Melphalan
Alkeran · Alkylator
SIADH in high-dose myeloma conditioning; renally cleared.
SIADHLYTE
MildOpen →
Oxazaphosphorine alkylator
Cyclophosphamide
Cytoxan · Cyclo
The water-retainer — a vasopressin-independent drive to hold on to free water.
MildOxazaphosphorine alkylator · approved 1959
LymphomaBreastAutoimmune diseaseConditioning
Signature kidney injury
SIADH / Hyponatremia
Dose-related hyponatremia (not reliably quantified); hemorrhagic cystitis ~5–20%, lower with mesna prophylaxis.
Source: Kim et al., Am J Physiol Renal Physiol 2015; Gupta et al., 2021
Mechanism of kidney injury
Up-regulates aquaporin-2 in the collecting duct independent of vasopressin, retaining free water — dangerous because large hydration volumes are co-administered to protect the bladder. The acrolein metabolite causes hemorrhagic cystitis.
Clinical presentation
Acute hyponatremia within hours of high-dose infusion, low serum osmolality with inappropriately concentrated urine; hematuria from cystitis.
Onset
Hyponatremia within hours; cystitis acute.
Reversibility
Reversible
Anticancer mechanism
Prodrug converted to phosphoramide mustard, cross-linking DNA. Lymphomas, breast cancer, autoimmune disease and transplant conditioning.
Management
Careful fluid management and sodium correction; mesna, hydration and bladder irrigation for cystitis.
Risk factors
- High-dose IV regimens
- Concurrent hypotonic fluids
Prevention
- Use isotonic rather than hypotonic fluids
- Monitor sodium
- Mesna + hydration for cystitis
Note · Less urotoxic than ifosfamide; the SIADH incidence is not formally quantified.
Where it strikes
Nephron segments
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Bladder / Urothelium
Urine storage (outflow, not a nephron segment)
Injury signatures
SIADH / HyponatremiaHemorrhagic 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
4 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkCyclophosphamide-induced vasopressin-independent activation of aquaporin-2 in the rat kidney.Kim S et al. · Am J Physiol Renal Physiol 2015 · PMID 26109089Mechanism of the vasopressin-independent hyponatremia.PMIDDrug-induced dilutional hyponatremia.Moses AM et al. · N Engl J Med 1974 · PMID 4607502Classic NEJM review establishing cyclophosphamide as a cause of dilutional hyponatremia.PMIDCyclophosphamide induced water intoxication in a woman with Sjögren's syndrome.Spital A et al. · J Rheumatol 1997 · PMID 9415661Life-threatening hyponatremia even after low-dose IV cyclophosphamide.PMIDAnticancer drug-induced kidney disorders.Kintzel PE et al. · Drug Saf 2001 · PMID 11219485Context on cyclophosphamide renal effects (cystitis, hyponatremia).