Cyclophosphamide
Cytoxan · Oxazaphosphorine alkylator
Vasopressin-independent hyponatremia; hemorrhagic cystitis.
SIADHCYST
MildOpen →
Alkylator
Temozolomide
Temodar · TMZ
The glioblastoma standard that is kind to the kidney but can occasionally drop the sodium.
MildAlkylator · approved 1999
Glioblastoma and anaplastic astrocytomaOther malignant gliomasSelected neuroendocrine tumors (off-label combinations)
Signature kidney injury
SIADH / Hyponatremia
Generally renally well tolerated; renal clearance of the parent drug is a minor elimination pathway and dedicated PubMed searches for temozolomide nephrotoxicity/SIADH return essentially no indexed series. Hyponatremia/SIADH is an occasional, case/toxicity-table-level event, and rare acute interstitial nephritis has been reported in combination contexts.
Source: Pouratian et al., J Neurooncol 2006
Mechanism of kidney injury
Direct tubular toxicity is not characteristic; the parent drug is largely eliminated by spontaneous chemical degradation with only a minor renal pathway, underpinning its renal safety. The relevant renal-electrolyte signal is occasional SIADH-type free-water retention with dilutional hyponatremia, compounded by CNS disease, nausea/vomiting and co-medications. A rare case of acute interstitial nephritis (with nephrogenic diabetes insipidus) has been described alongside trimethoprim-sulfamethoxazole.
Clinical presentation
Hyponatremia, usually mild and detected on routine monitoring; serum creatinine typically preserved. Rarely, AIN with a rising creatinine and, in the reported case, nephrogenic diabetes insipidus.
Onset
During cycles of therapy; variable.
Reversibility
Reversible
Anticancer mechanism
Oral imidazotetrazine prodrug that spontaneously hydrolyzes to the active methylating species MTIC, methylating DNA at O6- and N7-guanine; cytotoxicity depends on MGMT status and mismatch repair. Standard of care for glioblastoma and other malignant gliomas, and used in some neuroendocrine tumors.
Management
Manage hyponatremia by addressing the cause and fluid restriction; rarely requires drug interruption. For the rare AIN, withdraw the likely offender(s) and treat supportively. Renal function is generally unaffected.
Risk factors
- CNS tumor/edema and concurrent SIADH-promoting drugs
- Nausea/vomiting with hypotonic fluid intake
- Concomitant trimethoprim-sulfamethoxazole (PJP prophylaxis) as an AIN co-factor
- Older age
Prevention
- Periodic electrolyte monitoring
- Avoid unnecessary hypotonic fluids
- Review co-medications that promote SIADH or AIN
Note · Renal injury is not a hallmark of temozolomide; the conservative renal-relevant signals are hyponatremia and a single reported AIN case - the near-absence of indexed nephrotoxicity literature reflects genuine renal safety, not a search gap.
Clinical depth
Renal dose adjustment
No renal dose adjustment is established; temozolomide pharmacokinetics are dominated by non-renal chemical degradation. Standard dosing is used across normal-to-mild renal impairment, with caution and limited data in severe impairment/dialysis.
Dialyzability & ESKD dosing
Short half-life with predominantly non-renal (spontaneous hydrolysis) elimination; not a drug managed by dialysis. Limited ESKD data, but renal clearance contributes little to total elimination.
Differential diagnosis
Hyponatremia: SIADH (euvolemic, concentrated urine, natriuresis) vs cerebral salt wasting (hypovolemic, high urine output) - an important CNS-tumor distinction. A rising creatinine should prompt review for AIN from co-medications rather than attribution to temozolomide itself.
Monitoring
- Periodic serum sodium/electrolytes, especially with SIADH-promoting co-medications
- Serum creatinine if a new nephrotoxin (e.g., TMP-SMX) is co-prescribed
- CBC (myelosuppression is the dose-limiting toxicity, not renal injury)
Key trials & series
- Pivotal Stupp glioblastoma regimen (radiotherapy plus concomitant/adjuvant temozolomide) as the principal exposure context
- Phase I PK trials (Dhodapkar Clin Cancer Res 1997; Brock Cancer Res 1998) showing minor renal elimination
Clinical pearls
- Temozolomide is genuinely renally safe - myelosuppression, not nephrotoxicity, is the toxicity to watch.
- When sodium falls in a glioma patient, distinguish SIADH from cerebral salt wasting before restricting fluids.
- A creatinine bump on temozolomide is more likely from a co-prescribed nephrotoxin (e.g., TMP-SMX) than from the drug.
Where it strikes
Nephron segments
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Injury signatures
SIADH / HyponatremiaElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of 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
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkAcute interstitial nephritis and nephrogenic diabetes insipidus following treatment with sulfamethoxazole-trimethoprim and temozolomide.Athavale A et al. · Nephrology (Carlton) 2020 · PMID 32935422Only dedicated temozolomide renal case report (AIN with nephrogenic diabetes insipidus).PMIDToxicity and efficacy of protracted low dose temozolomide for the treatment of low grade gliomas.Pouratian N et al. · J Neurooncol 2006 · PMID 17082887Lists hyponatremia among high-grade toxicities of temozolomide therapy.PMIDPhase I trial of temozolomide (NSC 362856) in patients with advanced cancer.Dhodapkar M et al. · Clin Cancer Res 1997 · PMID 9815788PK trial showing renal clearance of parent drug is a minor elimination pathway.PMIDPhase I trial of temozolomide using an extended continuous oral schedule.Brock CS et al. · Cancer Res 1998 · PMID 9766665PK/elimination; dose-limiting toxicity is myelosuppression, not renal injury.PMIDConventional Chemotherapy Nephrotoxicity.Gupta S et al. · Adv Chronic Kidney Dis 2021 · PMID 35190107Onconephrology review of chemo AKI/electrolyte disturbances framing low-renal-risk agents.PMIDAnticancer drug-induced kidney disorders.Kintzel PE · Drug Saf 2001 · PMID 11219485Onconephrology framework for alkylator electrolyte effects.