Drug-Induced Nephrotoxicity
Every nephron compartment has its toxins, and each leaves a recognizable signature
Hemodynamic injury
NSAIDs. When effective circulating volume is low (heart failure, cirrhosis, dehydration, CKD, old age), vasodilating prostaglandins (PGE2, PGI2) hold the afferent arteriole open. Blocking COX constricts it, so renal plasma flow and GFR fall together and prerenal AKI follows. NSAIDs also cause sodium retention and hyperkalemia. An NSAID plus an ACE inhibitor or ARB plus a diuretic is the classic "triple whammy."
ACE inhibitors and ARBs. When renal perfusion is low (bilateral renal artery stenosis, stenosis of a solitary kidney, volume depletion, severe heart failure), angiotensin II constricts the efferent arteriole to preserve glomerular pressure. Removing it lowers GFR and filtration fraction and raises potassium. A creatinine rise of up to about 30% after starting therapy is expected; a larger jump suggests renal artery stenosis or volume depletion.
| Feature | NSAIDs | ACE inhibitors / ARBs | Calcineurin inhibitors |
|---|---|---|---|
| Vessel effect | Afferent constriction (loss of prostaglandins) | Efferent dilation (loss of angiotensin II) | Afferent constriction (more endothelin and thromboxane, less NO) |
| RPF, GFR, FF | RPF ↓, GFR ↓, FF unchanged | RPF ↑, GFR ↓, FF ↓ | RPF ↓, GFR ↓ |
| High-risk setting | Low effective volume | Renal artery stenosis | High trough levels, CYP3A4 inhibitors |
| Electrolytes | Hyperkalemia, Na+ retention | Hyperkalemia | Hyperkalemia, hypomagnesemia, hyperuricemia |
Calcineurin inhibitors. Cyclosporine and tacrolimus cause dose-related, reversible afferent vasoconstriction; chronic exposure leaves arteriolar hyalinosis and striped interstitial fibrosis with tubular atrophy, plus hypertension. CYP3A4 inhibitors (azoles, macrolides, grapefruit juice) raise their levels and precipitate toxicity, whereas inducers such as rifampin lower levels and risk rejection.
Contrast and osmotic agents. Iodinated contrast constricts renal vessels, leaving the medulla hypoxic, and is directly toxic to tubular cells. Creatinine rises within 24–72 hours, usually without oliguria, and typically recovers. Risk is greatest with CKD (especially diabetic), volume depletion and large doses; isotonic IV fluids are the main prevention, and metformin is held in patients at risk of AKI because of lactic acidosis. Mannitol, sucrose-containing IVIG and hydroxyethyl starch cause osmotic nephrosis: swollen, vacuolated proximal tubular cells with AKI.
Direct tubular toxins
| Toxin | Mechanism | Signature | Prevention |
|---|---|---|---|
| Aminoglycosides | Megalin uptake into proximal tubule lysosomes; phospholipidosis (myeloid bodies) | Nonoliguric ATN after about 5–7 days; K+ and Mg2+ wasting; ototoxicity | Once-daily dosing; avoid vancomycin and loop diuretics; keep volume replete |
| Amphotericin B | Sterol-binding pores in distal tubular membranes; afferent vasoconstriction | Distal (type 1) RTA, hypokalemia, hypomagnesemia, nephrogenic DI | Saline loading; liposomal formulation |
| Cisplatin | Accumulates in proximal tubule cells | Dose-dependent ATN; marked hypomagnesemia with refractory hypokalemia and hypocalcemia; ototoxicity, neuropathy | Saline hydration, magnesium, amifostine |
| Myoglobin | Heme-iron oxidant injury, pigment casts, NO scavenging with vasoconstriction | Tea-colored urine, heme-positive dipstick without RBCs, CK often >5,000 U/L, hyperkalemia, hyperphosphatemia | Aggressive IV fluids |
Aminoglycosides. Uptake through megalin is saturable, so once-daily dosing (a high peak, then a long drug-free interval) is less nephrotoxic than divided dosing. Necrotic tubular cells slough into muddy brown granular casts; long courses and volume depletion add risk.
Rhabdomyolysis. Statins, especially combined with fibrates such as gemfibrozil, plus cocaine, alcohol and crush injury, are classic triggers. Hemoglobinuria from intravascular hemolysis gives the same heme-positive, RBC-negative dipstick, but with low haptoglobin and pink plasma rather than a huge CK.
Proximal tubulopathy, interstitial nephritis and glomerular disease
Fanconi syndrome. Tenofovir disoproxil fumarate enters proximal cells through OAT1 and damages their mitochondria; ifosfamide's metabolite chloroacetaldehyde injures the same cells, especially in children; expired, degraded tetracyclines are a classic cause. The result is glycosuria with normal blood glucose, aminoaciduria, phosphaturia (osteomalacia), hypouricemia and proximal (type 2) RTA. Tenofovir alafenamide reaches lower plasma levels and is far less nephrotoxic.
Acute interstitial nephritis. An idiosyncratic, T-cell–mediated hypersensitivity fills the interstitium with lymphocytes and eosinophils days to weeks after exposure. Culprits are penicillins (classically methicillin; also nafcillin), cephalosporins, sulfonamides (including sulfonamide diuretics), rifampin, PPIs, NSAIDs and allopurinol. Fever, rash, eosinophilia, sterile pyuria, WBC casts and eosinophiluria accompany a rising creatinine, although the full triad appears in a minority. Treatment is stopping the drug, with or without glucocorticoids. Toxic ATN, by contrast, is dose-dependent, systemically bland and marked by muddy brown casts.
Glomerular and papillary injury. NSAIDs can cause minimal change disease with interstitial nephritis (nephrotic syndrome plus AKI) and occasionally membranous nephropathy; penicillamine and gold are classic causes of membranous nephropathy. Proteinuria usually remits after the drug is stopped. Chronic analgesic abuse (phenacetin, combination analgesics, NSAIDs) causes papillary necrosis and chronic interstitial nephritis and raises the risk of urothelial carcinoma.
Crystal nephropathy
Drugs. Poorly soluble drugs precipitate in tubules when urine is concentrated or acidic: IV acyclovir (birefringent needles), sulfonamides, indinavir and high-dose methotrexate. Hydration and dose adjustment prevent most cases. For methotrexate, the urine is alkalinized, leucovorin bypasses DHFR to rescue normal cells, and glucarpidase (carboxypeptidase G2) cleaves the drug when levels stay toxic.
Ethylene glycol. Alcohol dehydrogenase starts its conversion to glycolate and oxalate, which binds calcium into envelope- and needle-shaped crystals, with anion-gap acidosis, an osmolar gap and hypocalcemia. Fomepizole blocks alcohol dehydrogenase.
Tumor lysis. Uric acid floods and precipitates in tubules. Prevention is hydration plus allopurinol (HLA-B*58:01 predicts severe hypersensitivity), or rasburicase, a recombinant urate oxidase that generates hydrogen peroxide and so causes hemolysis and methemoglobinemia in G6PD deficiency.
Match the protector: leucovorin rescues cells from methotrexate, glucarpidase destroys methotrexate, mesna binds acrolein, amifostine scavenges cisplatin radicals and fomepizole blocks alcohol dehydrogenase.
Collecting duct and creatinine pitfalls
Lithium. Lithium enters principal cells through ENaC, disrupts ADH signaling (adenylyl cyclase, GSK-3β) and down-regulates aquaporin-2, producing nephrogenic diabetes insipidus: dilute polyuria unresponsive to desmopressin. Amiloride blocks lithium entry. Thiazides reduce polyuria by mild volume contraction but raise lithium levels. Long-term lithium also causes chronic interstitial nephritis and hypercalcemia from hyperparathyroidism.
Blocked creatinine secretion. About 10–15% of urinary creatinine is secreted by proximal tubular organic cation transporters. Trimethoprim, cimetidine and dolutegravir block this, so serum creatinine rises modestly while true GFR, BUN and cystatin C are unchanged. Trimethoprim also blocks ENaC like amiloride and causes hyperkalemia.