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Nephrotoxicity

Nephrotoxicity is defined as the rapid deterioration of kidney function due to the toxic effects of medications and chemicals, often manifesting as acute kidney injury (AKI) through various pathological forms such as tubular damage or glomerular dysfunction.^[1] This condition arises primarily from the kidneys' high blood filtration rate and metabolic activity, which expose renal tissues to concentrated toxins, making them particularly vulnerable to injury.^[2] Nephrotoxicity accounts for approximately 20% of hospital-acquired AKI cases and is more prevalent in elderly patients due to age-related declines in renal function and polypharmacy.^[3] The primary causes of nephrotoxicity are pharmaceutical agents, including antibiotics like aminoglycosides (e.g., gentamicin) and vancomycin, chemotherapeutic drugs such as cisplatin, nonsteroidal anti-inflammatory drugs (NSAIDs), and contrast media used in imaging procedures.^[4] Other contributors include environmental chemicals, heavy metals, and endogenous toxins exacerbated by conditions like dehydration or sepsis.^[1] Risk factors encompass pre-existing renal impairment, concurrent use of multiple nephrotoxic drugs, genetic predispositions, and comorbidities such as diabetes or heart failure, which collectively amplify susceptibility.^[3] Mechanistically, nephrotoxicity involves several pathways, including direct tubular cell toxicity leading to acute tubular necrosis (ATN), alterations in glomerular hemodynamics that reduce filtration, immune-mediated interstitial nephritis, and crystal-induced obstruction in the tubules.^[4] For instance, aminoglycosides accumulate in proximal tubules via endocytosis, causing oxidative stress and apoptosis, while NSAIDs inhibit prostaglandins, impairing renal blood flow.^[1] Inflammation and endothelial damage further contribute, often triggered by drug-protein adducts that provoke immune responses.^[5] Early detection relies on monitoring serum creatinine, blood urea nitrogen, and emerging biomarkers like kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), which signal damage before functional decline.^[1] Prevention strategies emphasize dose adjustments based on renal function, hydration protocols, avoidance of nephrotoxic combinations, and protective agents such as antioxidants for cisplatin-induced toxicity.^[4] Despite advances, nephrotoxicity remains a significant clinical challenge, contributing to prolonged hospital stays and increased mortality in affected patients.^[3]

Overview

Definition

Nephrotoxicity refers to functional or structural damage to the kidneys caused by exposure to toxic substances, resulting in impaired renal function.^[6] This damage arises from exogenous or endogenous toxicants that disrupt normal kidney physiology, often leading to a rapid deterioration in filtration and excretion capabilities.^[1] Common triggers include certain medications and environmental agents like heavy metals.^[7] The kidneys' susceptibility to such toxicity stems from their anatomical and physiological features. They receive 20-25% of the total cardiac output, approximately 1-1.1 liters per minute, which delivers a high volume of circulating toxins despite the organs comprising less than 1% of body mass.^[8] Furthermore, the extensive glomerular filtration surface enables a normal glomerular filtration rate of about 125 mL/min, concentrating potential nephrotoxins within tubular cells and amplifying exposure to these substances.^[9]^[10] Nephrotoxicity is classified by the duration and permanence of effects, distinguishing between acute and chronic forms as well as reversible and irreversible damage. Acute nephrotoxicity typically involves sudden onset injury that may resolve with prompt removal of the toxin, whereas chronic forms reflect prolonged exposure leading to persistent structural changes.^[6] Reversible damage allows functional recovery, but irreversible cases result in lasting impairment, often progressing to acute kidney injury (AKI) or chronic kidney disease (CKD).^[11]^[12]

Epidemiology

Nephrotoxicity, particularly in the form of drug-induced acute kidney injury (AKI), affects approximately 20% of both community- and hospital-acquired episodes of AKI globally.^[13] In hospitalized patients, drug-induced AKI accounts for 14-26% of all AKI cases, with prospective cohort studies highlighting its prevalence in up to 37.5% of cross-sectional assessments.^[11] For community-acquired AKI, drug-related causes comprise a similar proportion, around 20%, underscoring the widespread impact across care settings.^[13] Demographic patterns reveal heightened vulnerability among certain groups. Individuals over 65 years face a substantially elevated risk of drug-induced nephrotoxicity compared to younger populations, often exceeding 30% in vulnerable groups due to polypharmacy and comorbidities.^[14] This increased susceptibility is exacerbated by comorbidities such as diabetes and hypertension, which independently amplify AKI risk through underlying renal stress.^[13] In the United States, as of 2014, approximately 498,000 patients were discharged annually with an AKI diagnosis, with about 30% or roughly 150,000 cases stemming from nephrotoxic medications; recent trends indicate rising hospitalization rates.^[15]^[16]^[17] Recent trends indicate a rising incidence of nephrotoxicity, driven by factors like polypharmacy and expanded use of contrast agents in medical imaging, with AKI rates increasing during the COVID-19 pandemic (e.g., up to 26.8% of hospitalizations involving AKI in 2021 among Medicare beneficiaries).^[17] Polypharmacy, defined as concurrent use of five or more medications, is associated with an 18% pooled incidence of AKI and heightens risks in vulnerable populations.^[18] In developing regions, environmental toxins such as heavy metals and pesticides contribute notably to AKI outbreaks amid limited regulatory oversight.^[19] The public health impact is profound, with AKI from nephrotoxicity linked to substantial mortality and morbidity. Severe cases, particularly stage 3 AKI requiring renal replacement therapy, carry in-hospital mortality rates of 44-52%.^[20] Among survivors, pooled rates of CKD development reach 25.8 per 100 person-years post-AKI.^[21] These outcomes emphasize the need for targeted prevention strategies to mitigate long-term renal consequences.

Pathophysiology

Mechanisms of Renal Injury

Nephrotoxicity involves damage to specific kidney structures through distinct cellular and molecular pathways, primarily affecting the tubules, interstitium, glomeruli, and vasculature. These mechanisms often overlap, with toxins exploiting the kidney's unique physiology, such as high blood flow and concentration gradients in the nephron, leading to localized injury. Proximal tubular cells, for instance, are particularly vulnerable due to their role in reabsorption and secretion, where toxins accumulate via endocytic receptors like megalin or basolateral transporters, resulting in intracellular buildup.^[4] This accumulation triggers acute tubular necrosis (ATN) through oxidative stress from reactive oxygen species (ROS) generation, mitochondrial dysfunction impairing ATP production, and subsequent apoptosis or necrosis of tubular epithelial cells.^[1] The process is exacerbated by toxin concentration gradients along the tubules, where filtration and reabsorption amplify exposure in the proximal segments.^[4] Interstitial nephritis arises from immune-mediated inflammation, typically as a hypersensitivity reaction involving T-cell infiltration and eosinophil activation, leading to edema, tubular dysfunction, and progressive fibrosis in the renal interstitium.^[22] This type IV hypersensitivity response forms neoantigens that provoke cytokine release and inflammatory cascades; drug-induced acute interstitial nephritis accounts for approximately 20% of AKI cases of unexplained etiology.^[4] Chronic forms may evolve into interstitial fibrosis through sustained immune activation and extracellular matrix deposition.^[1] Glomerular injury manifests through hemodynamic alterations that reduce glomerular perfusion, disrupting the glomerular filtration barrier and causing proteinuria.^[1] Immune-mediated glomerulonephritis involves complement activation and neutrophil recruitment, while these pathways can lead to acute proliferative or crescentic glomerulonephritis, impairing overall renal filtration.^[4] Vascular effects primarily involve endothelial dysfunction and vasoconstriction, which precipitate ischemia by reducing renal blood flow and oxygen delivery to medullary and cortical regions.^[1] Crystal nephropathy, a subtype, occurs when poorly soluble toxins precipitate in tubular lumens or vessels, causing obstruction, inflammation, and further ischemic damage via NLRP3 inflammasome activation.^[22] Dehydration can amplify these ischemic effects by further compromising perfusion.^[4] Additional pathways, such as pervasive oxidative stress, underpin many forms of renal injury by generating ROS that damage lipids, proteins, and DNA across cell types, often originating from mitochondrial overload or enzymatic sources like NADPH oxidase.^[1] In the medulla, toxins may disrupt aquaporin channels and concentrating mechanisms, leading to nephrogenic diabetes insipidus through impaired water reabsorption and hyperosmolar stress.^[4] These mechanisms highlight the kidney's susceptibility to multifactorial injury, where early cellular perturbations cascade into broader functional decline.^[22]

Predisposing Risk Factors

Pre-existing chronic kidney disease (CKD) is a major patient-related risk factor for nephrotoxicity, as it impairs the renal clearance of toxic agents, leading to their accumulation and heightened tubular damage.^[5] Advanced age further exacerbates this susceptibility through age-related declines in glomerular filtration rate (GFR), reduced renal blood flow, and diminished physiological reserves that limit the kidney's ability to handle toxic insults.^[5] Diabetes mellitus contributes by causing underlying microvascular damage and glomerular hyperfiltration, which compromise renal autoregulation and amplify the nephrotoxic effects of agents such as iodinated contrast media.^[5] Similarly, heart failure reduces effective renal perfusion via decreased cardiac output and neurohormonal activation, creating a state of prerenal vulnerability that intensifies toxin-mediated injury.^[5] Obesity alters drug pharmacokinetics through changes in volume of distribution and hepatic metabolism, resulting in elevated systemic exposure to nephrotoxic compounds like vancomycin.^[23] Exposure-related factors play a critical role in predisposing individuals to nephrotoxic injury by modifying the delivery and concentration of toxins within the kidney. Dehydration, often from inadequate fluid intake or volume depletion, decreases renal perfusion and urine output, thereby concentrating nephrotoxins in the tubular lumen and promoting their uptake by proximal tubule cells.^[5] Concurrent administration of multiple nephrotoxic agents, such as the combination of nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, and diuretics—termed the "triple whammy"—produces additive hemodynamic and direct cytotoxic effects that substantially elevate the risk of acute kidney injury.^[5] High-dose or prolonged therapy with nephrotoxins, exemplified by aminoglycosides or vancomycin, leads to cumulative renal exposure, where toxicity correlates directly with the magnitude and duration of dosing.^[5] Genetic predispositions influence nephrotoxicity susceptibility through variations in drug transporters and metabolizing enzymes that affect toxin handling. Polymorphisms in the SLCO1B1 gene, which encodes the organic anion-transporting polypeptide 1B1 (OATP1B1), reduce hepatic uptake of statins, causing elevated plasma concentrations that increase the risk of statin-induced rhabdomyolysis; severe cases can lead to acute tubular necrosis.^[24] Iatrogenic risks are especially elevated in intensive care unit (ICU) environments, where hemodynamic instability and polypharmacy converge to heighten vulnerability. Up to 62% of critically ill patients receive at least one nephrotoxic drug, such as vancomycin, during their first week in the ICU, often in the context of multiple concurrent exposures that amplify renal insult risk.^[25]

Etiology

Drug-Induced Causes

Drug-induced nephrotoxicity represents a significant portion of acute kidney injury (AKI) cases in hospitalized patients, accounting for up to 60% of hospital-acquired AKI episodes.^[26] This iatrogenic form of renal injury arises from various classes of pharmaceuticals, often manifesting as acute tubular necrosis (ATN), interstitial nephritis, or hemodynamic alterations, with reversibility dependent on early detection and discontinuation of the offending agent. Common culprits include antimicrobials, analgesics, contrast agents, and other specialized therapies, where risk is amplified by factors such as dosing, duration, and patient comorbidities.

Antimicrobials

Aminoglycosides, such as gentamicin, are notorious for inducing ATN through accumulation in proximal tubular cells, with nephrotoxicity occurring in 10-25% of treated patients, particularly during prolonged therapy exceeding 7-10 days.^[27] Vancomycin contributes to dose-dependent AKI, with incidence rates ranging from 5-43% depending on trough levels above 15-20 mg/L and concurrent risk factors like dehydration or concomitant nephrotoxins.^[28] Amphotericin B, especially the conventional deoxycholate formulation, causes direct tubular damage leading to hypokalemia and renal wasting, affecting approximately 30-50% of recipients, though liposomal variants reduce this risk to 5-15%.^[13]^[29]

Analgesics and Anti-Inflammatories

Nonsteroidal anti-inflammatory drugs (NSAIDs) precipitate hemodynamic AKI by inhibiting renal prostaglandins, which normally maintain afferent arteriolar dilation, resulting in reduced glomerular filtration rate; this effect is seen in up to 5% of chronic users and higher in volume-depleted states.^[13] Acetaminophen overdose can lead to ATN via oxidative stress and mitochondrial dysfunction in the setting of supratherapeutic doses, contributing to AKI in severe hepatotoxicity cases, though chronic high-dose use (>1-2 g/day for years) may also induce interstitial nephritis.^[6]

Contrast Agents

Iodinated contrast media used in diagnostic imaging cause osmotic nephrosis and direct tubular toxicity, with AKI developing in approximately 5-20% of high-risk patients, such as those with baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² or diabetes, typically within 48-72 hours post-exposure.^[30] Preventive measures like hydration and minimizing contrast volume are crucial, as the injury is often reversible but can prolong hospital stays.

Other Drugs

Cisplatin, a platinum-based chemotherapeutic, induces dose-dependent tubular toxicity manifesting as magnesium wasting and polyuria, with cumulative doses exceeding 100 mg/m² linked to permanent renal impairment in 20-30% of oncology patients.^[6] Calcineurin inhibitors like tacrolimus and cyclosporine contribute to chronic allograft nephropathy in transplant recipients through afferent arteriolar vasoconstriction and fibrosis, evident in nearly all long-term users, with histological changes in virtually all allografts by 10 years post-transplantation and necessitating therapeutic drug monitoring.^[13]^[31] Proton pump inhibitors (PPIs), such as omeprazole, are associated with acute interstitial nephritis in approximately 0.01-0.3% of chronic users, often presenting subacutely with rash or eosinophilia after months to years of therapy.^[13]^[32]

Environmental and Other Toxins

Environmental toxins encompass a range of non-pharmaceutical substances from occupational, industrial, and natural sources that can impair renal function through direct cellular damage or indirect metabolic disruption. These agents contribute significantly to both acute and chronic kidney diseases, particularly in regions with high exposure levels due to pollution or agricultural practices. Unlike iatrogenic causes, environmental nephrotoxins often result from chronic low-level exposure, leading to progressive tubular or glomerular injury.^[33] Heavy metals represent a major class of environmental nephrotoxins, with lead primarily inducing chronic tubulointerstitial disease by accumulating in proximal tubules and causing fibrosis and inflammation over time.^[34] Mercury exposure, often through contaminated water or fish, leads to glomerular damage via immune complex deposition and podocyte injury, resulting in proteinuria and nephrotic syndrome.^[35] Cadmium, prevalent in smokers due to tobacco contamination, targets the proximal tubule, causing toxicity through oxidative stress and mitochondrial dysfunction, which manifests as Fanconi syndrome with glycosuria and aminoaciduria.^[36] Industrial chemicals also pose substantial risks; for instance, ethylene glycol, found in antifreeze and solvents, metabolizes to oxalate crystals that precipitate in renal tubules, obstructing flow and causing acute kidney injury (AKI) with rapid oliguria.^[37] Aristolochic acid, present in certain herbal remedies and historically linked to soil contamination in endemic areas, induces Balkan nephropathy—a progressive interstitial fibrosis and urothelial cancer—through DNA adduct formation in renal cells.^[38] Endogenous toxins arise from internal physiological disruptions; rhabdomyolysis releases myoglobin, which induces acute tubular necrosis (ATN) by generating reactive oxygen species and cast formation in the distal nephron, often following trauma or strenuous exercise.^[39] Tumor lysis syndrome, triggered by rapid cancer cell breakdown during chemotherapy or spontaneous tumor necrosis, elevates uric acid levels, leading to uric acid nephropathy with crystal precipitation and intratubular obstruction.^[40] Emerging concerns in 2025 highlight microplastics and per- and polyfluoroalkyl substances (PFAS); cohort studies indicate that PFAS exposure correlates with glomerular filtration rate decline and increased chronic kidney disease (CKD) risk, likely via peroxisome proliferator-activated receptor alpha disruption and inflammation.^[41] As of 2025, longitudinal studies show PFAS exposure linked to eGFR decline and CKD risk, potentially via PPARα disruption and inflammation. Microplastics, ingested through water and food, have been detected in human renal tissues, with experimental models indicating oxidative stress and fibrosis, though large-scale human cohorts remain preliminary.^[42]^[43] In endemic areas such as agricultural regions in Central America and the Balkans, environmental toxins account for 10-20% of CKD cases, underscoring the need for targeted exposure mitigation.^[44]

Clinical Features

Acute Nephrotoxicity

Acute nephrotoxicity refers to the sudden impairment of kidney function resulting from exposure to nephrotoxic agents, such as certain drugs or environmental toxins, manifesting as acute kidney injury (AKI) within a short timeframe.^[45] This form of injury is characterized by a rapid decline in glomerular filtration rate, often detectable through an abrupt rise in serum creatinine levels, typically occurring within days of exposure.^[46] Common symptoms include oliguria or anuria, reflecting reduced urine output; peripheral edema due to fluid retention; fatigue from uremic toxin accumulation; and hypertension, particularly in cases involving glomerular involvement.^[45]^[47]^[48] The clinical syndromes of acute nephrotoxicity align with the broader categories of AKI, classified by etiology into prerenal (due to hemodynamic compromise reducing renal perfusion), intrinsic (direct damage to renal parenchyma, such as tubular or interstitial injury), and postrenal (obstruction of urinary outflow).^[45] Severity is staged using criteria like RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) or AKIN (Acute Kidney Injury Network), which define stages based on changes in serum creatinine (e.g., ≥0.3 mg/dL increase for stage 1) or urine output (e.g., <0.5 mL/kg/h for 6 hours).^[49] In nephrotoxic contexts, intrinsic AKI predominates, encompassing acute tubular necrosis (ATN) from ischemic or toxic insults and acute interstitial nephritis (AIN) from hypersensitivity reactions.^[50] Specific manifestations provide clues to the underlying subtype. For instance, hematuria—often gross or microscopic—may occur in toxin-induced glomerulonephritis, a form of intrinsic injury where immune-mediated glomerular damage leads to red blood cell leakage into the urine.^[51] Eosinophiluria, the presence of eosinophils in urine, is a hallmark of AIN, indicating allergic interstitial inflammation commonly triggered by drugs like antibiotics or NSAIDs.^[52] In ATN, urinalysis typically reveals muddy brown granular casts, representing sloughed tubular epithelial cells and debris, alongside renal tubular epithelial cells.^[53] The time course of acute nephrotoxicity is typically rapid, with onset of AKI symptoms and serum creatinine elevation often within 24-72 hours following exposure to the offending agent, such as in drug-induced cases.^[54] With prompt removal of the toxin and supportive care, recovery is frequent, occurring in many cases without residual damage, though untreated episodes may progress to chronic kidney disease.^[46]

Chronic Nephrotoxicity

Chronic nephrotoxicity refers to the gradual and persistent damage to kidney structures resulting from prolonged exposure to toxic agents, leading to irreversible decline in renal function over months to years. This form of toxicity contrasts with acute episodes by involving cumulative insults that promote ongoing inflammation, fibrosis, and scarring within the renal parenchyma. Unlike rapid-onset injuries, chronic nephrotoxicity often remains subclinical until significant functional impairment occurs, emphasizing the importance of monitoring in at-risk populations.^[55] Common symptoms of chronic nephrotoxicity include progressive fatigue due to accumulating metabolic waste, anemia from reduced erythropoietin production, and bone disease associated with disrupted mineral metabolism, such as renal osteodystrophy. Laboratory findings typically reveal an insidious rise in serum creatinine levels over extended periods, reflecting a slow diminution in glomerular filtration rate (GFR). These manifestations arise as the kidneys lose their capacity to maintain homeostasis, often without early warning signs.^[55] The condition manifests as chronic kidney disease (CKD), defined by a GFR less than 60 mL/min/1.73 m² persisting for more than three months, with or without evidence of kidney damage. Pathologically, it involves tubulointerstitial fibrosis, where excessive extracellular matrix deposition replaces functional tissue, and glomerular sclerosis, leading to obliteration of filtration units. Specific clinical features include proteinuria, indicating glomerular barrier dysfunction, and hypertension, driven by renin-angiotensin system activation and vascular stiffness. These changes can progress to end-stage renal disease (ESRD) in affected individuals, necessitating dialysis or transplantation.^[56]^[57]^[58] The time course of chronic nephrotoxicity is characterized by cumulative exposure to offending agents, such as years of lithium therapy, which can induce persistent concentrating defects resembling nephrogenic diabetes insipidus through downregulation of aquaporin-2 channels in the collecting ducts. This example illustrates how sustained toxin accumulation fosters maladaptive renal responses, culminating in long-term dysfunction. Acute nephrotoxic events may occasionally accelerate this progression, but the core process remains one of indolent deterioration.^[59]

Diagnosis

Clinical Evaluation

The clinical evaluation of suspected nephrotoxicity begins with a thorough history taking to identify potential causative factors and contextualize the patient's presentation. Clinicians should inquire about recent exposure to nephrotoxic agents, including prescription medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), aminoglycosides, or contrast agents, as well as over-the-counter drugs, herbal supplements, or environmental toxins like heavy metals or ethylene glycol.^[60]^[61] The onset and progression of symptoms, such as oliguria, fatigue, or nausea, should be documented, along with relevant comorbidities like diabetes, hypertension, or chronic heart failure that may predispose to renal injury.^[2] Assessment of volume status is critical, including queries about fluid intake, gastrointestinal losses, or diuretic use, to differentiate hypovolemic states from intrinsic renal damage.^[60] Physical examination focuses on identifying signs of renal dysfunction and volume imbalance. Signs of fluid overload, such as peripheral edema, periorbital swelling, or pulmonary crackles on lung auscultation, may indicate nephrotic syndrome or acute kidney injury with retention.^[62] Conversely, dehydration manifests as dry mucous membranes, reduced skin turgor, tachycardia, or orthostatic hypotension, often linked to prerenal contributions in nephrotoxic states.^[60] Flank tenderness or costovertebral angle pain should be elicited through palpation, as it may suggest interstitial nephritis or obstructive complications secondary to toxin exposure.^[62] Additional findings, such as rash or hypertension, can point to allergic or vasculitic mechanisms in drug-induced cases.^[61] Differential diagnosis during evaluation aims to distinguish nephrotoxicity from other causes of acute kidney injury, such as prerenal azotemia due to hypovolemia or postrenal obstruction from urinary tract issues. Prerenal azotemia is suspected in patients with evident volume depletion without toxin history, while obstruction may present with suprapubic tenderness or a palpable bladder.^[60] Nephrotoxicity is more likely when a temporal link to drug or toxin exposure aligns with acute renal decline, often requiring subsequent laboratory confirmation.^[2] Red flags prompting urgent evaluation include a rapid rise in serum creatinine of greater than 0.3 mg/dL within 48 hours, as defined by KDIGO criteria for acute kidney injury, which signals potential severe or progressive nephrotoxic injury.^[49]

Laboratory and Imaging Studies

Laboratory and imaging studies play a crucial role in confirming and characterizing nephrotoxicity by providing objective measures of renal function and structure. Blood tests are foundational, with serum creatinine serving as a primary marker of glomerular filtration rate (GFR) decline in acute kidney injury (AKI) associated with nephrotoxic agents.^[63] Elevations in serum creatinine, often defined as a rise of 0.3 mg/dL or 50% from baseline within 48 hours, indicate potential nephrotoxic damage, though it lags behind actual injury onset.^[63] Blood urea nitrogen (BUN) levels also rise in response to reduced renal clearance, and a BUN-to-creatinine ratio exceeding 20:1 typically suggests prerenal azotemia secondary to hypoperfusion rather than direct nephrotoxic tubular injury.^[64] Electrolyte panels frequently reveal hyperkalemia due to impaired potassium excretion in AKI, which can exacerbate cardiac risks and requires prompt monitoring.^[46] For earlier GFR estimation, cystatin C offers advantages over creatinine, as it rises 6–48 hours sooner in AKI and provides a more accurate reflection of renal function, particularly in patients with muscle mass variations.^[65] Urinalysis provides insights into tubular and interstitial involvement in nephrotoxicity. Proteinuria may signal glomerular or tubular damage from toxins, while the presence of granular casts in urine sediment is characteristic of acute tubular necrosis (ATN) induced by nephrotoxins like aminoglycosides or cisplatin.^[52] Urinary eosinophils may be detected in drug-induced acute interstitial nephritis (AIN), a common hypersensitivity reaction to medications such as NSAIDs or antibiotics, but the test has low sensitivity (approximately 30-35% at a 1% cutoff) and limited specificity; it is not recommended for routine diagnostic use per recent reviews.^[66]^[67] The fractional excretion of sodium (FE Na) helps differentiate prerenal from intrinsic causes; values below 1% indicate avid sodium reabsorption consistent with prerenal states, whereas higher values suggest ATN from direct nephrotoxic effects.^[68] Emerging biomarkers enhance early detection of nephrotoxicity, surpassing traditional markers like creatinine in sensitivity and timeliness. Neutrophil gelatinase-associated lipocalin (NGAL) levels in urine or plasma rise within 2–6 hours of tubular injury, enabling prediction of AKI progression and outcomes in nephrotoxic settings such as chemotherapy or contrast exposure.^[69] Kidney injury molecule-1 (KIM-1), a proximal tubule-specific marker, demonstrates high specificity for nephrotoxic ATN and correlates with histological damage severity, with urinary KIM-1 showing superior prognostic value for AKI recovery compared to creatinine in recent meta-analyses.^[70] These biomarkers, validated in 2024–2025 reviews, facilitate risk stratification and timely intervention, particularly in high-risk patients.^[71] Imaging modalities assess structural complications of nephrotoxicity. Renal ultrasound is the initial noninvasive test to detect hydronephrosis or obstruction from crystal nephropathy, as seen with acyclovir or indinavir toxicity, and can evaluate kidney size and echogenicity for chronic changes.^[72] Computed tomography (CT) or magnetic resonance imaging (MRI) is employed for suspected vascular issues, such as renal artery thrombosis or infarction from calcineurin inhibitors, providing detailed cross-sectional views without ionizing radiation in the case of MRI.^[73] When noninvasive tests are inconclusive, renal biopsy remains the gold standard for histological confirmation, revealing patterns like interstitial fibrosis in chronic nephrotoxicity or tubular vacuolization in calcineurin inhibitor toxicity.^[74]

Prevention and Treatment

Preventive Strategies

Preventive strategies for nephrotoxicity focus on identifying at-risk individuals and implementing targeted interventions prior to exposure to nephrotoxic agents. Risk stratification is a cornerstone, utilizing validated scoring systems such as the Mehran risk score for contrast-induced nephropathy (CIN), which incorporates factors like hypotension, intra-arterial contrast volume, congestive heart failure, age over 75, anemia, diabetes, and baseline renal function to predict CIN risk, with scores above 16 indicating up to a 57% probability.^[75] Similarly, estimating glomerular filtration rate (GFR) via the Cockcroft-Gault equation enables dose adjustments for renally cleared drugs in patients with impaired renal function, thereby minimizing accumulation and toxicity.^[76] Hydration protocols are widely recommended to maintain renal perfusion and dilute nephrotoxins, particularly for contrast media. Intravenous isotonic saline at 1 mL/kg/hour for 6-12 hours before and after contrast administration has been shown to reduce the incidence of acute kidney injury (AKI) by approximately 50% in high-risk patients.^[77] For cisplatin-induced nephrotoxicity, short-duration hydration regimens with lower fluid volumes are effective, often combined with forced diuresis to enhance toxin excretion.^[78] Close monitoring of renal function is essential in high-risk patients to enable early intervention. Baseline serum creatinine measurement followed by serial monitoring post-exposure allows detection of subtle changes, guiding the avoidance of additional nephrotoxins such as nonsteroidal anti-inflammatory drugs (NSAIDs) in dehydrated or volume-depleted individuals.^[2] Nephrotoxin stewardship programs emphasize withholding or substituting high-risk agents in vulnerable populations, including those with chronic kidney disease.^[79] Alternative agents and personalized approaches further mitigate risk. Iso-osmolar contrast media, such as iodixanol, demonstrate lower CIN rates compared to low-osmolar agents in patients with renal impairment and diabetes, due to reduced osmotic stress on renal tubules.^[80] Pharmacogenomic testing identifies at-risk genotypes, such as variants in RBMS3 associated with platinum-induced AKI, allowing for tailored dosing or alternative therapies in genetically susceptible individuals.^[81]

Management Approaches

The primary management of established nephrotoxicity involves immediate discontinuation of the offending agent, which is critical for restoring renal function and maximizing recovery.^[4] Supportive care focuses on maintaining volume status through careful fluid management to ensure adequate renal perfusion and correcting electrolyte imbalances, such as hyperkalemia or hypomagnesemia, to prevent further complications.^[45] Specific therapies are tailored to the underlying mechanism of nephrotoxicity. For contrast-induced acute kidney injury, N-acetylcysteine is sometimes administered despite conflicting evidence on its efficacy in treating established injury, as meta-analyses show mixed results regarding renal protection post-exposure.^[82] In cases of acute interstitial nephritis, corticosteroids such as prednisone (typically 0.5–1 mg/kg/day) are the mainstay, with response rates of 60–80% achieving partial or complete renal recovery.^[83] Renal replacement therapy, including dialysis, is indicated for severe acute kidney injury manifesting as anuria, refractory uremia, severe hyperkalemia (>6.5 mmol/L unresponsive to medical therapy), or volume overload with pulmonary edema.^[45] In intensive care settings, continuous renal replacement therapy is preferred for hemodynamically unstable patients to provide gentle solute and fluid removal while minimizing cardiovascular stress.^[84] Outcomes vary by etiology and severity, but in acute tubular necrosis—a common form of nephrotoxic injury—approximately 70% of patients achieve renal recovery within weeks following discontinuation and supportive measures, though monitoring for progression to chronic kidney disease is essential.^[85] Diagnostic confirmation, such as via biopsy or laboratory trends, guides the selection of these targeted interventions.^[45]

History and Etymology

Historical Development

The understanding of nephrotoxicity began to emerge in the 19th century with early observations of heavy metal poisoning leading to renal failure. Reports from the late 1800s documented lead exposure in industrial workers causing chronic kidney damage, with physicians recognizing it as a form of progressive renal insufficiency during the era of rapid industrialization.^[86] Similarly, mercury poisoning, prevalent among hat makers using mercuric nitrate in felt processing—a condition colloquially termed "hatters' disease" by the 1820s—resulted in acute and chronic renal impairment alongside neurological symptoms, as evidenced by clinical cases of proteinuria and tubular necrosis in exposed artisans.^[87] These initial recognitions laid the groundwork for identifying environmental toxins as renal hazards, though causal links were often anecdotal until systematic pathology studies in the era's medical literature.^[88] The 20th century marked significant milestones in delineating drug-induced nephrotoxicity, particularly during wartime medical advancements. In the 1940s, the introduction of streptomycin, the first aminoglycoside antibiotic isolated in 1943 and widely deployed against tuberculosis in World War II, revealed substantial renal toxicity through clinical trials and battlefield use, manifesting as non-oliguric acute kidney injury in significant rates, up to 25% of patients in early uses due to proximal tubular accumulation.^[89] By the 1950s, researcher Richard W. Lippman advanced the classification of interstitial nephritis by elucidating proteinuria mechanisms and renal functional changes in toxin-exposed models, contributing to the histopathological framework distinguishing toxic interstitial damage from glomerular diseases.^[90] The 1960s saw the proliferation of nonsteroidal anti-inflammatory drugs (NSAIDs), with early reports linking chronic analgesic use—such as phenacetin and aspirin derivatives—to papillary necrosis and interstitial nephritis, prompting initial regulatory scrutiny of their renal risks.^[91] In the 1970s, the advent of platinum-based chemotherapeutics like cisplatin highlighted severe nephrotoxicity, with early clinical trials showing dose-limiting renal injury, spurring investigations into hydration and protective agents.^[92] Further progress in the 1980s focused on contrast-induced nephropathy, as larger case series following intravenous iodinated contrast in angiography procedures documented acute renal failure in vulnerable patients, spurring studies on osmotic and direct tubular effects.^[93] Recent advances up to 2025 have emphasized biomarkers and surveillance for early detection and risk mitigation. The discovery of neutrophil gelatinase-associated lipocalin (NGAL) in the early 2000s revolutionized nephrotoxicity assessment; initial studies in 2004 demonstrated its rapid urinary elevation in cisplatin-induced tubular injury models, while 2005 clinical trials confirmed its predictive value for acute kidney injury hours before creatinine rises.^[94] Complementing this, pharmacovigilance databases like the FDA Adverse Event Reporting System (FAERS) have enabled real-world tracking of polypharmacy-related risks; analyses up to 2023 highlighted increased AKI risks from polypharmacy in the elderly, including common nephrotoxic drug classes like antihypertensives, antibiotics, and NSAIDs, informing deprescribing guidelines.^[95] These developments underscore a shift toward proactive, data-driven strategies in nephrotoxicity management.

Etymology

The term "nephrotoxicity" is a compound word formed in English by combining the prefix "nephro-" and the suffix "-toxicity."^[96] The prefix "nephro-" derives from the Ancient Greek word nephros (νεφρός), meaning "kidney," a term that has been used in medical contexts since at least the time of Hippocrates around 400 BCE to describe renal anatomy and related conditions.^[97]^[98] The suffix "-toxicity" originates from the adjective "toxic," which entered English in the mid-17th century via Latin toxicus, itself borrowed from Greek toxikon (τοξικόν), originally denoting "poison for use on arrows" or "poison in general."^[99] The noun form "toxicity," meaning the state or quality of being poisonous, first appeared in medical English in the late 19th century, around 1880, to describe the harmful effects of poisons on biological systems.^[100]^[99] The full term "nephrotoxicity" emerged in the early 20th century within pharmacology and toxicology literature to specifically denote damage to the kidneys caused by toxic substances, building on earlier concepts like "nephrotoxin," which appeared around 1900 in studies of renal effects from serums and chemicals.^[101] This coinage reflected growing recognition in the 1920s of "chemical nephritis," a condition involving kidney inflammation from exogenous toxins, distinct from infectious or idiopathic forms.^[102] Related terminology evolved from "nephritis," an ancient Greek-derived word (nephros + -itis, meaning inflammation of the kidney) attested as early as the 16th century in Latin medical texts, which broadly encompassed inflammatory kidney disorders regardless of cause.^[103] In contrast, "nephrotoxicity" shifted emphasis to exogenous, poison-induced renal harm, aligning with advances in understanding chemical and drug-related kidney injuries.^[104]

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In general, several mechanisms underlying the development of drug-related nephrotoxicity can be distinguished: inflammatory and immune-related mechanisms ...
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