What drugs cause cortical necrosis? A look at pharmacological and illicit culprits

October 12, 2025 •

5 min read

Renal cortical necrosis is a rare but catastrophic form of acute kidney injury, accounting for less than 1% of all AKI cases. Among the documented causes, certain medications and illicit drugs have been definitively linked to this severe pathology, raising critical concerns regarding nephrotoxicity.

Quick Summary

This article details specific medications and illicit substances, like NSAIDs and cocaine, that can induce cortical necrosis through severe vasoconstriction and microvascular thrombosis.

Key Points

NSAID Dangers: Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause cortical necrosis by blocking protective prostaglandins, leading to unopposed renal vasoconstriction in at-risk individuals.
Cocaine's Vascular Assault: Illicit stimulants like cocaine trigger severe vasoconstriction, hypertension, and microvascular thrombosis that can induce irreversible renal cortical necrosis.
Cyclosporine's Nephrotoxicity: Immunosuppressants like cyclosporine can cause a thrombotic microangiopathy that leads to ischemic damage and cortical necrosis, a known risk with chronic use.
Irreversible Damage: Cortical necrosis is fundamentally different from reversible acute tubular necrosis (ATN); it is an irreversible ischemic event that often results in permanent kidney failure and dependence on dialysis.
High-Risk Patients: Individuals with pre-existing kidney disease, dehydration, heart failure, or those using multiple nephrotoxins are at a significantly higher risk for drug-induced cortical necrosis.
Vigilance is Key: Prevention involves carefully assessing patient risk factors, monitoring renal function when using nephrotoxic agents, and discontinuing the offending drug at the earliest sign of kidney injury.

Understanding the devastating impact of cortical necrosis

Renal cortical necrosis (RCN) is the irreversible, ischemic death of tissue within the outer layer of the kidney (the cortex), often leading to permanent kidney failure. Unlike more common forms of drug-induced kidney injury, such as acute tubular necrosis (ATN), which are often reversible, RCN is a much more severe and final outcome. While a variety of medical conditions can cause RCN, certain drugs and toxins are well-documented culprits, particularly when combined with pre-existing risk factors. The mechanism typically involves severe and sustained constriction of small renal blood vessels and microthrombosis, starving the cortical tissue of oxygen and nutrients.

The mechanism behind drug-induced cortical necrosis

The fundamental cause of RCN is severe and persistent ischemia to the renal cortex. This can be triggered by drugs in two primary ways:

Intense Renal Vasoconstriction: Some substances cause a massive, unopposed constriction of the tiny blood vessels in the kidney. When this constriction is sustained, it critically reduces blood flow to the cortex, causing widespread tissue death. This mechanism is amplified in patients who are already dehydrated or have compromised kidney perfusion.
Microvascular Thrombosis: Other drugs can trigger a pro-thrombotic state, leading to the formation of blood clots in the small vessels of the renal microvasculature. These clots block blood flow, causing multifocal areas of ischemic necrosis.

Key drug categories linked to cortical necrosis

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs are one of the most frequently implicated drug classes in various forms of drug-induced kidney injury. While most commonly causing less severe forms like interstitial nephritis or acute tubular necrosis, they can, in rare cases, trigger RCN.

Mechanism: NSAIDs work by inhibiting the cyclooxygenase (COX) enzyme, blocking the production of prostaglandins. In healthy individuals, this is usually not an issue. However, in patients with pre-existing conditions like heart failure, cirrhosis, or volume depletion, the kidneys rely on vasodilatory prostaglandins to maintain adequate blood flow. By blocking this protective mechanism, NSAIDs can cause intense, unopposed vasoconstriction, leading to medullary ischemia and potentially RCN. Case studies have documented NSAID-induced RCN, such as with Naproxen.

Illicit Stimulants (Cocaine and Methamphetamine)

Abuse of stimulants like cocaine and methamphetamine is a recognized cause of severe kidney damage, including RCN.

Mechanism: These drugs induce profound sympathetic nervous system activation, leading to intense and widespread vasoconstriction, including in the renal arteries. This can lead to malignant hypertension and thrombotic microangiopathy (TMA). Additionally, these drugs can cause rhabdomyolysis, where muscle tissue breaks down and releases myoglobin. The myoglobin is filtered by the kidneys, where it can be directly toxic to the renal tubules and contribute to ischemia. This combination of direct vascular injury, vasoconstriction, and myoglobin toxicity can culminate in RCN.

Calcineurin Inhibitors (e.g., Cyclosporine, Tacrolimus)

Immunosuppressants such as cyclosporine and tacrolimus are essential for preventing organ transplant rejection but are also notorious for their nephrotoxic effects.

Mechanism: Chronic use of these inhibitors can cause microvascular damage, leading to thrombotic microangiopathy and associated RCN. The mechanism involves vasoconstriction, endothelial damage, and an imbalance of vasoactive substances that favor vessel constriction. Early clinical trials with higher doses of cyclosporine showed a significant incidence of acute kidney injury, including rare cases of RCN, particularly when combined with renal ischemia.

Other implicated agents

Mitomycin-C: A chemotherapeutic agent known to cause thrombotic microangiopathy, which can progress to RCN.
Anticoagulants: While rare, conditions like warfarin-induced cutaneous necrosis involve microvascular thrombosis and illustrate a mechanism potentially relevant to renal injury. Heparin-induced thrombocytopenia can also cause a pro-thrombotic state.
Antifibrinolytic Agents: Case reports have implicated drugs like tranexamic acid in arterial thrombosis leading to RCN.
Radiocontrast Media: Can cause acute kidney injury, particularly in at-risk patients, through renal hypoperfusion and direct tubular toxicity.

Table: Cortical Necrosis vs. Acute Tubular Necrosis


Feature	Renal Cortical Necrosis (RCN)	Acute Tubular Necrosis (ATN)
Pathology	Irreversible ischemic necrosis of the renal cortex due to arterial and arteriolar blockage.	Reversible damage to the tubular epithelial cells, often caused by ischemia or toxins.
Reversibility	Irreversible. Often leads to permanent end-stage renal disease.	Often reversible, with kidney function potentially recovering after the insult is removed.
Drug-Related Cause	Triggered by severe, sustained vasoconstriction or microthrombosis (e.g., cocaine, high-dose NSAIDs).	Caused by direct tubular toxicity or less severe ischemia (e.g., aminoglycosides, contrast agents).
Clinical Outcome	Poor prognosis. High likelihood of needing long-term dialysis or kidney transplantation.	Variable outcome, but often results in recovery of renal function, especially with early intervention.
Underlying Mechanism	Severe and prolonged reduction of cortical blood flow due to vascular spasm or clots.	Cell death of tubular cells due to lack of oxygen or direct toxic effect of a substance.

Risk factors and prevention

Drug-induced RCN is rare but more likely to occur in individuals with specific pre-existing risk factors. These include:

Pre-existing chronic kidney disease or renal insufficiency
States of reduced kidney perfusion, such as dehydration, heart failure, or cirrhosis
Older age
Diabetes mellitus
Concurrent use of multiple nephrotoxic medications
High-risk medical settings, such as intensive care units

Prevention is paramount and focuses on identifying and managing these risk factors. Healthcare providers should carefully evaluate the patient's renal function before and during the use of potentially nephrotoxic drugs. Avoiding nephrotoxins in high-risk patients, ensuring proper hydration, and managing underlying conditions are all critical prophylactic measures.

Diagnosis and treatment

Diagnosis of RCN often requires a high degree of clinical suspicion, especially when a patient with pre-existing risk factors presents with abrupt and severe kidney failure, sometimes anuric.

Clinical Signs: Sudden onset of flank pain, decreased urine output (oliguria or anuria), fever, and dark urine (hematuria) may occur.
Laboratory Findings: Blood tests typically show elevated creatinine and blood urea nitrogen (BUN). Elevated serum lactate dehydrogenase (LDH) can also be a strong indicator of renal infarction.
Imaging: Contrast-enhanced CT scans can reveal the characteristic appearance of RCN, showing a lack of contrast enhancement in the renal cortex.
Renal Biopsy: This is the gold standard for definitive diagnosis, revealing the ischemic necrosis of cortical tissue.

Unfortunately, treatment for established RCN is largely supportive, as the damage is irreversible. The cornerstone of management is to immediately discontinue the offending drug. Supportive care includes managing fluid and electrolyte imbalances and, frequently, initiating renal replacement therapy (dialysis). Many patients will ultimately require long-term dialysis or a kidney transplant.

Conclusion

Drug-induced cortical necrosis, though rare, is a severe and often irreversible condition caused by a select group of medications and illicit substances. The pathophysiology centers on extreme vasoconstriction and microvascular thrombosis that cut off blood supply to the renal cortex. Key culprits include NSAIDs, illicit stimulants like cocaine, and immunosuppressants such as cyclosporine. Recognizing risk factors, including pre-existing kidney disease and dehydration, is crucial for prevention. Given the poor prognosis associated with established RCN, especially the frequent need for long-term dialysis, clinicians must exercise vigilance when prescribing and monitoring patients on potentially nephrotoxic agents. Early detection and withdrawal of the causative drug, combined with aggressive supportive care, are the only avenues for mitigating the devastating consequences of this condition. For more detailed information on drug-induced renal disorders, resources like the NCBI provide extensive reviews.

Frequently Asked Questions

Drug-induced cortical necrosis is the irreversible death of kidney cortical tissue due to severe, prolonged ischemia. In contrast, acute tubular necrosis (ATN) is often a reversible injury to the kidney's tubular cells, with the potential for renal function recovery after the drug is stopped.

No, while all NSAIDs carry a risk, especially in high-risk patients, the occurrence of cortical necrosis is very rare and often depends on patient-specific factors like pre-existing kidney disease or dehydration. The risk is not uniform across the class or all individuals.

Cocaine causes cortical necrosis primarily by triggering severe vasoconstriction and microvascular thrombosis in the kidneys. This intense and sustained reduction of blood flow leads to ischemic tissue death in the renal cortex. Associated effects like malignant hypertension and rhabdomyolysis further contribute to the kidney damage.

Immunosuppressants such as cyclosporine can induce nephrotoxicity through microvascular damage and thrombotic microangiopathy (TMA). This can block the small blood vessels in the kidneys, leading to ischemic injury and, in severe cases, cortical necrosis.

Individuals with pre-existing kidney disease, dehydration, heart failure, diabetes, or those concurrently taking multiple nephrotoxic medications are at the highest risk. These conditions make the kidneys more vulnerable to the vasoconstrictive effects of certain drugs.

Diagnosis is based on clinical presentation (e.g., sudden kidney failure, oliguria), laboratory findings (elevated creatinine, BUN, LDH), and imaging (e.g., CECT showing cortical hypoperfusion). A renal biopsy is the definitive diagnostic method.

Treatment for established cortical necrosis is primarily supportive, as the damage is irreversible. The main treatment involves stopping the offending drug and providing supportive care like dialysis. Many patients will face long-term renal replacement therapy or transplantation.