Streptozocin
Zanosar · Nitrosourea alkylator
Classic proximal tubular toxin → Fanconi and dose-limiting AKI.
FANCATNLYTE
SevereOpen →
Oxazaphosphorine alkylator
Ifosfamide
Ifex · Ifos
The Fanconi-maker — its metabolite poisons proximal tubule mitochondria.
SevereOxazaphosphorine alkylator · approved 1988
SarcomaGerm-cellPediatric solid tumors
Signature kidney injury
Fanconi Syndrome
Representative incidence5%
Subclinical proximal tubulopathy is near-universal; overt Fanconi ~5% (range 1.4–30%), higher in young children.
Source: Skinner et al., J Clin Oncol 1993; Ensergueix et al., Nephrol Ther 2018
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeveritySevere
ReversibilityOften irreversible
Evidence0 refs
Nephron map
Proximal TubuleBulk reabsorption + drug uptake (OCT2, OATs)
Distal Tubule / Collecting Duct
Bladder / Urothelium
Fanconi Syndrome
Global failure of proximal tubule reabsorption — glucosuria, phosphaturia and acidosis, classically from ifosfamide.
Mechanism of kidney injury
The toxic metabolite chloroacetaldehyde damages proximal tubular mitochondria, collapsing reabsorption and producing Fanconi syndrome (glucosuria, aminoaciduria, phosphaturia, bicarbonaturia). Acrolein separately injures the bladder urothelium.
Clinical presentation
Hypophosphatemia (rickets/osteomalacia in children), proximal renal tubular acidosis, glucosuria with normal blood glucose, hypokalemia, low-molecular-weight proteinuria; hematuria from cystitis.
Onset
Acute tubulopathy during therapy; chronic Fanconi/CKD can emerge months–years later.
Reversibility
Often irreversible
Anticancer mechanism
Oxazaphosphorine prodrug activated by hepatic CYP450 into a DNA-alkylating mustard. Sarcomas, germ-cell and pediatric tumors.
Management
Electrolyte, phosphate and bicarbonate repletion; vitamin D for rickets; stop drug if severe.
Risk factors
- Young age (<5 yr)
- High cumulative dose
- Prior / concurrent cisplatin
- Reduced renal mass
Prevention
- Mesna (protects bladder, NOT tubules)
- Hydration
- Dose limitation
- Tubular-marker monitoring
Note · Mesna protects the bladder but not the tubule — a common point of confusion.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Bladder / Urothelium
Urine storage (outflow, not a nephron segment)
Injury signatures
Fanconi SyndromeAcute Tubular NecrosisElectrolyte WastingHemorrhagic Cystitis
Beyond the kidney
Class-level context for the major non-renal toxicities of oxazaphosphorine alkylators.
Hematologic
Cytopenias, thrombosis, TMA
- Myelosuppression; secondary malignancy risk
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- Ifosfamide encephalopathy (chloroacetaldehyde)
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- High-dose cyclophosphamide cardiotoxicity
Evidence
5 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkIfosfamide, mesna, and nephrotoxicity in children.Skinner R et al. · J Clin Oncol 1993 · PMID 8418231Landmark work establishing the nephrotoxicity grading and chloroacetaldehyde's role.PMIDIfosfamide, Fanconi's syndrome, and rickets.Pratt CB et al. · J Clin Oncol 1991 · PMID 1649270Prior platinum exposure raises risk of irreversible Fanconi syndrome.PMID[Ifosphamide nephrotoxicity].Ensergueix G et al. · Nephrol Ther 2018 · PMID 29606257Adult cohort showing severe, often irreversible proximal tubulopathy and CKD.PMIDPartial Fanconi syndrome induced by ifosfamide.Panezai MA et al. · Proc (Bayl Univ Med Cent) 2019 · PMID 30956588Case detailing partial Fanconi syndrome and proposed mechanism.PMIDConventional Chemotherapy Nephrotoxicity.Gupta S et al. · Adv Chronic Kidney Dis 2021 · PMID 35190107Review summarizing ifosfamide proximal tubulopathy and Fanconi syndrome.
Related agents
Other agents sharing the same signature kidney injury.
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