Cisplatin
Platinol · Platinum agent
Proximal tubular ATN + magnesium wasting; the archetype.
ATNLYTEPRE
SevereOpen →
Platinum agent
Nedaplatin
Aqupla · NDP
A second-generation platinum engineered to spare the kidney that cisplatin punishes.
ModerateSecond-generation platinum · approved 1995
Head and neck squamous cell carcinomaNon-small cell and small cell lung cancerEsophageal carcinomaCervical and ovarian cancerGerm cell tumors
Signature kidney injury
Acute Tubular Necrosis
Lower renal cortical platinum accumulation and less frequent nephrotoxicity than equimolar cisplatin; dose-related proximal tubular injury still occurs, but high-grade AKI is uncommon and not robustly quantified in the renal literature. Myelosuppression (notably thrombocytopenia), not nephrotoxicity, is the dose-limiting toxicity.
Source: Kawai et al., Biol Pharm Bull 2005
Mechanism of kidney injury
Platinum is taken up into S3-segment proximal tubular epithelium (organic cation/OCT2-type and passive transport), where it binds nuclear and mitochondrial DNA and proteins, generating reactive oxygen species and triggering apoptosis/necrosis. The cardinal pharmacologic point is quantitative: at equitoxic systemic exposure, nedaplatin reaches roughly half the renal cortical platinum concentration of cisplatin, so tubular necrosis, urinary NAG, and glycosuria are correspondingly milder. Magnesium and other electrolyte wasting follows tubular damage but is less pronounced than with cisplatin.
Clinical presentation
Rise in serum creatinine, increased urinary N-acetyl-beta-D-glucosaminidase and glucosuria; electrolyte wasting (hypomagnesemia, hypokalemia) can occur but is generally milder than with cisplatin. In renal dysfunction or ascites, free-platinum exposure is prolonged.
Onset
Days after dosing; cumulative with repeated cycles.
Reversibility
Partially reversible
Anticancer mechanism
Cytotoxic platinum(II) compound (cis-diammine-glycolato-platinum) that, after aquation, forms intrastrand 1,2-d(GpG) DNA cross-links, blocking replication and transcription and triggering apoptosis. Its glycolate leaving group gives more favorable aqueous handling and lower tissue retention than cisplatin. Used mainly in Japan for head and neck, esophageal, lung, cervical, ovarian, and germ cell cancers.
Management
Hold or dose-reduce for rising creatinine, correct volume and electrolytes (magnesium, potassium), and provide supportive care. Substituting nedaplatin into platinum regimens has been used to deliver therapy in patients with impaired renal function or prior cisplatin nephrotoxicity.
Risk factors
- Pre-existing renal impairment
- Volume depletion
- Prior cisplatin exposure / high cumulative platinum dose
- Concomitant nephrotoxins
- Ascites or third-spacing (prolonged free-platinum exposure)
Prevention
- Adequate hydration (>=1000 mL infusion accompanies dosing)
- Avoid concurrent nephrotoxins
- Dose by renal function and monitor creatinine/electrolytes
Note · Marketed largely in Japan; the renal-sparing advantage over cisplatin rests on accumulation/pharmacology data and small clinical series rather than large randomized nephrotoxicity trials.
Clinical depth
Renal dose adjustment
No formally validated CrCl-banded schema in Western labeling; in practice dose is reduced and free-platinum AUC monitored when CrCl is low. Reduce dose / extend interval for baseline renal impairment and avoid stacking with cisplatin-level cumulative platinum.
Dialyzability & ESKD dosing
Free (unbound) platinum is dialyzable like other small-molecule platinums; protein-bound platinum is not. Timing of any platinum agent around hemodialysis should be individualized with pharmacy. Renal clearance is a major elimination route, so ESKD prolongs exposure.
Differential diagnosis
Distinguish platinum ATN (bland-to-granular sediment, tubular proteinuria, Mg wasting, days after dosing) from prerenal azotemia (low FeNa, responds to volume) and from cisplatin carryover injury. Persistent isolated hypomagnesemia favors platinum tubulopathy over prerenal physiology.
Monitoring
- Serum creatinine and electrolytes (Mg, K) each cycle
- Platelet count and CBC (dose-limiting thrombocytopenia)
- Urinalysis for glycosuria / tubular proteinuria when concerned
Key trials & series
- Japanese phase II program (Ota, Gan To Kagaku Ryoho 1996) establishing 80-100 mg/m2 dosing and the reduced GI/renal toxicity signal
- Nedaplatin-vindesine vs cisplatin-vindesine randomized NSCLC comparison showing significantly less nephro/GI toxicity
Clinical pearls
- The renal advantage is a tissue-accumulation phenomenon: nedaplatin deposits less platinum in renal cortex than cisplatin at comparable systemic exposure.
- Thrombocytopenia, not AKI, is the dose-limiting toxicity - watch platelets as closely as creatinine.
- Useful as a platinum substitute when cisplatin nephrotoxicity precludes further cisplatin, but it is not nephrotoxicity-free.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Acute Tubular NecrosisElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of platinum agents.
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- Peripheral neuropathy (esp. oxaliplatin) and ototoxicity (cisplatin)
Hematologic
Cytopenias, thrombosis, TMA
- Myelosuppression — thrombocytopenia prominent with carboplatin
Gastrointestinal
Diarrhea, colitis, mucositis, perforation
- Severe nausea and vomiting
Evidence
8 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkRelationship between cisplatin or nedaplatin-induced nephrotoxicity and renal accumulation.Kawai Y et al. · Biol Pharm Bull 2005 · PMID 16079479Shows lower renal cortical platinum accumulation underlies reduced nephrotoxicity vs cisplatin.PMIDComparative nephrotoxicity of Cisplatin and nedaplatin: mechanisms and histopathological characteristics.Uehara T et al. · J Toxicol Pathol 2011 · PMID 22272048Review of the molecular and histopathologic basis for nedaplatin's reduced tubular toxicity.PMIDComparative analysis of gene expression between renal cortex and papilla in nedaplatin-induced nephrotoxicity in rats.Uehara T et al. · Hum Exp Toxicol 2007 · PMID 18025048Characterizes tubular necrosis and regeneration signatures in nedaplatin nephrotoxicity.PMIDChronotoxicity of nedaplatin in rats.Cui Y et al. · Chronobiol Int 2004 · PMID 15470957Links renal cortical platinum accumulation directly to degree of kidney injury.PMIDThe effect of fosfomycin on nedaplatin-induced nephrotoxicity in rats.Yoshiyama Y et al. · J Infect Chemother 2005 · PMID 15729482Cytoprotection model reducing cortical platinum, BUN, creatinine and urinary NAG.PMIDLess nephrotoxicity of paclitaxel and ifosfamide plus nedaplatin for refractory or relapsed germ cell tumors in patients with impaired renal function.Shiraishi T et al. · Int J Urol 2019 · PMID 31701563Clinical use as a less nephrotoxic platinum option in renal dysfunction.PMID[Nedaplatin].Ota K · Gan To Kagaku Ryoho 1996 · PMID 8712835Phase I/II program; reduced nephrotoxicity and GI toxicity with thrombocytopenia as DLT.PMIDAnticancer drug-induced kidney disorders.Kintzel PE · Drug Saf 2001 · PMID 11219485Onconephrology review of platinum and related agent renal toxicity.