ICU · Renal/Metabolic
Drug-induced kidney injury and acute interstitial nephritis
Also known as Acute interstitial nephritis (AIN) · Drug-induced nephrotoxicity · Acute tubular necrosis (ATN) · Contrast nephropathy · Contrast-associated AKI (CA-AKI)
Drug-induced kidney injury is a leading cause of AKI in ICU (20-35% of hospital-acquired AKI). Mechanisms map onto the pre-renal / intrinsic / post-renal framework: PRE-RENAL (haemodynamic) — NSAIDs inhibit prostaglandins → afferent arteriolar constriction; ACEi/ARBs dilate the efferent arteriole → fall in GFR; calcineurin inhibitors (cyclosporin, tacrolimus) cause afferent constriction; the 'triple whammy' (NSAID + ACEi + diuretic) abolishes all three autoregulatory limbs. INTRINSIC — ATN from direct tubular toxicity (aminoglycosides accumulate in proximal tubule via the megalin receptor; amphotericin B injures the distal tubule; iodinated contrast causes renal vasoconstriction plus direct tubular toxicity; cisplatin, methotrexate, tenofovir); AIN is a Type IV hypersensitivity interstitial infiltrate (penicillins, PPIs, NSAIDs, sulphonamides, rifampicin, allopurinol, 5-ASA). POST-RENAL — crystal nephropathy (aciclovir, sulphonamides, methotrexate, indinavir, triamterene). Prevention: avoid nephrotoxin combinations, isotonic saline hydration before contrast (PRESERVE: saline = bicarbonate, NAC no benefit), statins (TRACK-D showed benefit in CKD + diabetes), dose adjustment for renal function, therapeutic drug monitoring (vancomycin AUC, aminoglycoside troughs). AIN: STOP the drug ± corticosteroids. Aminoglycosides: once-daily extended-interval dosing reduces nephrotoxicity.
On this page & tools
Your progress
Saved locally on this device.
Target exams
Red flags
Glomerular autoregulation — the foundation for understanding nephrotoxicity
Every haemodynamic drug-induced AKI makes sense once the two-gate model of the glomerulus is clear. GFR is governed by the net filtration pressure across the glomerular capillary wall, which depends on the balance between afferent (inflow) and efferent (outflow) arteriolar tone: [1]
- Afferent arteriole (the IN-gate) — regulated mainly by prostaglandins (PGE2, PGI2), which keep it dilated. Block prostaglandin synthesis (NSAIDs inhibit COX-1/COX-2) and the afferent arteriole constricts → less blood reaches the glomerulus → GFR falls. The calcineurin inhibitors (cyclosporin, tacrolimus) also constrict the afferent arteriole (endothelin-mediated, reduced NO).
- Efferent arteriole (the OUT-gate) — regulated mainly by angiotensin II, which keeps it constricted. This constriction maintains glomerular capillary pressure and therefore GFR. Block angiotensin II (ACE inhibitors, or block its receptor with ARBs) and the efferent arteriole dilates → intraglomerular pressure drops → GFR falls.
- Tubuloglomerular feedback (TGF) — the macula densa senses distal NaCl delivery and adjusts afferent tone via adenosine. Tubular toxins that increase distal delivery (or contrast, which increases proximal pressure) feed back through adenosine to constrict the afferent arteriole, compounding the GFR fall. [1]
Clinical corollary — the "triple whammy": when a patient is simultaneously on an NSAID (constricts afferent) + ACEi/ARB (dilates efferent) + diuretic (depletes circulating volume), all three compensatory mechanisms that defend GFR are abolished at once → an abrupt, often severe, fall in GFR. This is the single highest-yield drug-AKI mechanism in the exam.[3]
Three patterns
Pre-renal (haemodynamic)
Altered renal perfusion
- Mechanism: disruption of afferent/efferent autoregulation → reduced GFR (no tubular cell death)
- NSAIDs: inhibit prostaglandins → AFFERENT arteriolar vasoconstriction → reduced inflow
- ACEi/ARB: inhibit angiotensin II → EFFERENT arteriolar dilation → reduced intraglomerular pressure
- Calcineurin inhibitors (cyclosporine, tacrolimus): AFFERENT arteriolar vasoconstriction (endothelin, ↓NO)
- Combined NSAID + ACEi + diuretic = "triple whammy" — high risk of AKI
- Urine: BUN:Cr >20, urine Na <20, FENa <1% (preserved tubular function)
- Treatment: stop offending drug, restore volume; renal function usually recovers quickly
ATN (toxic)
Direct tubular damage
- Mechanism: direct toxic injury to tubular epithelial cells → necrosis + shedding
- Aminoglycosides: accumulate in PROXIMAL tubule (via megalin/cubilin receptor) → lysosomal disruption
- Amphotericin B: forms pores in the DISTAL tubule cell membrane → electrolyte wasting + cell death
- Iodinated contrast: renal vasoconstriction (medullary hypoxia) + direct tubular toxicity
- Cisplatin: accumulates in proximal tubule via OCT2/copper transporter → mitochondrial injury
- Tenofovir: proximal tubular mitochondrial toxicity → Fanconi syndrome
- Rhabdomyolysis (indirect): myoglobin casts + free-radical injury to tubules
- Urine: FENa >2%, muddy brown granular casts, isosthenuria
- Timeline: days (aminoglycoside, amphotericin) to 48h (contrast)
- Treatment: stop/reduce nephrotoxin, supportive care; most recover in 1-2 weeks
AIN (allergic)
Hypersensitivity
- Mechanism: Type IV (delayed) hypersensitivity → interstitial oedema + inflammatory infiltrate (eosinophils, lymphocytes)
- Drugs: penicillins (methicillin classic), PPIs (increasingly common), NSAIDs, sulphonamides, rifampicin, ciprofloxacin, allopurinol, 5-ASA, mesalazine
- Presentation: AKI + fever + rash + eosinophilia + eosinophiluria + sterile pyuria + WBC casts
- Timeline: days-weeks after drug exposure (NSAID-AIN can be months)
- Diagnosis: clinical + kidney biopsy (gold standard); urinary eosinophils now less relied on
- Treatment: STOP drug ± corticosteroids (prednisolone 1 mg/kg/day — benefit most pronounced if started early; trials show no clear benefit)
Post-renal (crystal)
Intratubular obstruction
- Mechanism: drug or metabolite precipitates as crystals in the distal tubule/collecting duct → intrarenal obstruction + tubular injury
- Aciclovir: poorly soluble at low flow — precipitates at high IV doses, especially in dehydration
- Sulphonamides (sulfadiazine, co-trimoxazole): acetylated metabolites precipitate in acidic urine
- Methotrexate: high-dose → 7-OH-methotrexate crystals in acidic urine
- Indinavir / atazanavir (PIs), triamterene, vitamin C (oxalate), massive doses of many drugs
- Urine: crystals on microscopy (birefringent needles/rosettes), haematuria, sterile pyuria
- Treatment: STOP drug, aggressive IV hydration (increase urine flow), alkalinise urine (for acids like methotrexate, sulphonamides)
Mechanisms in depth
Pre-renal (haemodynamic) — drug-induced loss of GFR
The kidney defends GFR across a wide range of perfusion pressures through autoregulation, which depends on three endogenous systems acting on the two arterioles. Drugs that interfere with any one cause a functional (reversible) fall in GFR; drugs that interfere with several at once cause severe AKI: [1]
- NSAIDs (afferent limb) — COX inhibition depletes vasodilatory prostaglandins (PGE2, PGI2). In a well-perfused kidney this is harmless, but in any state of high vasoconstrictor tone (volume depletion, sepsis, cirrhosis, heart failure, "effective circulating volume" depletion) the prostaglandins are the only thing keeping the afferent arteriole open. Block them and GFR collapses. NSAIDs also cause AIN (a separate intrinsic mechanism — weeks after exposure).
- ACEi / ARB (efferent limb) — angiotensin II normally constricts the efferent arteriole, holding up glomerular capillary pressure. Blocking it lowers GFR. This is physiological and benign in most patients — a small creatinine rise on starting an ACEi is expected and acceptable (up to 30% baseline creatinine). It becomes pathological when: (a) the patient is volume-depleted; (b) there is bilateral renal artery stenosis (the stenotic kidney is exquisitely dependent on efferent constriction to filter); (c) combined with NSAIDs/diuretics (triple whammy); or (d) in cardiorenal or hepatorenal states.
- Calcineurin inhibitors (cyclosporin, tacrolimus) — cause afferent arteriolar vasoconstriction (endothelin release, reduced nitric oxide, increased sympathetic tone). Chronic use causes structural arteriolar hyalinosis and striped interstitial fibrosis — irreversible. CNI also cause a distal tubular toxicity (type IV RTA, hyperkalaemia, magnesium wasting) distinct from the haemodynamic effect. [1]
Intrinsic — acute tubular necrosis (ATN)
ATN is the common endpoint of direct tubular cell injury. The subsegment and mechanism matter because they explain the timing, urine findings and prevention: [1]
- Aminoglycosides (gentamicin, tobramycin, amikacin) — filtered freely, then re-absorbed into proximal tubular cells via the megalin/cubilin endocytic receptor on the apical membrane. Inside the cell they accumulate in lysosomes, disrupt phospholipid metabolism (inhibit phospholipase, mimicking a phospholipidosis) and ultimately trigger apoptosis/necrosis. Nephrotoxicity is cumulative and dose-dependent, typically appearing after 5–7 days; non-oliguric initially. The ototoxicity runs in parallel and is also concentration-dependent.
- Amphotericin B — binds to ergosterol-like sterols in the cholesterol-rich distal tubular cell membrane, forming pores → leaks → electrolyte wasting (kaliuresis, magnesiuria, type I distal RTA) before frank ATN. The deoxycholate formulation is the most nephrotoxic; lipid formulations (liposomal amphotericin, ABLC) target the fungal cell preferentially and markedly reduce nephrotoxicity. Sodium loading (pre-hydration with saline) reduces amphotericin nephrotoxicity.
- Iodinated contrast — a dual insult: (1) an initial transient vasodilation followed by sustained renal vasoconstriction causing outer medullary hypoxia (the thick ascending limb has high O2 demand and a tenuous supply); (2) direct cytotoxicity to tubular cells from the hyperosmolar iodine load, plus cast formation. Risk is highest with high-osmolar contrast, large volumes, dehydration, CKD, diabetes and concurrent nephrotoxins.
- Cisplatin — enters the proximal tubule cell via the OCT2 transporter; causes mitochondrial injury, oxidative stress and DNA cross-linking → ATN with prominent magnesium and potassium wasting. Carboplatin is less nephrotoxic; amifostine and aggressive hydration mitigate.
- Methotrexate — at high dose (>1 g/m²), precipitates as crystals (post-renal component) and causes direct tubular injury; concentrates in tubules; alkalinisation of urine (preventing precipitation) plus leucovorin rescue plus high urine flow are the protective measures.
- Tenofovir (and adefovir) — proximal tubular mitochondrial toxicity → Fanconi syndrome (glycosuria with normal serum glucose, phosphaturia, aminoaciduria, uricosuria) and occasionally full ATN. The proximal tubule expresses high levels of the transporters (OAT1) that take tenofovir up.
- Rhabdomyolysis (indirect nephrotoxicity) — myoglobin is filtered, taken up by proximal tubule cells and is directly cytotoxic (ferrous iron, free radicals); it also forms casts that obstruct the tubule when urine is acidic and concentrated. The drug link is anything that destroys muscle: statins (especially with CYP3A inhibitors — azoles, macrolides), colchicine, neuroleptic malignant syndrome, serotonin syndrome, ecstasy, prolonged immobilisation. [1]
Intrinsic — acute interstitial nephritis (AIN)
AIN is an immune-mediated (predominantly Type IV hypersensitivity) inflammatory infiltrate of the tubulointerstitium, not a direct toxic effect. The classic clinical tetrad — fever, rash, eosinophilia, eosinophiluria — is insensitive and is absent in the majority; AKI with sterile pyuria and WBC casts after a new drug is enough to suspect it. NSAID-AIN is distinctive: it can present with nephrotic-range proteinuria (minimal-change-like podocyte injury) and may occur only after months of exposure. Methicillin was the original culprit (classic exam answer); today PPIs and NSAIDs are the most common. Diagnosis is confirmed by kidney biopsy (interstitial oedema with eosinophils and lymphocytes, tubulitis); biopsy is recommended when the diagnosis is unclear, AKI is not recovering, or steroids are being contemplated.[1]
Post-renal — crystal (intratubular) nephropathy
Drug crystals precipitate when three conditions align: high drug concentration (high dose/rapid infusion), low urine flow (dehydration), and unfavourable urine pH. The result is intratubular obstruction plus an inflammatory foreign-body reaction: [1]
- Aciclovir — solubility is limited; high-dose IV boluses in dehydrated patients precipitate as birefringent needle crystals in the distal tubule. Prevention: slow the infusion (>1 h), hydrate, and dose-adjust for renal function.
- Sulphonamides (sulfadiazine in PCP-toxoplasmosis prophylaxis, co-trimoxazole) — acetylated metabolites precipitate in acidic urine → crystals, haematuria, AKI. Prevention: alkalinise urine (sodium bicarbonate) + high fluid intake.
- Methotrexate (high-dose) — 7-OH-methotrexate precipitates in acidic urine. Prevention: alkalinisation to keep urine pH >7.0, high fluid intake, leucovorin rescue.
- Indinavir / atazanavir (HIV protease inhibitors), triamterene, large vitamin C doses (oxalate), massive ethylene glycol (oxalate — toxicology, not prescribed drug). [1]
Nephrotoxic drugs — examiner reference table
Common ICU nephrotoxins: mechanism, site and mitigation
| Drug / class | Primary site | Mechanism of injury | Pattern | Risk factors / timing | Mitigation |
|---|---|---|---|---|---|
| NSAIDs (ibuprofen, ketorolac, diclofenac) | Afferent arteriole | COX inhibition → ↓prostaglandins → afferent vasoconstriction (also AIN) | Pre-renal ± AIN | Volume depletion, CKD, cirrhosis, CHF | Avoid; if essential, limit to <5 days, avoid "triple whammy" |
| ACEi / ARB (ramipril, enalapril, valsartan) | Efferent arteriole | ↓Angiotensin II → efferent dilation → ↓GFR | Pre-renal | Bilateral RAS, volume depletion, sepsis | Hold in AKI/hypovolaemia; expect ≤30% Cr rise acceptable |
| Calcineurin inhibitors (cyclosporin, tacrolimus) | Afferent arteriole | Endothelin-mediated afferent vasoconstriction; chronic arteriolar hyalinosis | Pre-renal + distal tubular (type IV RTA, Mg wasting) | High trough levels, chronic use | Monitor trough; use lowest effective dose; CCB co-therapy |
| Aminoglycosides (gentamicin, tobramycin, amikacin) | Proximal tubule | Receptor-mediated (megalin) uptake → lysosomal disruption → ATN | ATN | Course >5–7 days, high trough, elderly, CKD, sepsis | Once-daily extended-interval dosing; monitor trough (<1 mg/L); limit duration |
| Amphotericin B (deoxycholate) | Distal tubule | Membrane pore formation → electrolyte wasting → ATN | ATN (± distal RTA) | Cumulative dose >2–3 g, dehydration | Lipid formulation preferred; pre-hydration with saline |
| Iodinated contrast | Medulla + tubules | Vasoconstriction (medullary hypoxia) + direct cytotoxicity | ATN | CKD, diabetes, dehydration, high volume, multiple doses | Isotonic saline pre-hydration; low/iso-osmolar contrast; minimise volume; hold nephrotoxins |
| Vancomycin (± piperacillin-tazobactam) | Proximal tubule | Concentration-dependent oxidative/apoptotic injury (± AIN) | ATN (± AIN) | Trough >15–20, AUC high, course >7 days, concomitant pip-tazo | AUC-guided TDM (400–600 mg·h/L); prefer cefepime over pip-tazo |
| Cisplatin / carboplatin | Proximal tubule (S3) | OCT2-mediated uptake → mitochondrial/DNA injury | ATN (Mg, K wasting) | High cumulative dose | Aggressive saline hydration; amifostine; Mg/K replacement |
| Methotrexate (high dose) | Tubules | Crystal (7-OH-MTX) + direct toxicity | ATN ± post-renal crystal | Dose >1 g/m², acidic urine | High urine flow + alkalinisation (urine pH >7) + leucovorin |
| Tenofovir / adefovir | Proximal tubule | OAT1 uptake → mitochondrial toxicity → Fanconi syndrome | ATN + Fanconi | Long-term use, low body weight, CKD | Monitor phosphate/glucose; tenofovir alafenamide (TAF) less toxic |
| Aciclovir | Distal tubule | Crystal precipitation (low solubility) | Post-renal crystal | High IV dose, dehydration, rapid infusion | Slow infusion >1 h, hydrate, dose-adjust for eGFR |
| Sulphonamides (sulfadiazine, co-trimoxazole) | Distal tubule | Acetylated metabolite crystals in acidic urine (also AIN) | Post-renal crystal ± AIN | High dose, acidic urine, dehydration | High fluid intake; alkalinise urine |
| Statins (rhabdo-indirect) | Skeletal muscle → tubules | Myoglobin cast nephropathy | ATN | High dose, CYP3A inhibitors, elderly, hypothyroid | Check CK; avoid statin + azole/macrolide combinations |
| Chemotherapy (ifosfamide, mitomycin, gemcitabine) | Glomerulus/tubules | Endothelial injury (TMA) or direct toxicity | ATN / TMA | High cumulative dose | Hydration; dose limits; monitor |
Acute interstitial nephritis (AIN) — dedicated approach
AIN is the most reversible form of drug-induced intrinsic AKI provided the offending drug is stopped early. The examiner's high-yield facts:[1]
AIN — diagnostic and management flow
1. SUSPECT on clinical grounds
AKI + recent new drug (within days–weeks) + any of: fever, rash, eosinophilia, sterile pyuria, WBC casts, flank pain. Remember the classic tetrad is insensitive — drug history is the key. NSAID-AIN can present after MONTHS and with nephrotic-range proteinuria.
2. BUILD the differential
Distinguish from ATN (muddy brown casts, FENa >2%, no eosinophilia, no rash) and from pre-renal (BUN:Cr >20, FENa <1%, rapid recovery with volume). Urinary eosinophils (Hansel stain) historically >1% supportive but low sensitivity/specificity — not reliable alone.
3. REVIEW EVERY drug started in the last 6 months
Common culprits by frequency: PPIs, penicillins/cephalosporins, NSAIDs, sulphonamides/co-trimoxazole, rifampicin, ciprofloxacin, allopurinol, 5-ASA/mesalazine, furosemide/thiazides, omeprazole. PPI-AIN is increasingly the #1 cause.
4. BIOPSY if diagnosis uncertain or steroids contemplated
Kidney biopsy is the gold standard: interstitial oedema with eosinophil-rich inflammatory infiltrate and tubulitis. Indicated if: AKI not recovering after stopping drug, suspected concurrent glomerular disease, or steroids being considered.
5. STOP the offending drug — the single most important intervention
Withdraw the most likely culprit and any unnecessary drug. In polypharmacy, stop the most recently introduced likely offender first. Document the reaction to prevent re-exposure. Most patients begin to improve within days of withdrawal.
6. CONSIDER corticosteroids — controversial, often used
Prednisolone 1 mg/kg/day (max 60 mg) if AKI severe or biopsy-confirmed with interstitial granulomas/edema, started EARLY (within 7–14 days). Wean over 4–6 weeks if renal function recovers. Trials have NOT shown a clear mortality/renal-recovery benefit — but most nephrologists use steroids in severe/progressive AIN.
7. SUPPORTIVE care and follow-up
Manage volume status, electrolytes (hyperkalaemia is common), and dialyse if urgent indications arise (AEIOU). Monitor creatinine to recovery — incomplete recovery predicts CKD. Lifelong documentation of the causative drug as an "allergy" to prevent re-challenge.
Top causes of AIN — examiner mnemonic and frequency
| Rank | Drug class | Notes |
|---|---|---|
| 1 | PPIs (omeprazole, pantoprazole) | Increasingly the #1 cause; onset weeks–months; often subclinical until AKI noticed |
| 2 | Antibiotics — penicillins (methicillin classic), cephalosporins, rifampicin, sulphonamides, ciprofloxacin | Classic fever + rash + eosinophilia; rifampicin AIN is dose/intermittent-dose related |
| 3 | NSAIDs (including COX-2) | Distinctive: may be delayed (months) and present with nephrotic-range proteinuria (podocyte injury) |
| 4 | Diuretics — furosemide, thiazides, triamterene | Sulphonamide structural similarity; triamterene also forms crystals |
| 5 | Miscellaneous — allopurinol, 5-ASA/mesalazine, omeprazole, cimetidine, phenytoin, indinavir | Allopurinol AIN often severe with long recovery; check IgA levels / HLA-B*5801 in at-risk |
Aminoglycoside nephrotoxicity — the prototypic tubular toxin
Aminoglycosides (gentamicin, tobramycin, amikacin) remain a frequent cause of ICU ATN, and the mechanism is exam-favourite territory:[3]
- Uptake via megalin/cubilin — aminoglycosides are filtered, then bind to the megalin–cubilin complex on the apical membrane of proximal tubular cells and are endocytosed. This concentrates the drug inside the cell many-fold above plasma.
- Lysosomal accumulation — within lysosomes aminoglycosides inhibit phospholipase A1/A2 → phospholipidosis → myeloid body formation → lysosomal rupture → release of lysosomal enzymes → mitochondrial injury → apoptosis and necrosis.
- Non-oliguric onset — classically the AKI is non-oliguric for the first several days (in contrast to ischaemic ATN), appearing after 5–7 days of therapy.
- Ototoxicity runs in parallel — cochlear and vestibular hair cell damage; irreversible (unlike the renal injury). Risk relates to cumulative dose and high trough concentrations.
- Prevention — once-daily extended-interval dosing — giving the entire daily dose as a single infusion produces a high peak (efficacy is concentration-dependent) and a low trough (less time for megalin-mediated uptake), so the tubular cell accumulates less drug. Meta-analyses confirm extended-interval dosing is at least as effective and less nephrotoxic than divided dosing. Limit courses to 5–7 days where possible; monitor troughs (goal <1 mg/L for gent/tobra at 18–24 h after dose). [1]
Contrast-associated AKI (CA-AKI)
Definition (KDIGO-aligned): a rise in serum creatinine ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours of intravascular iodinated contrast administration, after excluding alternative causes. Onset typically 24–72 h, peak 3–5 days, recovery within 1–3 weeks.[5]
Pathophysiology — a dual insult: (1) initial brief vasodilation is followed by sustained renal vasoconstriction causing outer-medullary hypoxia (the S3 segment/thick ascending limb has high O2 demand and a precarious supply); (2) direct cytotoxicity of the contrast molecule to tubular cells plus osmotic diuresis-induced cast formation. High-osmolar agents are worse than low-/iso-osmolar agents. [1]
CA-AKI prevention and management
Define risk
High risk: eGFR <30, diabetes, heart failure, hypovolaemia, multiple contrast doses, high-osmolar contrast, age >75, concurrent nephrotoxins, myeloma. Low risk: eGFR >60, single dose, no comorbidities. Use the Mehran score to stratify.
Pre-hydrate
IV crystalloid before AND after contrast. PRESERVE trial (NEJM 2018): IV bicarbonate = IV saline (no difference in 90-day composite). Oral hydration alone is insufficient. Protocol: isotonic saline 1 mL/kg/hr × 6–12 h before and 6–12 h after contrast (1.5 mL/kg/hr if no CHF). Hold diuretics in high-risk patients.
Minimise contrast
Use the LOWEST possible contrast volume. Use iso-osmolar (iodixanol) or low-osmolar (iopamidol, iohexol) contrast — less toxic than high-osmolar. Consider alternative imaging (ultrasound, MRI without contrast) in high-risk patients.
Hold nephrotoxic drugs
Hold METFORMIN at the time of contrast (resume after 48 h if renal function stable — risk of lactic acidosis if AKI develops). Hold NSAIDs. ACEi/ARB: continue unless volume-depleted. Hold aminoglycosides if possible. Hold loop diuretics in high-risk patients.
Consider statins (TRACK-D)
Short-course high-dose statin (e.g. rosuvastatin) before elective contrast reduced CA-AKI in patients with CKD + diabetes (TRACK-D, JACC 2014). Benefit not confirmed in all populations — reasonable in statin-tolerant high-risk patients undergoing elective procedures.
NAC — do NOT use
N-acetylcysteine has NO benefit over placebo (PRESERVE 2018, multiple meta-analyses). Stop prescribing NAC for contrast prophylaxis — the correct answer on the exam is isotonic saline alone.
PRESERVE
NEJM 2018
5177 patients at risk of CA-AKI undergoing angiography — 2×2 factorial of IV bicarbonate vs isotonic saline AND oral NAC vs placebo
Key finding
No benefit of NAC over placebo, and no benefit of bicarbonate over saline, for the composite of death, RRT or persistent renal impairment at 90 days.
Practice change
Use isotonic saline (NOT bicarbonate) and placebo (NOT NAC) for contrast prophylaxis
TRACK-D
JACC 2014
2998 patients with diabetes + CKD undergoing coronary/contrast procedures — short-course rosuvastatin vs placebo
Key finding
Rosuvastatin reduced CA-AKI (2.4% vs 5.9%, p<0.01) with no excess hepatic/muscle adverse effects.
Practice change
Short-course statin is a reasonable adjunct in CKD + diabetes before elective contrast
Prevention strategy — a systematic approach
The cheapest, safest and most effective "treatment" for drug-induced AKI is to not cause it in the first place. Prevention is a recurring exam theme:[3][4]
Preventing drug-induced nephrotoxicity — the six-step bundle
1. IDENTIFY the high-risk patient BEFORE prescribing
Risk factors: AGE >65, baseline CKD (eGFR <60), DIABETES, SEPSIS/hypovolaemia, HEART FAILURE/cirrhosis (low effective circulating volume), CONCURRENT NEPHROTOXINS (already on vancomycin — adding contrast?), HAEMODYNAMIC instability, myeloma. If high risk → AVOID nephrotoxins; if unavoidable → reduce dose, monitor, hydrate.
2. AVOID or LIMIT nephrotoxin combinations
Never combine NSAID + ACEi + diuretic (triple whammy). Avoid vancomycin + piperacillin-tazobactam (prefer cefepime). Avoid aminoglycoside + loop diuretic. Avoid two nephrotoxins together unless absolutely essential — synergy of injury is real.
3. DOSE-ADJUST for renal function
Renally clear most drugs (vancomycin, aminoglycosides, gabapentin, digoxin, LMWH, many antibiotics). Use eGFR or measured CrCl to adjust; re-check renal function frequently in acute illness. A common iatrogenic cause of AKI is failing to reduce a CKD dose when AKI develops.
4. HYDRATE before contrast / crystals / amphotericin
Contrast: isotonic saline 1 mL/kg/hr × 6–12 h pre and post (PRESERVE: saline = bicarb; NAC no benefit). Aciclovir/methotrexate/sulphonamides: high urine flow + alkalinise urine (where appropriate). Amphotericin: sodium loading with saline reduces toxicity.
5. THERAPEUTIC DRUG MONITORING (TDM)
Vancomycin: AUC-guided dosing (target AUC 400–600 mg·h/L) reduces AKI vs trough-only dosing. Aminoglycosides: once-daily extended-interval dosing with trough <1 mg/L. Tacrolimus/cyclosporin: trough in target range. TDM prevents the high-exposure nephrotoxicity window.
6. MONITOR AND REVIEW DAILY
Daily creatinine + urine output while on a nephrotoxin. Stop the drug at the first sign of rising creatinine (do not "finish the course"). Renal ultrasound to exclude obstruction. If AKI persists >3–5 days after stopping → consider biopsy (AIN?). Document intolerance to prevent re-exposure.
SAQ — Septic patient with rising creatinine on gentamicin and vancomycin
10 minutes · 10 marks
A 68-year-old man with septic shock from a urinary source has been in ICU for 6 days. He is on vasopressor-supported noradrenaline 0.25 mcg/kg/min, intubated, and receiving vancomycin (trough 22 mg/L) plus gentamicin (trough 3.1 mg/L) and piperacillin-tazobactam. His creatinine has risen from 95 to 290 µmol/L over 48 hours and urine output has fallen to 0.3 mL/kg/hr. FENa is 2.8% and urine microscopy shows muddy brown granular casts.
SAQ — Contrast-associated AKI prevention in a diabetic CKD patient before coronary angiography
10 minutes · 10 marks
A 72-year-old woman with type 2 diabetes, baseline eGFR 28 mL/min/1.73 m², heart failure (NYHA III) and peripheral vascular disease is scheduled for elective coronary angiography with possible PCI. She takes metformin 1 g BD, ramipril 10 mg daily, furosemide 40 mg daily and atorvastatin. She is euvolaemic. The cardiology team asks your advice on preventing contrast-associated AKI (CA-AKI).
Clinical pearls
Trial evidence
Drug-induced nephrotoxicity — landmark evidence
Epidemiology: drugs cause ~20% of hospital-acquired AKI; up to 35% in ICU. The commonest culprits are NSAIDs, ACEi, contrast, aminoglycosides and vancomycin.[4]
PRESERVE (Weisbord, NEJM 2018, PMID 29130810): 5177 patients at risk of CA-AKI undergoing angiography. 2×2 factorial of IV bicarbonate vs isotonic saline AND oral N-acetylcysteine vs placebo. Primary composite (death, RRT, persistent renal impairment at 90 days): NO benefit of NAC and NO benefit of bicarbonate. Practice-changing: stop prescribing NAC; use isotonic saline.[2]
TRACK-D (Han, JACC 2014, PMID 24076297): 2998 patients with diabetes + CKD undergoing coronary procedures. Short-course rosuvastatin reduced CA-AKI (2.4% vs 5.9%, p<0.01) with no excess hepatic/muscle toxicity. Supports short-course statins in high-risk elective procedures.[6]
Contrast-associated AKI review (Mehran, NEJM 2019, PMID 31141635): defines CA-AKI, stratifies risk (Mehran score), and codifies prevention — isotonic saline hydration, minimise contrast volume, low-/iso-osmolar agents, hold nephrotoxins. NAC not recommended.[5]
Aminoglycoside dosing: meta-analyses confirm once-daily extended-interval dosing is at least as effective as divided dosing and less nephrotoxic (lower trough → less megalin-mediated tubular uptake).[3]
Vancomycin + pip-tazo: multiple cohort/meta-analyses show ~2–3× AKI risk vs vancomycin + cefepime (synergistic tubular toxicity / vancomycin AIN). Prefer cefepime; AUC-guided vancomycin TDM reduces nephrotoxicity.[3]
Renal biomarkers (NGAL, TIMP-2•IGFBP7, [TIMP-2]•[IGFBP7]): detect tubular injury 12–24 h before creatinine rises — emerging clinical role in early drug-AKI detection.
Prognosis
- Pre-renal (drug-induced haemodynamic) AKI — usually fully reversible within 24–72 h of stopping the offending drug and restoring volume. No residual injury in most cases.
- ATN — recovery typically over 1–3 weeks after the insult; incomplete recovery (persistent CKD) in ~10–20% of severe cases, especially with pre-existing CKD, diabetes, older age.
- AIN — recovery over weeks; early drug withdrawal is the single biggest determinant of full recovery. Incomplete recovery / progression to CKD in ~30–40% (higher if steroids delayed or drug continued). Biopsy with granulomas or extensive interstitial fibrosis predicts worse outcome.
- Crystal nephropathy — usually fully reversible with hydration and drug cessation; irreversible tubular injury if obstruction prolonged.
- Mortality — drug-induced AKI carries a mortality similar to other AKI of equivalent severity (ICU AKI Stage 3 mortality ~40–50%); the underlying illness is usually the driver.
- AKI → CKD — 10–30% of severe AKI survivors progress to CKD within 1 year — nephrology follow-up and avoidance of further nephrotoxins are essential.[1]
Red flags
References
- [1]Moledina DG, Perazella MA. Drug-Induced Acute Interstitial Nephritis Clin J Am Soc Nephrol, 2017.PMID 28893923
- [2]Weisbord SD, Gallagher M, Jneid H, et al. Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine N Engl J Med, 2018.PMID 29130810
- [3]Perazella MA. Pharmacology behind Common Drug Nephrotoxicities Clin J Am Soc Nephrol, 2018.PMID 29622670
- [4]Perazella MA. Renal vulnerability to drug toxicity Clin J Am Soc Nephrol, 2009.PMID 19520747
- [5]Mehran R, Dangas GD, Weisbord SD. Contrast-Associated Acute Kidney Injury N Engl J Med, 2019.PMID 31141635
- [6]Han Y, Zhu G, Han L, et al. Short-term rosuvastatin therapy for prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease J Am Coll Cardiol, 2014.PMID 24076297