Cisplatin
Platinol · Platinum agent
Proximal tubular ATN + magnesium wasting; the archetype.
ATNLYTEPRE
SevereOpen →
Alkylating agent (methylmelamine)
Altretamine (hexamethylmelamine)
Hexalen · ALT
Oral melamine antineoplastic for ovarian cancer; dose-limiting toxicities are neurologic and GI, with only mild, reversible renal changes reported.
Mildclassic-cytotoxic · approved 1990
Persistent or recurrent ovarian cancer after first-line platinum/alkylator-based therapy (single-agent salvage)
Signature kidney injury
Acute Tubular Necrosis
Altretamine is not regarded as substantially nephrotoxic. Mild, generally reversible elevations in serum creatinine have been noted in trials, but the dose-limiting toxicities are gastrointestinal (nausea/vomiting), neurologic (peripheral and central neurotoxicity) and hematologic. No reliable renal incidence figure is established, and reported renal changes are confounded by frequent combination with cisplatin.
Source: Lee et al., Drugs 1995 (renal effects mild, confounded by cisplatin); not quantified
Mechanism of kidney injury
No characteristic, well-defined tubular lesion is attributed to altretamine. Mild reversible creatinine rises may reflect modest, transient tubular effects of reactive metabolites, but because altretamine has frequently been studied alongside cisplatin, attributing renal changes to altretamine alone is difficult. The predominant organ toxicities are neurologic and gastrointestinal.
Clinical presentation
Usually no overt renal syndrome; at most a mild, reversible creatinine increase. Clinically dominant features are nausea/vomiting, peripheral neuropathy and CNS symptoms, plus myelosuppression.
Onset
Any mild creatinine change tends to occur during cycles and to reverse after dosing; timing is not well defined.
Reversibility
Reversible
Anticancer mechanism
Methylmelamine that requires hepatic microsomal N-demethylation to generate reactive methylol and formaldehyde intermediates; these are thought to act as alkylating species damaging DNA, though it is not directly cross-resistant with classical alkylators.
Management
Manage any mild renal change supportively with attention to hydration and antiemesis; dose modification is generally driven by neurologic and GI toxicity rather than kidney function. No specific renal antidote is required.
Risk factors
- Concurrent or prior cisplatin exposure (the dominant nephrotoxic confounder)
- Pre-existing kidney impairment
- Volume depletion from drug-induced vomiting
- Older age and reduced renal reserve
Prevention
- Maintain hydration, especially given prominent emetogenicity
- Antiemetic prophylaxis to prevent prerenal volume depletion
- Monitor renal function periodically
- Account for cisplatin co-toxicity when interpreting creatinine changes
Note · Neurotoxicity (peripheral neuropathy, mood/CNS changes) and refractory nausea/vomiting are the practical limits to therapy; pyridoxine has been studied for neurotoxicity. Renal effects are a minor part of the safety profile.
Clinical depth
Renal dose adjustment
No established renal-specific dosing algorithm; altretamine is extensively hepatically metabolized with low urinary excretion of unchanged drug. Dose reductions and interruptions are primarily for GI, neurologic and hematologic toxicity.
Dialyzability & ESKD dosing
Not characterized as dialyzable; high lipid solubility, extensive hepatic metabolism and tissue distribution make significant dialytic removal unlikely. Dialysis is not used for drug clearance.
Differential diagnosis
Distinguish mild altretamine-associated creatinine rise from cisplatin nephrotoxicity, prerenal azotemia due to vomiting, and obstruction by pelvic/ovarian disease. True intrinsic altretamine nephrotoxicity is mild and not well established as an independent entity.
Monitoring
- Serum creatinine periodically
- Neurologic examination for peripheral/central neurotoxicity
- CBC for myelosuppression
- Assessment of nausea/vomiting and volume status
Key trials & series
- Phase II single-agent altretamine trials in recurrent/platinum-pretreated ovarian cancer (response rates ~14-33%), summarized in pharmacologic reviews (PMID 7641606, PMID 1905441)
Clinical pearls
- The dose-limiting toxicities of altretamine are neurologic and gastrointestinal, not renal.
- Reported creatinine elevations are mild, reversible, and confounded by frequent cisplatin co-administration.
- Aggressive antiemesis and hydration prevent the most likely renal problem, prerenal volume depletion from vomiting.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Acute Tubular Necrosis
Beyond the kidney
Class-level context for the major non-renal toxicities of alkylating agent (methylmelamine)s.
Ophthalmic
Keratopathy, uveitis, retinopathy
- Visual disturbance (crizotinib)
Hepatic / Liver
Transaminitis, hepatitis, VOD/SOS
- Transaminitis
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- CNS effects (lorlatinib)
Evidence
3 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkAltretamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cancer chemotherapy.Lee CR et al. · Drugs 1995 · PMID 7641606Comprehensive pharmacology review describing altretamine's GI, neurologic and hematologic dose-limiting toxicities and noting that incidence assessment is complicated by concurrent cisplatin use.PMIDAltretamine.Hansen LA et al. · DICP 1991 · PMID 1905441Drug review summarizing altretamine pharmacology, ovarian cancer activity, and a toxicity profile dominated by GI, hematologic and neurotoxic effects rather than nephrotoxicity.LandmarkAcute Kidney Injury in Patients with Cancer.Rosner MH et al. · N Engl J Med 2017 · PMID 28467867Onconephrology review providing context for distinguishing drug-related AKI from prerenal and co-medication (cisplatin) effects in patients with gynecologic cancer.