Ifosfamide
Ifex · Oxazaphosphorine alkylator
Chloroacetaldehyde → Fanconi syndrome.
FANCATNLYTE
SevereOpen →
Nitrosourea alkylator
Streptozocin
Zanosar · STZ
A glucose-mimicking nitrosourea that the proximal tubule eagerly takes up and pays for with Fanconi syndrome.
SevereNitrosourea alkylator · approved 1982
Metastatic pancreatic neuroendocrine (islet cell) carcinomaMalignant carcinoid tumors
Signature kidney injury
Fanconi Syndrome
Nephrotoxicity is the major dose-limiting toxicity; transient proteinuria, tubular dysfunction and azotemia are common and a sizable minority develop clinically significant renal impairment, though precise rates are not uniformly quantified. A single re-challenge after a stable course can still precipitate acute renal failure.
Source: Hall-Craggs et al., Hum Pathol 1982
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeveritySevere
ReversibilityPartially reversible
Evidence0 refs
Nephron map
Proximal TubuleBulk reabsorption + drug uptake (OCT2, OATs)
Distal Tubule / Collecting Duct
Fanconi Syndrome
Global failure of proximal tubule reabsorption — glucosuria, phosphaturia and acidosis, classically from ifosfamide.
Mechanism of kidney injury
GLUT2-mediated uptake concentrates the drug in S1-S3 proximal tubular cells, where alkylation and NAD+ depletion produce tubular cell injury and a proximal (type II) renal tubular acidosis / Fanconi picture - urinary wasting of phosphate, potassium, bicarbonate, glucose and amino acids. Defective tubular acidification is demonstrable functionally. Progressive tubular necrosis, squamous metaplasia and tubulointerstitial damage with azotemia follow cumulative dosing.
Clinical presentation
Proteinuria is typically the earliest sign, followed by glycosuria with normal blood glucose, aminoaciduria, hypophosphatemia, hypokalemia, hypouricemia, type II RTA, and rising creatinine. Abrupt AKI can follow a single additional dose after a previously tolerated course.
Onset
Within weeks of therapy; worsens with cumulative dose; abrupt AKI possible on re-challenge.
Reversibility
Partially reversible
Anticancer mechanism
Glucosamine-nitrosourea that alkylates DNA (and depletes NAD+ via PARP activation) and is preferentially taken up by GLUT2-expressing cells, the basis of both its islet-cell selectivity and its proximal tubular toxicity. Used for metastatic islet cell (pancreatic neuroendocrine) tumors and malignant carcinoid.
Management
Discontinue or reduce dose at the first sign of tubular proteinuria or falling GFR; supportive correction of electrolytes, phosphate and acidosis. Early injury may stabilize, but advanced damage can be irreversible and progress to chronic kidney disease.
Risk factors
- High cumulative dose
- Pre-existing renal impairment
- Volume depletion
- Concurrent nephrotoxins
- Re-challenge after a treatment interval
Prevention
- Aggressive hydration
- Check urine protein before each dose and hold for significant proteinuria
- Avoid concomitant nephrotoxins
- Dose reduction for renal dysfunction; consider divided/lower scheduling
Note · Proteinuria monitoring before each cycle is the classic safeguard; the proximal tubular/Fanconi signature is well described in onconephrology reviews and pathology series.
Clinical depth
Renal dose adjustment
Reduce dose and lengthen interval for impaired renal function; hold for new or worsening proteinuria or rising creatinine. Modern reviews emphasize scheduling (lower per-dose, fractionated) to cap cumulative tubular exposure in pNET.
Dialyzability & ESKD dosing
Small, renally cleared molecule; specific HD removal data are limited and it is rarely used in ESKD. Avoid in significant renal impairment rather than relying on dialytic clearance.
Differential diagnosis
Fanconi physiology (glycosuria with normal glucose, hypophosphatemia, hypouricemia, type II RTA, low-molecular-weight proteinuria) distinguishes streptozocin tubulopathy from glomerular proteinuria and from prerenal azotemia. The combination of euglycemic glycosuria plus phosphaturia is the fingerprint.
Monitoring
- Quantitative urine protein before every dose (hold for significant proteinuria)
- Serum creatinine, phosphate, potassium, bicarbonate each cycle
- Urine glucose / serum glucose discordance (glycosuria with euglycemia)
Key trials & series
- Hall-Craggs Hum Pathol 1982 - classic clinical AKI-on-re-challenge case with tubular pathology
- Fennell & Falls Clin Nephrol 1981 - functional proof of the tubular acidification defect
- Fazio Cancer Treat Rev 2026 - modern pNET scheduling to minimize nephrotoxicity
Clinical pearls
- Check a urine protein BEFORE each dose - rising proteinuria is the earliest, most actionable warning.
- A single re-challenge dose after a stable course can trigger abrupt acute renal failure; do not assume prior tolerance protects the kidney.
- The same GLUT2 uptake that makes it islet-selective makes the proximal tubule the target organ.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Fanconi SyndromeAcute Tubular NecrosisElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of nitrosourea 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
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkAcute renal failure and renal tubular squamous metaplasia following treatment with streptozotocin.Hall-Craggs M et al. · Hum Pathol 1982 · PMID 6281169Classic clinical case: AKI after re-challenge with proximal tubular morphologic injury.PMIDStreptozotocin nephrotoxicity: studies on the defect in renal tubular acidification.Fennell JS et al. · Clin Nephrol 1981 · PMID 6260405Documents the proximal (type II) renal tubular acidification defect.PMIDStreptozotocin revisited: Pharmacological determinants supporting new scheduling strategies in neuroendocrine tumours.Fazio N et al. · Cancer Treat Rev 2026 · PMID 42061024Modern review of renal elimination and scheduling to minimize nephrotoxicity in pNET.PMIDComparative nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) and chlorozotocin: functional-structural correlations in the Fischer 344 rat.Kramer RA et al. · Toxicol Appl Pharmacol 1986 · PMID 2937179Mechanistic proximal tubular necrosis from a streptozocin-class chloroethyl-nitrosourea.PMIDSequential morphologic analysis of the nephrotoxicity produced in rats by single doses of chlorozotocin.Dees JH et al. · Toxicol Pathol 1986 · PMID 2945250Dose-response proximal tubular/cortical necrosis in the streptozocin class.PMIDAnticancer drug-induced kidney disorders.Kintzel PE · Drug Saf 2001 · PMID 11219485Details streptozocin proximal tubular toxicity: proteinuria, RTA, glucosuria, aminoaciduria, hypophosphatemia.PMIDNephrotoxicity of semustine.Weiss RB et al. · Cancer Treat Rep 1983 · PMID 6360348Class context for cumulative dose-related nitrosourea nephrotoxicity.
Related agents
Other agents sharing the same signature kidney injury.
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