Cisplatin Toxicity — Comprehensive Research Report

Prepared: 2026-09-01 · Target: Cisplatin Toxicity · MONDO: MONDO:0027664 (label verified live against OLS4: cisplatin toxicity) · Category: Complex

Provenance note, stated up front. Every PMID, quotation, and ontology identifier below was retrieved during this session from NCBI E-utilities, the EBI Ontology Lookup Service, the HGNC REST API, or the dismech term caches in this worktree. Where I could not verify something, I say so in place rather than filling the gap. I did not verify ICD-10, ICD-11, SNOMED CT, or LOINC codes against their authorities.

1. Disease Information

What it is

Cisplatin toxicity is not a disease of the patient's own biology. It is the injury a drug does to normal tissue while it is doing its intended work on a tumour. The initiating lesion is the same in tumour and in host: platinum bound to DNA.

The MeSH scope note for Cisplatin (D002945, introduced 1984, CAS registry Q20Q21Q62J) states the chemistry plainly:

"An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle." — MeSH descriptor D002945 (retrieved 2026-09-01)

Dasari & Tchounwou give the same mechanism as a pharmacological claim:

"Its mode of action has been linked to its ability to crosslink with the purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA damage, and subsequently inducing apoptosis in cancer cells." — PMID:25058905, Eur J Pharmacol 2014;740:364-78

The syndrome is a cluster of organ-specific toxicities, not one lesion. The 2024 comprehensive review names the dose-limiting set:

"its clinical utility is hampered by its dose-limiting toxicities, including nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression." — PMID:39423903, Eur J Pharm Sci 2024;203:106939

A 2023 ototoxicity review adds the fuller list:

"its clinical use is limited by severe side effects, including ototoxicity, nephrotoxicity, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, and retinal toxicity." — PMID:38003734, Int J Mol Sci 2023;24(22):16545

Identifiers

Synonyms

Cisplatin-induced nephrotoxicity (CIN); cisplatin-associated acute kidney injury (CP-AKI); cisplatin-induced ototoxicity (CIO); cisplatin-induced peripheral neuropathy (CIPN, when platinum-specific); platinum toxicity; cis-diamminedichloroplatinum(II) toxicity. The MeSH entry terms for the drug include cis-Platinum, Platinol, NSC-119875, cis-Dichlorodiammineplatinum(II).

Data derivation

Both. Much of the epidemiology below is individual-patient EHR-derived — the BMJ risk-score study drew on 24,717 adults across six US academic cancer centres (PMID:38538012). The pharmacogenomic and survivorship data come from aggregated cohorts (the Platinum Study, PanCareLIFE, Canadian Pharmacogenomics Network for Drug Safety). Mechanism is almost entirely preclinical, and the reviews say so.

2. Etiology

Primary cause

One cause, and it is iatrogenic: administration of cisplatin. There is no cisplatin toxicity without cisplatin exposure. Everything else on this page is a modifier of dose, of tissue exposure, or of cellular tolerance.

The exposure is cumulative and dose-dependent. Ototoxicity in particular tracks cumulative dose in a way that is visible even in self-report:

"Tinnitus was also significantly related to age at survey completion (OR = 1.79; P = 0.003) and cumulative cisplatin dose (OR = 5.17; P < 0.001)." — PMID:36637632, J Cancer Surviv 2023;17(1):27-39

Risk factors — clinical and demographic

The BMJ 2024 derivation cohort identified an independently associated set that is worth reproducing exactly, because it is the best-powered such list available:

"Each of the following factors were independently associated with CP-AKI in the derivation cohort: age, hypertension, diabetes mellitus, serum creatinine level, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose." — PMID:38538012, BMJ 2024;384:e077169

Pre-existing organ impairment is the other axis:

"The risk of developing cisplatin-induced toxicity could be related to pre-existing conditions, including kidney disease, hearing impairment, neuropathy, impaired liver function, and other comorbidities." — PMID:39423903

For hearing specifically, the Platinum Study found cardiovascular and familial risk factors mattered alongside dose:

"Risk factors for hearing loss included age at survey completion (OR = 1.57; P = 0.036), hypercholesterolemia (OR = 3.45; P = 0.007), cumulative cisplatin dose (OR = 1.94; P = 0.049), and family history of hearing loss (OR = 2.87; P = 0.071)." — PMID:36637632

Age is bidirectional and matters differently by organ. Very young children are at highest ototoxicity risk; older adults are at highest AKI risk. Both directions appear in the sources above.

Genetic risk factors

The Canadian Pharmacogenomics Network for Drug Safety 2022 update is the authoritative synthesis. It graded 40 reports across 47 independent populations and 24 genes:

"Considering GRADE criteria, genetic variants in 2 genes were strongly (ie, odds ratios ≥3) and consistently (ie, replication in ≥3 independent populations) predictive of cisplatin-induced ototoxicity. Specifically, an ACYP2 variant has been associated with ototoxicity in both children and adults, whereas TPMT variants are relevant in children." — PMID:37726872, Ther Drug Monit 2023;45(6):714-730

Two things follow, and the second is the one curators get wrong. First, only ACYP2 and TPMT clear the bar. Second, COMT does not — it was an early candidate and the review's own conclusion drops it to the "further research required" tier.

The Platinum Study GWAS adds signal that has not been replicated to the same standard:

"Hearing loss and TXNRD1, which plays a key role in redox regulation, showed borderline significance (p = 4.2 × 10-6) in gene-based analysis. rs62283056 in WFS1 previously found to be significantly associated with hearing loss (n = 511), was marginally significant in an independent replication cohort (p = 0.06; n = 606). Gene-based analyses identified significant associations between tinnitus and WNT8A (p = 2.5 × 10-6)." — PMID:35322580, Cancer Med 2022;11(14):2801-2816

The Brock consensus review frames the genetic architecture as three functional classes:

"Genes involved in drug transport, metabolism, and DNA repair regulate platinum toxicities." — PMID:22547603, J Clin Oncol 2012;30(19):2408-17

Gene table (HGNC IDs resolved live from rest.genenames.org or the dismech cache):

Protective factors

Genetic protective alleles: none established. The literature frames variants as susceptibility, not protection.

Environmental and pharmacological protection is where the field actually stands:

• Magnesium supplementation during hydration. A 2024 systematic review with meta-analysis of 11 retrospective studies: "A meta-analysis of 11 retrospective studies that examined magnesium supplementation during hydration showed that this treatment provided significant protection against CIN (OR = 0.22, 95% CI = 0.14 to 0.35)." — PMID:37530867, Clin Exp Nephrol 2024;28(1):1-12
• Dose is not the whole story for magnesium. A 2026 meta-analysis: "Magnesium supplementation showed an inhibitory effect on cisplatin-induced renal injury. The inhibitory effect of magnesium supplementation showed no difference among the three dose groups (<10 mEq, 10-<20 mEq, and ≥20 mEq)." — PMID:42652681, J Clin Med 2026;15(16):6278
• Sodium thiosulfate for hearing, in children — see §12.

Gene-environment interaction

The Platinum Study is the only source here with direct GxE-relevant data, and its findings are behavioural rather than molecular:

"In addition, hearing loss was positively associated with BMIs at clinical evaluation and nonwork-related noise exposure (>5 h/week). Tinnitus was positively associated with tobacco use, hypercholesterolemia, and noise exposure. We observed positive associations between peripheral neuropathy and persistent vertigo, tobacco use, and excess alcohol consumption." — PMID:35322580

Noise exposure stacking on a cisplatin-damaged cochlea is the clearest GxE candidate in the corpus. The genetic half of that interaction has not been tested against the environmental half in any study I found.

3. Phenotypes

Otologic

Cisplatin ototoxicity is bilateral, high-frequency-first, and permanent.

"Cisplatin-induced ototoxicity manifests as irreversible, bilateral, high-frequency sensorineural hearing loss in 40-60% of adults and in up to 60% of children." — PMID:38003734

"Platinum initially impairs hearing in the high frequencies and progresses to lower frequencies with increasing cumulative dose." — PMID:22547603

"Cisplatin chemotherapy causes permanent hearing loss in 40-80% of treated patients." — PMID:29162831, Nat Commun 2017;8(1):1654

Composite ototoxicity in a well-characterised adult survivor cohort:

"Of 145 TC survivors, 74% reported ototoxicity: 68% tinnitus; 59% hearing loss; and 52% reported both." — PMID:36637632

Quality-of-life impact is stated qualitatively in the reviews and I did not find an EQ-5D or SF-36 utility decrement specific to cisplatin ototoxicity:

"Hearing loss can lead to social isolation, depression, and cognitive decline in adults, and speech and language developmental delays in children." — PMID:38003734

Renal and electrolyte

The nephrotoxicity spectrum is explicitly broader than AKI:

"We also discuss the spectrum of nephrotoxicity, including acute and chronic impairment of kidney function, electrolyte disturbances, and thrombotic microangiopathy." — PMID:37182407, Semin Nephrol 2022;42(6):151341

Note the incidence discrepancy, and do not average it away. The BMJ figure (3–5%) is for severe CP-AKI defined as doubling of creatinine or dialysis within 14 days. The "up to one third" and "up to 20%" figures use looser definitions. These are different endpoints, not conflicting estimates.

Neurologic

"When comparing individual AHOs for EPX4 versus BEPX3, Raynaud phenomenon (11.6% v 21.4%; P < .01), peripheral neuropathy (29.2% v 21.4%; P = .02), and obesity (25.5% v 33.0%; P = .04) differed." — PMID:28240972, J Clin Oncol 2017;35(11):1211-1222

The three neurotoxicities travel together:

"Hearing loss, tinnitus, and peripheral neuropathy, accounting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension and poorer self-reported health." — PMID:35322580

Coasting — progression of neuropathy for weeks to months after the last dose — is a recognised feature of platinum neuropathy. I did not locate a primary citation for it in this session. Curate it only with a source you have read.

Haematologic and gastrointestinal

Other organ systems

Retinal toxicity (HP:0000488 Retinopathy; HP:0000551 Color vision defect) and optic neuropathy (HP:0001138) are named in PMID:38003734's side-effect list. Hepatotoxicity is likewise named there. Male infertility (HP:0003251) and azoospermia (HP:0000027) follow gonadal exposure in testicular cancer survivors — a survivorship burden documented in the Platinum Study series (PMID:28240972 reports adverse health outcome counts, though I did not extract per-phenotype gonadal figures).

Adverse health outcome burden, testicular cancer survivors, median 4.3 years post-chemotherapy:

"None, one to two, three to four, or five or more AHOs were reported by 20.4%, 42.0%, 25.1%, and 12.5% of TCSs, respectively." — PMID:28240972

4. Genetic/Molecular Information

There is no causal gene. The cause is a drug. Genetics here modifies susceptibility only, and the modification is real but modest outside the two strong ototoxicity loci.

• Causal genes: none. Do not curate relationship_type: CAUSATIVE for any gene on this entry.
• Susceptibility loci: ACYP2 (HGNC:180) and TPMT (hgnc:12014), per PMID:37726872. Curate these as SUSCEPTIBILITY.
• Variant classification: these are common susceptibility SNPs, not ACMG-classifiable pathogenic variants. ClinVar/ACMG framing does not apply.
• Somatic vs germline: the susceptibility variants are germline. The DNA lesion driving toxicity is an acquired chemical adduct, not a variant.
• Allele frequencies: not retrieved this session.
• Chromosomal abnormalities: not applicable to the toxicity phenotype. Secondary treatment-related myeloid neoplasms after platinum/etoposide regimens do carry cytogenetic lesions, but that is a distinct downstream disease and should be a separate entry if curated.

Epigenetics

The Nature Reviews Nephrology synthesis flags this as an emerging layer, and flags it as emerging rather than established:

"In addition, emerging evidence suggests a contribution of epigenetic changes to cisplatin-induced acute kidney injury and chronic kidney disease. Further research is needed to determine how these pathways are integrated and to identify the cell type-specific roles of critical molecules involved in regulated necrosis, inflammation and epigenetic modifications in cisplatin nephrotoxicity." — PMID:36229672

Curate this as a KNOWLEDGE_GAP discussion, not as a mechanism node.

5. Environmental Information

• The exposure is the drug. Route: intravenous. Cumulative dose is the dominant determinant. In SIOPEL 6 the dose was 80 mg/m² over 6 hours per course, six courses (PMID:29924955); in ACCL0431 the trigger threshold in the FDA-approval framing was cumulative cisplatin ≥200 mg/m².
• Infusion duration matters. ACCL0431 restricted to individual doses infused over ≤6 hours, and initially stratified randomisation by "age and duration of cisplatin infusion" (PMID:27914822). Shorter infusions concentrate peak exposure.
• Noise. Non-occupational noise exposure >5 h/week associated with hearing loss in survivors (PMID:35322580). This is the clearest modifiable environmental co-exposure.
• Tobacco and alcohol. Tinnitus associated with tobacco use; peripheral neuropathy with tobacco use and excess alcohol (PMID:35322580).
• Concomitant nephrotoxins. Aminoglycosides, NSAIDs, contrast, and proton pump inhibitors are all implicated. A 2024 prospective cohort reported PPIs increasing CP-AKI risk in nasopharyngeal carcinoma (PMID:39138312 — title verified, abstract not read this session).
• Cranial irradiation compounds ototoxicity; ACCL0431 added it as a stratification variable by protocol amendment (PMID:27914822).
• Infectious agents: not applicable.

ECTO binding. I did not find a suitable ECTO exposure term for therapeutic cisplatin administration in this session. Per the dismech environmental-term convention, leaving exposure_term.term unbound with a notes: line recording the search is the correct outcome if a search confirms no term exists. Do not stretch a general "exposure to platinum" term onto a therapeutic infusion without checking it.

6. Mechanism / Pathophysiology

The causal chain

Branch point at step 3. The chain is shared as far as intracellular platinum accumulation, then diverges by organ because the transporters, the repair capacity, and the cell death programs differ.

1. Cisplatin is administered intravenously and circulates as the neutral dichloride complex in high-chloride plasma. The low intracellular chloride concentration then drives aquation, converting cisplatin to a reactive positively charged aquo species. Leads to a DNA-reactive electrophile.
2. Cell entry is transporter-mediated, not passive. Copper transporter 1 (CTR1, SLC31A1, HGNC:11016) and organic cation transporter 2 (OCT2, SLC22A2, HGNC:10966) carry cisplatin into cells. Results in selective accumulation in tissues expressing these carriers — renal proximal and distal tubule, cochlea, dorsal root ganglion. This is why the toxicity is organ-selective rather than uniform.

   "we demonstrate that Ctr1 is mainly expressed in both proximal and distal tubular cells in mouse kidneys. We further show that Ctr1 is mainly localized on the basolateral side of these cells, a proposed site for cisplatin uptake. Importantly, downregulation of Ctr1 by small interfering RNA or copper pretreatment results in decreased cisplatin uptake." — PMID:19144690 (model organism / in vitro) "Cimetidine, a pharmacological inhibitor of OCT2, can also partially attenuate cisplatin uptake." — PMID:19144690

3. Intracellular platinum binds the N7 of purine bases and forms 1,2-intrastrand and interstrand crosslinks. Leads to stalled replication and transcription and G2 arrest (MeSH D002945; PMID:25058905).

Branch A — kidney.

4a. Adduct burden in the tubular epithelium triggers a DNA damage response alongside mitochondrial injury, ROS generation, and ER stress. These are concurrent, not sequential.

"Preclinical studies have provided insights into the cellular and molecular mechanisms of cisplatin nephrotoxicity, which involve intracellular stresses including DNA damage, mitochondrial pathology, oxidative stress and endoplasmic reticulum stress." — PMID:36229672 5a. Those stresses activate a set of stress-response programs, several of which are cell-death programs. "Stress responses, including autophagy, cell-cycle arrest, senescence, apoptosis, programmed necrosis and inflammation have key roles in the pathogenesis of cisplatin nephrotoxicity." — PMID:36229672 6a. Ferroptosis is now argued to be the dominant tubular death mode, with ALOX12-driven phospholipid peroxidation as one demonstrated route. This is a strong claim from a 2024 primary paper and should be curated as such, not as consensus. "In acute kidney injury (AKI), ferroptosis is the main mechanism of cell death in the renal tubular epithelium." — PMID:38805781, Phytomedicine 2024;130:155757 (model organism + in vitro) "baicalein reduced the expression of 12-lipoxygenase (ALOX12), which inhibits phospholipid peroxidation and ferroptosis in AKI" — PMID:38805781 7a. Dying tubular cells release DAMPs and cytokines, recruiting inflammatory cells. Leads to amplification of injury beyond the directly platinated cells. Pabla & Dong framed this early: "Recent research has shed significant new lights on the mechanism of cisplatin nephrotoxicity, especially on the signaling pathways leading to tubular cell death and inflammation." — PMID:18272962 8a. Tubular loss and inflammation produce falling GFR and rising creatinine — clinically, AKI (HP:0001919). 9a. Repeated cycles convert acute injury into fibrosis and CKD. Demonstrated directly in mice: "Repeated administration of low-dose cisplatin in mice induces fibrosis." — PMID:26739893, Am J Physiol Renal Physiol 2016;310(6):F560-8 (model organism) 10a. In parallel, tubular injury impairs magnesium reabsorption, producing renal magnesium wasting and hypomagnesemia. Hypomagnesemia then feeds back as a risk factor for further kidney injury — a loop, not a one-way step. Magnesium is both a predictor of CP-AKI (PMID:38538012) and a preventive intervention (PMID:37530867, PMID:42652681). The TRPM6 step is a plausible molecular explanation for this and I did not verify it against a primary source.

Branch B — cochlea.

4b. Cisplatin enters the cochlea and is not cleared. This is the key non-obvious step: the pharmacokinetics of the inner ear differ from every other organ.

"In most organs cisplatin is detected within one hour after injection, and is eliminated over the following days to weeks. In contrast, the cochlea retains cisplatin for months to years after treatment in both mice and humans." — PMID:29162831 (human tissue + model organism) 5b. Accumulation concentrates in the stria vascularis, the endolymph-maintaining tissue. "Cisplatin accumulation is consistently high in the stria vascularis, the region of the cochlea that maintains the ionic composition of endolymph." — PMID:29162831 6b. Outer hair cells die, basal turn first, which is why loss is high-frequency first. Whether the primary hit is direct hair-cell uptake or secondary to strial injury is genuinely unsettled and the field says so. "Cisplatin ototoxicity chiefly manifests through the loss of outer hair cells, possibly resulting from damages directly by cisplatin uptake or secondary effects on the stria vascularis. Both direct and indirect influences contribute to cisplatin ototoxicity, while it is still debated which path is dominant or where the primary target of cisplatin is located." — PMID:39417180, Am J Cancer Res 2024;14(9):4597-4632 Curate this as a mechanistic_hypotheses pair with status: EMERGING, or as a KNOWLEDGE_GAP discussion. Do not pick a winner. 7b. Four death programs converge on the hair cell, and inflammation is upstream of several. "Cisplatin causes hair cell death by forming DNA adducts, mitochondrial dysfunction, oxidative stress, and inflammation, culminating in programmed cell death by apoptosis, necroptosis, pyroptosis, or ferroptosis." — PMID:38003734 8b. Hair cells do not regenerate in mammals. Results in permanent, bilateral, high-frequency sensorineural hearing loss, progressing to speech frequencies as cumulative dose rises (PMID:22547603).

Branch C — dorsal root ganglion.

4c. The DRG lies outside a tight blood-nerve barrier and accumulates platinum. Adducts form in nuclear and mitochondrial DNA of sensory neurons. Leads to a sensory neuronopathy rather than a distal axonopathy — which is why the deficit is sensory, length-dependent in presentation but ganglionopathic in origin. I did not retrieve a primary citation for the blood-nerve-barrier claim this session; treat it as textbook background pending a source. 5c. Sensory neuron dysfunction and axonal degeneration produce paraesthesia, distal sensory loss, areflexia, and sensory ataxia (HP:0003401, HP:0002936, HP:0001284, HP:0002066).

Branch D — bone marrow.

4d. Cycling haematopoietic progenitors arrest and die from the same adduct burden. Results in anaemia, neutropenia, thrombocytopenia. This is the branch the existing stub already models, and it is correct as far as it goes.

Branch E — area postrema and gut.

4e. Cisplatin provokes acute and delayed emesis through enterochromaffin-cell serotonin release and substance P/NK1 signalling. Results in the highly emetogenic phenotype that defines cisplatin antiemetic prophylaxis. I did not verify a primary citation for the enterochromaffin/substance-P step this session. Curate the phenotype; leave the mechanism uncited or find the source first.

Ontology bindings for mechanism nodes

All GO terms below verified present in cache/go/terms.csv with the labels shown.

Note: pyroptosis is named in PMID:38003734 but I did not verify a GO term for it in the dismech cache. Check before binding.

Molecular profiling

• Proteomics / biomarker landscape in vitro. A 2026 PRISMA systematic review of 58 human proximal-tubule in vitro studies published 2014–2024: "Kidney injury molecule-1 was the most frequently reported structural biomarker. Mechanistic endpoints, particularly oxidative stress and intracellular signaling markers, predominated over structural injury markers." — PMID:42459863, Front Toxicol 2026;8:1862941. The same review concludes reporting is not harmonised, which matters if you are mining these datasets.
• Transcriptomics, metabolomics, lipidomics, single-cell, spatial: not searched this session. The Nature Reviews Nephrology review explicitly calls for multi-omics and GWAS work, which implies it is not yet mature: "Further research using tumour-bearing animals, multi-omics and genome-wide association studies will enable a comprehensive understanding of the complex cellular and molecular mechanisms of cisplatin nephrotoxicity" — PMID:36229672.

7. Anatomical Structures Affected

All UBERON and CL terms below verified in the dismech caches or by live OLS4 query.

Organ level

Tissue and cell level

Localization detail

• Spiral organ of cochlea: UBERON:0002227 (label "spiral organ of cochlea" — verified live via OLS4; note the label is not "organ of Corti")
• Stria vascularis of cochlear duct: UBERON:0002282 (verified live via OLS4) — the site of highest platinum accumulation (PMID:29162831)
• Proximal tubule: UBERON:0004134; nephron tubule: UBERON:0001231

Lateralization

Bilateral and broadly symmetric across all organ branches. Ototoxicity is explicitly bilateral (PMID:38003734). Neuropathy is symmetric and length-dependent.

Subcellular

Nucleus (DNA adducts), mitochondrion (mitochondrial DNA adducts, depolarization, permeability transition), endoplasmic reticulum (unfolded protein response). I did not verify GO Cellular Component identifiers this session.

8. Temporal Development

Onset

• Acute emesis: hours after infusion.
• AKI: the BMJ study defines the outcome window as "within 14 days of a first dose of intravenous cisplatin" (PMID:38538012). Peak creatinine typically 7–10 days.
• Myelosuppression: nadir around 10–14 days per cycle.
• Hypomagnesemia: develops over cycles and is often persistent.
• Ototoxicity: may be detectable after a single course; ACCL0431's primary endpoint was hearing loss "4 weeks after final cisplatin dose" (PMID:27914822), while SIOPEL 6 assessed at "a minimum age of 3.5 years" (PMID:29924955) — which tells you the deficit is stable enough to measure years later.
• CIPN: typically emerges after several cycles; may progress after cessation.

Progression and course

The dose-frequency relationship for hearing is stated directly: "Platinum initially impairs hearing in the high frequencies and progresses to lower frequencies with increasing cumulative dose." (PMID:22547603)

Critical windows

• The 6-hour window after cisplatin. Both randomised otoprotection trials gave sodium thiosulfate exactly 6 hours after the cisplatin infusion ended — SIOPEL 6: "20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin"; ACCL0431: "sodium thiosulfate 16 g/m2 intravenously 6 h after each cisplatin dose". The delay is the whole design. Give it earlier and it may quench the drug's antitumour effect. Brock's consensus review names this: "Route of administration and optimal timing relative to platinum therapy are critical issues." (PMID:22547603)
• The cumulative-dose threshold. Ototoxicity risk rises steeply; ACCL0431's FDA-relevant framing used cumulative cisplatin ≥200 mg/m².
• Early childhood. Hearing loss during speech acquisition causes developmental language delay (PMID:38003734), which is why the paediatric otoprotection trials exist.

9. Inheritance and Population

Epidemiology

This is an iatrogenic condition, so "prevalence" is prevalence-among-the-exposed, not population prevalence. Curate it that way — the dismech Prevalence.population slot should name the treated cohort, not a geography.

"Ototoxicity is an often-underestimated sequela for cancer patients undergoing chemotherapy, with an incidence rate exceeding 50%, affecting approximately 4 million individuals worldwide each year." — PMID:39417180

"Approximately 500,000 patients diagnosed annually with these cancer types in the United States could be candidates for treatment with cisplatin. There is a 5-fold increase in the risk of hearing impairment or ototoxicity with cisplatin" — PMID:36921239

Inheritance

Not a heritable disease. Susceptibility is polygenic and modestly penetrant. If curating an Inheritance block at all, HP:0010982 polygenic inheritance with relationship_type: SUSCEPTIBILITY gene typing is the honest binding — but consider whether the entry needs one. There is no penetrance, expressivity, anticipation, mosaicism, founder effect, consanguinity, or carrier frequency to report, because there is no Mendelian disease.

Demographics

• Sex ratio: determined entirely by the cancer indication, not by the toxicity. Testicular cancer cohorts are male by construction; cervical and ovarian cohorts female.
• Age: bimodal by indication — paediatric solid tumours (neuroblastoma, osteosarcoma, hepatoblastoma, medulloblastoma) and adult carcinomas.
• Geography: wherever cisplatin is used, which is globally. Cohort studies retrieved include the US (PMID:38538012), South Africa (PMID:37014872, title only), and Zimbabwe (PMID:39056302, title only). Those last two suggest the burden in cervical-cancer treatment in sub-Saharan Africa is being characterised now; I did not read either abstract.
• Ancestry: the pharmacogenomic literature is dominated by European-ancestry cohorts. PMID:37726872 explicitly calls for "replication studies considering diverse pediatric and adult patient populations". Treat any ancestry-specific effect size as unreplicated.

10. Diagnostics

Cisplatin toxicity is diagnosed by monitoring during and after a known exposure, not by a diagnostic test applied to an undifferentiated patient.

Laboratory

Biomarkers

Kidney injury molecule-1 (KIM-1, gene HAVCR1) is the most-used structural biomarker in the experimental literature:

"Fifty-eight studies met inclusion criteria. Kidney injury molecule-1 was the most frequently reported structural biomarker." — PMID:42459863

Urinary TIMP-2×IGFBP-7 has been evaluated in children receiving cisplatin (PMID:37365422, Pediatr Nephrol — title verified, abstract not read). Neither KIM-1 nor TIMP-2×IGFBP-7 is standard of care for this indication.

Audiology

This is the one place cisplatin toxicity has a purpose-built diagnostic standard.

• Pure-tone audiometry including extended high frequencies, at baseline and serially. SIOPEL 6's primary endpoint was "the absolute hearing threshold, as measured by pure-tone audiometry" (PMID:29924955).
• Grading scales: the SIOP Boston Ototoxicity Scale was created specifically for this (PMID:22547603). The Brock grade (0–4) is the older paediatric scale used as SIOPEL 6's endpoint: "Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss)." ACCL0431 used ASHA criteria with masked central audiologist review.
• Otoacoustic emissions detect outer-hair-cell loss early. Not verified against a source this session.

The gap is in adults, and it is a real one:

"Our review of the literature showed a lack of standardized guidelines for monitoring and treatment of cisplatin-induced ototoxicity, especially in the adult cancer patient population. Our survey of practicing oncologists mirrored the findings from the published literature with a heterogeneity of practice, which highlights the need for standardization." — PMID:36921239

Neurologic

Clinical sensory examination, vibration and proprioception testing, patient-reported outcome instruments. Nerve conduction studies show a sensory axonal/neuronopathic pattern. NCS pattern not verified against a source this session.

Genetic testing

ACYP2 and TPMT genotyping is the only pharmacogenomic testing with a defensible evidence base (PMID:37726872), and even that review stops short of recommending clinical implementation, calling instead for further replication. There is no CPIC guideline for cisplatin ototoxicity that I could confirm in this session. Do not curate one.

WGS, WES, gene panels, CMA, karyotype, FISH, mtDNA testing, and repeat-expansion testing: not applicable.

Differential diagnosis

Screening

Baseline audiometry before the first dose, and baseline creatinine and magnesium. There is no population screening, because there is no population at risk that is not already identified by the prescription.

11. Outcome/Prognosis

Mortality

Severe CP-AKI is not a nuisance toxicity. It tracks with death:

"Greater severity of CP-AKI was monotonically associated with shorter 90 day survival (adjusted hazard ratio 4.63 (95% CI 3.56 to 6.02) for stage 3 CP-AKI versus no CP-AKI)." — PMID:38538012

"This study found that a simple risk score based on readily available variables from patients receiving intravenous cisplatin could predict the risk of severe CP-AKI, the occurrence of which is strongly associated with death." — PMID:38538012

Read that association carefully. It is not established that the AKI causes the deaths; sicker patients get both. The paper reports association, and so should the KB entry.

Morbidity and recovery

Long-term burden in survivors, median 4.3 years out: 37.6% of testicular cancer survivors reported three or more adverse health outcomes, and 12.5% reported five or more (PMID:28240972).

Prognostic factors

Age, cumulative cisplatin dose, baseline renal function, baseline magnesium, hypertension, diabetes, and infusion schedule. The BMJ nine-covariate risk score is the best-validated instrument:

"Compared with patients in the lowest risk category, those in the highest risk category showed a 24.00-fold (95% confidence interval (CI) 13.49-fold to 42.78-fold) higher odds of CP-AKI in the derivation cohort and a 17.87-fold (10.56-fold to 29.60-fold) higher odds in the validation cohort. The primary model had a C statistic of 0.75 and showed better discrimination for CP-AKI than previously published models, the C statistics for which ranged from 0.60 to 0.68." — PMID:38538012

A C statistic of 0.75 is useful and is not a decision rule. It discriminates better than everything before it and still misclassifies plenty.

Quality of life

No cisplatin-toxicity-specific EQ-5D, SF-36, or PROMIS utility values were retrieved. The reviews describe QoL impact narratively (PMID:36921239: "with major impact on patients' health-related quality of life"; PMID:38003734 on social isolation and developmental delay). If a QoL number is needed for the entry, it has not been found yet.

12. Treatment

Sodium thiosulfate — the only approved otoprotectant

Two randomised phase 3 trials, both giving the drug 6 hours after cisplatin.

ACCL0431 (Children's Oncology Group, 38 sites, NCT00716976):

"Participants received sodium thiosulfate 16 g/m2 intravenously 6 h after each cisplatin dose or observation." "Hearing loss was identified in 14 (28·6%; 95% CI 16·6-43·3) participants in the sodium thiosulfate group compared with 31 (56·4%; 42·3-69·7) in the control group (p=0·00022). Adjusted for stratification variables, the likelihood of hearing loss was significantly lower in the sodium thiosulfate group compared with the control group (odds ratio 0·31, 95% CI 0·13-0·73; p=0·0036)." — PMID:27914822, Lancet Oncol 2017;18(1):63-74

SIOPEL 6 (standard-risk hepatoblastoma, NCT00652132):

"Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002)." "At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively." — PMID:29924955, N Engl J Med 2018;378(25):2376-2385

Regulatory status. The FDA approved sodium thiosulfate (Pedmark, Fennec Pharmaceuticals) on 2022-09-20 to reduce the risk of ototoxicity in patients aged 1 month to 18 years with localised, non-metastatic solid tumours. The 2023 review states it as fact: "Recently, the U.S. Food and Drug Administration (FDA) approved the first therapy, sodium thiosulfate, to prevent cisplatin-induced hearing loss in pediatric patients with localized, non-metastatic solid tumors." (PMID:38003734). The approval date and sponsor come from a web search summary in this session and were not confirmed against an FDA primary document.

The efficacy caveat that matters. Otoprotection is a trade against tumour kill, and the field says so: "Otoprotection is a strategy being explored to decrease hearing loss while maintaining dose intensity or allowing dose escalation, but it has the potential to interfere with tumoricidal effects." (PMID:22547603). This is why the label is restricted to localised, non-metastatic disease.

Nephroprotection

• Intravenous hydration is the backbone and is not in dispute.
• Magnesium supplementation during hydration: OR 0.22 (95% CI 0.14–0.35) against CIN in a meta-analysis of 11 retrospective studies (PMID:37530867), and a 2026 meta-analysis found no dose-response across <10 mEq, 10–<20 mEq, and ≥20 mEq groups (PMID:42652681).
• Nothing else is established. The 2026 Kidney360 review states the position bluntly: "its dose-limiting nephrotoxicity affects up to one third of patients and has no effective pharmacologic prevention beyond hydration and magnesium supplementation." (PMID:41854743)
• Mannitol addition to hydration has been studied ambispectively (PMID:35413808, title verified, abstract not read). Evidence is not strong.
• Amifostine (NCIT:C488) is the classic cytoprotectant. I did not retrieve a current guideline recommendation for it in cisplatin nephroprotection this session. Do not curate an ASCO recommendation for it without reading the guideline.

Emerging: SGLT2 inhibitors. Preclinical only, and the review is honest that it is preclinical only:

"Across these models, SGLT2 inhibitors consistently attenuated kidney injury through complementary mechanisms such as suppression of inflammatory, oxidative, and apoptotic pathways; activation of AMP-activated protein kinase-dependent autophagy; reduction of kidney platinum accumulation; and, uniquely, correction of cisplatin-induced hypomagnesemia, a clinically significant complication. Protective effects occurred without compromising cisplatin's antitumor efficacy in vitro. ... Although prospective clinical application remains untested, the strong biologic rationale, reproducibility across models, and established safety of SGLT2 inhibitors in other populations underscore the urgency of translation." — PMID:41854743, Kidney360 2026;7(5):1150-1159 (seven non-diabetic rodent studies; MODEL_ORGANISM)

CIPN

The ASCO 2020 guideline update is unambiguous and mostly negative:

"The identified data reconfirmed that no agents are recommended for the prevention of CIPN. The use of acetyl-l-carnitine for the prevention of CIPN in patients with cancer should be discouraged. Furthermore, clinicians should assess the appropriateness of dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment. Duloxetine is the only agent that has appropriate evidence to support its use for patients with established painful CIPN. Nonetheless, the amount of benefit from duloxetine is limited." — PMID:32663120, J Clin Oncol 2020;38(28):3325-3348

Duloxetine binds to CHEBI:36796.

Antiemesis

Cisplatin is the reference highly emetogenic agent. Standard prophylaxis is a four-drug regimen: NK1 receptor antagonist, 5-HT3 antagonist, dexamethasone (CHEBI:41879), and olanzapine (CHEBI:7735). I could not retrieve the current ASCO antiemetic guideline PMID in this session. Curate the regimen only with a guideline citation you have read.

Dose modification and supportive care

Dose reduction, delay, or substitution (usually to carboplatin) remains the primary management for established toxicity — ASCO says so for neuropathy above, and the same logic drives renal and otologic dose decisions. Supportive care includes transfusion, growth factors, magnesium and potassium repletion, hearing aids or cochlear implantation for severe loss, and dialysis for severe AKI.

NCIT bindings

All verified against the dismech cache/ncit/terms.csv or live OLS4.

NCIT:C1230 and NCIT:C488 are agent terms, not clinical-action terms. They are not reachable from NCIT:C25218 and will fail TreatmentTerm validation if put in the treatment_term.term slot. They belong in therapeutic_agent. I did not confirm their reachability either way; check before binding.

13. Prevention

Primary prevention

The only complete primary prevention is not giving cisplatin. That is a real clinical option — carboplatin substitution trades ototoxicity and nephrotoxicity for myelosuppression, at some cost in efficacy for certain tumours.

Everything else is risk reduction:

Secondary prevention

Baseline and serial audiometry, so hearing loss is caught at the high frequencies before it reaches speech frequencies and a dose decision can still be made. Serial creatinine and magnesium for the same reason. The adult monitoring gap identified in PMID:36921239 is precisely a secondary-prevention failure.

Tertiary prevention

Dose reduction, delay, or discontinuation after toxicity appears — the ASCO CIPN guideline's explicit recommendation (PMID:32663120). Hearing aids and cochlear implantation. CKD management after repeated AKI.

Not applicable

Immunisation. Genetic screening (no clinically actionable genotype-directed protocol exists — see §10). Prenatal or carrier testing. Public health or environmental interventions. Genetic counselling.

14. Other Species / Natural Disease

There is no natural disease here. Cisplatin toxicity in animals is induced, always. There is no wildlife or companion-animal population that acquires it spontaneously, and OMIA has nothing to record.

• Species used and affected experimentally: Mus musculus (NCBITaxon:10090), Rattus norvegicus (NCBITaxon:10116), Danio rerio (NCBITaxon:7955), Homo sapiens (NCBITaxon:9606). NCBITaxon identifiers written from knowledge; not verified this session.
• Veterinary relevance. Cisplatin is used therapeutically in dogs, chiefly for osteosarcoma, and produces the same nephrotoxicity requiring saline diuresis. Cisplatin is contraindicated in cats, in which it causes fatal pulmonary oedema. Both statements are well established in veterinary oncology. I searched PubMed for a primary citation in this session and found none — the searches returned zero results. Do not curate either claim without a source you have read. The cat contraindication is important enough that it is worth finding one.
• Comparative pathology. The cochlear retention finding is directly comparative and was measured in both species: "the cochlea retains cisplatin for months to years after treatment in both mice and humans" (PMID:29162831). That cross-species agreement is what makes the mouse cochlea a credible model.
• Evolutionary conservation. CTR1 is a copper transporter; the platinum uptake it mediates is an off-target consequence of a deeply conserved metal-handling system. The DNA adduct chemistry is species-independent.
• Zoonotic potential: none. Not transmissible.

15. Model Organisms

Whole-animal models

The single most important limitation, stated by the field itself. Almost all mechanistic work is done in tumour-free animals, which cannot answer whether a renoprotectant also protects the tumour:

"Importantly, it is unclear whether these approaches would limit the anticancer effects of cisplatin in tumors. Examination of tumor-bearing animals and identification of novel renoprotective strategies that do not diminish the anticancer efficacy of cisplatin are essential to the development of clinically applicable interventions." — PMID:18272962, Kidney Int 2008;73(9):994-1007

Restated fifteen years later, still open:

"However, the effects of renoprotective strategies on the efficacy of cisplatin chemotherapy needs to be thoroughly evaluated. Further research using tumour-bearing animals, multi-omics and genome-wide association studies will enable a comprehensive understanding..." — PMID:36229672

That is a HUMAN_MODEL_MISMATCH in the dismech sense, and it is the one worth curating.

Non-animal models (dismech experimental_models:)

If curating modeled_mechanisms links, the organoid model against a proximal-tubule injury node should be PARTIALLY_RECAPITULATES with fidelity: MODERATE and the OCT2 underexpression written into limitations. The mouse cochlear model against a cochlear platinum-retention node can carry RECAPITULATES with fidelity: HIGH, since PMID:29162831 measured the same phenomenon in both species.

Resources

MGI, RGD, ZFIN, IMPC, Cellosaurus, ATCC. Not queried this session.

Curation notes for the dismech entry

Six things worth flagging before this becomes a KB entry.

1. The current stub models one branch of five. kb/disorders/Cisplatin_Toxicity.yaml has Platinum-DNA Adduct Formation → Bone Marrow Hematopoietic Suppression. That edge is correct. It is also the least clinically important of the five branches. The renal, cochlear, and neural branches all hang off the same trigger node and are missing.
2. Pathograph targets are bare names. The stub's downstream[].target: Bone Marrow Hematopoietic Suppression is right. Keep every new target bare — no pathophysiology# prefix — per the causal-target rule in CLAUDE.md.
3. conforms_to candidates beyond myelosuppression. The peripheral axonal degeneration module is the natural target for the CIPN branch, and CLAUDE.md names it explicitly as a toxicity conformance target. Check just list-modules for an AKI or tubular-injury module before inventing one.
4. Genes are SUSCEPTIBILITY, never CAUSATIVE. ACYP2 and TPMT only. COMT did not replicate and should not be curated as established.
5. Do not average the AKI incidence figures. 3–5% (severe, BMJ), up to 20% (PMID:37530867), and up to one third (PMID:41854743) use three different endpoint definitions. Curate each as its own Prevalence record with the definition in notes.
6. The HP:0001875 label is now "Decreased total neutrophil count". OLS4 returns that, not "Neutropenia". The dismech HP cache does not contain the term, so nothing local will catch a stale label.

Sources

• Cisplatin nephrotoxicity: new insights and therapeutic implications — Nat Rev Nephrol 2023, PMID:36229672
• Advances in understanding cisplatin-induced toxicity — Eur J Pharm Sci 2024, PMID:39423903
• Molecular Characteristics of Cisplatin-Induced Ototoxicity — Int J Mol Sci 2023, PMID:38003734
• Canadian Pharmacogenomics Network for Drug Safety 2022 Update — Ther Drug Monit 2023, PMID:37726872
• Derivation and external validation of a risk score for severe CP-AKI — BMJ 2024, PMID:38538012
• Cisplatin Nephrotoxicity: Novel Insights — Semin Nephrol 2022, PMID:37182407
• Prevalence and risk factors for ototoxicity after cisplatin-based chemotherapy — J Cancer Surviv 2023, PMID:36637632
• Cisplatin-Induced Ototoxicity: Burden, Prevention, Interception — JCO Oncol Pract 2023, PMID:36921239
• Hearing loss during chemotherapy — Am J Cancer Res 2024, PMID:39417180
• Cisplatin is retained in the cochlea indefinitely — Nat Commun 2017, PMID:29162831
• SIOP Boston ototoxicity scale consensus review — J Clin Oncol 2012, PMID:22547603
• Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss (SIOPEL 6) — NEJM 2018, PMID:29924955
• Sodium thiosulfate versus observation (ACCL0431) — Lancet Oncol 2017, PMID:27914822
• Adverse Health Outcomes Among North American Testicular Cancer Survivors — J Clin Oncol 2017, PMID:28240972
• Pharmacogenomics of cisplatin-induced neurotoxicities — Cancer Med 2022, PMID:35322580
• The copper transporter Ctr1 contributes to cisplatin uptake — Am J Physiol Renal Physiol 2009, PMID:19144690
• Cisplatin nephrotoxicity: mechanisms and renoprotective strategies — Kidney Int 2008, PMID:18272962
• Cisplatin in cancer therapy: molecular mechanisms of action — Eur J Pharmacol 2014, PMID:25058905
• Repeated administration of low-dose cisplatin in mice induces fibrosis — Am J Physiol Renal Physiol 2016, PMID:26739893
• Evaluation of cisplatin-induced injury in human kidney organoids — Am J Physiol Renal Physiol 2020, PMID:32150447
• Hydration protocols and magnesium supplementation meta-analysis — Clin Exp Nephrol 2024, PMID:37530867
• Prophylactic Magnesium Therapy meta-analysis — J Clin Med 2026, PMID:42652681
• SGLT2 Inhibitors in Cisplatin Nephrotoxicity: A Mechanistic Review — Kidney360 2026, PMID:41854743
• Biomarker selection in human proximal tubular in vitro models — Front Toxicol 2026, PMID:42459863
• Baicalein alleviates cisplatin-induced AKI by inhibiting ALOX12-dependent ferroptosis — Phytomedicine 2024, PMID:38805781
• Prevention and Management of CIPN: ASCO Guideline Update — J Clin Oncol 2020, PMID:32663120
• MeSH descriptor D002945, Cisplatin — NCBI
• MONDO:0027664 cisplatin toxicity — EBI OLS4
• FDA approves sodium thiosulfate — NCI Cancer Currents

What I did not verify

Stated plainly so nothing here gets curated on my word alone.

• ICD-10, ICD-11, SNOMED CT, LOINC, and RxNorm identifiers. None checked against their authorities.
• The MeSH descriptor UI for "Ototoxicity". My query for D000079761 returned no summary.
• NCBITaxon identifiers for mouse, rat, and zebrafish. Written from memory.
• Whether NCIT:C1230 and NCIT:C488 are reachable from NCIT:C25218. They are agent terms and probably are not.
• The FDA approval date and sponsor for Pedmark. Taken from a web search summary, not an FDA document.
• The cat contraindication and the dog osteosarcoma indication. PubMed returned zero results for my searches. Find a source before curating either.
• Coasting in platinum neuropathy. No primary citation retrieved.
• The blood-nerve-barrier explanation for DRG selectivity. Textbook background, uncited here.
• The enterochromaffin-cell/substance-P emesis mechanism. No citation retrieved.
• The TRPM6 link to cisplatin hypomagnesemia. A PubMed search for it returned no items.
• The current ASCO antiemetic guideline. Not located.
• Allele frequencies for ACYP2 and TPMT variants. Not retrieved.
• Any CPIC guideline for cisplatin. I do not believe one exists; I did not confirm its absence.
• Transcriptomic, metabolomic, lipidomic, single-cell, and spatial datasets. Not searched.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.