney injury molecule 1.[10][16] Urinary biomarker neutrophil gelatinase-associated lipocalin is reliably upregulated in renal ischemia after tubular injury and is one of the best-studied markers for kidney injury; it is considered sensitive and specific and begins to rise 2–6 hours after initial kidney injury, significantly earlier than creatinine.[37][38][39]

Treatment / Management

The mainstay of management is the prevention of acute tubular necrosis by identifying the patients undergoing high-risk procedures and having comorbidities such as diabetes mellitus, heart failure, advanced malignancy, atherosclerosis, and CKD that can potentiate the effects of acute tubular necrosis. The following are some of the high-risk procedures and conditions:

• Cardiogenic shock
• Hemorrhagic shock
• Pancreatitis
• Severe burns
• Sepsis
• Hypovolemia
• Major surgery (cardiac bypass, vascular surgery such as abdominal aortic aneurysm, peripheral limb surgery, hepatobiliary surgery, emergent surgical exploration)

Interventions to decrease the risk of acute tubular necrosis in the above conditions include prevention of hypovolemia or hypotension, including cessation of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in patients with low blood pressure, and optimization of volume status via intravenous fluids, such as crystalloids, to ensure adequate renal perfusion. Nephrotoxic medications that can lead to acute tubular necrosis should be avoided, including nonsteroidal anti-inflammatory drugs, antibiotics such as amphotericin B, aminoglycosides, vancomycin, piperacillin/tazobactam, and radiocontrast agents.

Diuretics are used only to manage the volume status but are not recommended for treating ATN in the Kidney Disease: Improving Global Outcomes 2012 guidelines. Other pharmacological agents, such as dopamine, fenoldopam, and atrial natriuretic peptides, do not provide any survival benefit in patients with acute tubular necrosis. Renal replacement therapy has the same indications and is used in volume overload refractory to diuretics, hyperkalemia, signs of uremia, and metabolic acidosis. In critically ill hemodynamically unstable patients, continuous renal replacement therapy is often used.[40]

Differential Diagnosis

The differential diagnosis for acute renal tubular necrosis includes the following:

• Acute interstitial nephritis
• Acute glomerulonephritis
• Azotemia
• Tubulointerstitial nephritis
• Chronic kidney disease
• Drug-induced nephrotoxicity

Pertinent Studies and Ongoing Trials

Much research focuses on the effects of ferrostatin-1 (Fer-1), an antioxidant that inhibits ferroptosis and shows the potential to protect against cell injury. Prior formulations had issues with solubility, but newer Fer-1 analogs have shown increased stability and solubility and demonstrated efficacy against multiorgan failure in animal models.[30][41] One of these analogs is UAMC-2418, which has been found to provide superior multi-organ protection compared to Fer-1.[30] Liproxstatin-1 is also an antioxidant and decreases ferroptosis by blocking phospholipid peroxidation. Phenoxazines and phenothiazines (both currently used for other indications) are thought to be potent inhibitors of ferroptosis.[30][42]

Iron chelators have also been studied but found less effective than the previously mentioned drugs.[30] Over 1000 ferroptosis regulators are being studied, and a full database can be accessed at http://www.zhounan.org/ferrdb/current/. Animal studies have shown that small molecules can target ferroptosis in animal models. One such molecule is Nec-1f, which targets receptor-interacting protein kinase 1 and ferroptosis in cell lines.[29]

Another animal study showed that hypoxia-inducible factor 1α helps upregulate glutathione peroxidase 4, which helps decrease the accumulation of lipid peroxides, thereby decreasing ferroptosis.[43] Much attention has been paid to using antioxidants since a large part of renal damage is attributed to damage from reactive oxygen species. One of these is oleanolic acid paired with liposomes for solubility. In vitro and in vivo studies demonstrate that the compound reduces inflammation and reactive oxygen species while exhibiting antioxidant and antiapoptotic properties.[4]

Prognosis

As noted above, the incidence of CKD and ESRD is difficult to estimate given that ATN is often clinically diagnosed rather than by biopsy, and renal biopsy is reserved for patients with more complicated or unclear cases. Traditionally, it was thought that ATN has a good prognosis and that most patients recover completely. However, other studies have shown that over half of the patients with biopsy-proven ATN do not recover to an estimated glomerular filtration rate greater than 60 mL/min/1.73m2. Results from another study of United States veterans found that 20% of patients with ATN developed stage 4 CKD within 6 years of follow-up.[44]

Complications

Complications related to acute tubular necrosis are the same as related to AKI, which include acid-base and electrolyte disturbances such as hypocalcemia, hyperkalemia related to metabolic acidosis, and hyperphosphatemia. Volume overload is related to anuria or oliguria. Uremic complications lead to pericarditis, bleeding diathesis, and altered mental status.