Cisplatin Toxicity

Complex MONDO:0027664 Pathograph 28 Show in embeddings browser Drug Toxicity

Cisplatin toxicity is the injury a platinum drug does to the patient it is meant to cure. The drug works by crosslinking DNA, and it does that in whatever cell it enters, so the question of which tissue is harmed is not a question about the lesion at all. It is a question about which cells take the platinum up, and whether those cells can repair the damage or be replaced. Kidney proximal tubule takes it in through OCT2 and Ctr1 and dies. Cochlear hair cells take it in and cannot be regenerated, so the hearing loss is permanent. Dorsal root ganglion neurons sit outside the blood-nerve barrier, accumulate platinum, and go on degenerating for months after the last dose. Marrow is hit because marrow divides. Four dose-limiting toxicities, one lesion, and the difference between them is transport and repair rather than mechanism.

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14
Pathophys.
10
Phenotypes
28
Pathograph
3
Genes
5
Medical Actions
2
Trials
1
Deep Research
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Pathophysiology

14
Cisplatin Uptake by Transporter-Expressing Cells
Cisplatin does not enter cells freely. It is carried in, chiefly by the organic cation transporter OCT2 and the copper transporter Ctr1, and the tissues that express those transporters most heavily are the tissues that are injured. This node is the selectivity step of the whole disease - it explains why a drug that crosslinks DNA everywhere produces damage in four particular organs and not uniformly.
Downstream
Platinum-DNA Adduct Formation Uptake delivers platinum to intracellular DNA. Everything downstream follows from the adducts; this edge is what makes uptake rate-limiting.
Emetogenic Response to Cisplatin Administration of cisplatin is also followed by severe emesis. The edge is recorded as indirect with unknown intermediates on purpose: unlike the four injury arms, this one is not established here as running through OCT2 or Ctr1 uptake into the affected tissue, and the sources cited in this entry do not supply the route.
Show evidence (2 references)
PMID:16242669 SUPPORT Model Organism
"the present results indicated that renal rOCT2 expression was the major determinant of cisplatin-induced tubular toxicity"
Identifies transporter expression, not intrinsic cellular sensitivity, as what determines where the toxicity falls. This is the claim the node is built on. Graded MODEL_ORGANISM because the quoted conclusion rests on the in vivo rat arm - sex differences in renal uptake clearance, urinary N-acetyl-beta-D-glucosaminidase, and the castrated-male comparison - even though the paper also reports transfected-cell work.
PMID:19144690 SUPPORT In Vitro
"downregulation of Ctr1 suppresses cisplatin toxicity, including cell death by both apoptosis and necrosis"
Shows the second transporter arm, and shows it causally - removing the transporter removes the toxicity.
Platinum-DNA Adduct Formation
Aquated cisplatin binds DNA and forms crosslinks. This is the therapeutic mechanism and the toxic mechanism, and they are the same mechanism - there is no separate off-target lesion to find. Adducts form in nuclear DNA and in mitochondrial DNA, and the distinction matters because the mitochondrion cannot repair them.
DNA damage response GO:0006974 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Oxidative Stress and Mitochondrial Injury Adduct formation is accompanied by reactive oxygen species generation and mitochondrial damage, which is the arm that reaches post-mitotic cells.
Apoptotic Cell Death in Platinum-Loaded Tissue Unrepaired adducts activate the damage response and drive apoptosis.
Show evidence (2 references)
PMID:39423903 SUPPORT Other
"The mechanisms of cisplatin toxicity are multifactorial and involve oxidative stress, inflammation, DNA damage, and cellular apoptosis."
Names DNA damage alongside oxidative stress and apoptosis as the shared mechanisms across the toxicities, which is how this entry arranges them.
PMID:21145397 SUPPORT In Vitro
"cisplatin induces apoptosis in dorsal root ganglion (DRG) sensory neurons by covalently binding to nuclear DNA (nDNA), resulting in DNA damage, subsequent p53 activation and Bax-mediated apoptosis via the mitochondria"
Gives the covalent binding, the damage response and the apoptotic route in one of the four affected tissues.
Oxidative Stress and Mitochondrial Injury
Reactive oxygen species generation and mitochondrial damage. This arm matters most in the tissues that do not divide, because a post-mitotic cell is not threatened by a stalled replication fork but is threatened by losing its mitochondria.
cellular response to oxidative stress GO:0034599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to oxidative stress (GO:0034599). GO:0034599 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Apoptotic Cell Death in Platinum-Loaded Tissue Oxidative and mitochondrial injury converge on the same apoptotic endpoint as the direct DNA damage arm.
Mitochondrial DNA Damage in Sensory Neurons In dorsal root ganglion neurons the mitochondrial arm is not merely accompanying injury; platinum binds mitochondrial DNA directly.
Show evidence (2 references)
PMID:39423903 SUPPORT Other
"The mechanisms of cisplatin toxicity are multifactorial and involve oxidative stress, inflammation, DNA damage, and cellular apoptosis."
Names oxidative stress as one of the shared mechanisms across cisplatin's toxicities.
PMID:36455457 SUPPORT Other
"Upon entering hair cells, cisplatin disrupts organelle metabolism, induces oxidative stress, and targets DNA to cause intracellular damage."
Gives the same three-part injury - organelle, oxidative, DNA - in the cochlear arm specifically.
Apoptotic Cell Death in Platinum-Loaded Tissue
Programmed death of the cells that took up the most platinum. The same endpoint in four tissues, which is why the four toxicities look mechanistically alike while behaving very differently in the clinic. What differs downstream is whether the dead cell can be replaced.
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Proximal Tubular Epithelial Cell Death The renal arm. Tubular epithelium can regenerate, which is why this toxicity is often reversible where the cochlear one is not.
Cochlear Hair Cell Death The cochlear arm. Mammalian hair cells do not regenerate, so this cell death is the permanent one.
Cytotoxic Insult to Proliferating Hematopoietic Progenitors The marrow arm. Progenitors are hit for the ordinary antiproliferative reason rather than for any transporter-specific one.
Dorsal Root Ganglion Sensory Neuron Injury The neural arm. Sensory neurons are post-mitotic and irreplaceable, so this arm shares the cochlear arm's arithmetic rather than the marrow's.
Show evidence (1 reference)
PMID:21145397 SUPPORT In Vitro
"cisplatin induces apoptosis in dorsal root ganglion (DRG) sensory neurons by covalently binding to nuclear DNA (nDNA), resulting in DNA damage, subsequent p53 activation and Bax-mediated apoptosis via the mitochondria"
Gives the apoptotic pathway from adduct to p53 to Bax in one of the affected tissues.
Proximal Tubular Epithelial Cell Death
Death of proximal tubule epithelium, the cells that concentrated the drug. Distal segments are affected too, which is where the magnesium wasting comes from.
epithelial cell of proximal tubule CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
Downstream
Cisplatin-Induced Acute Kidney Injury Loss of tubular epithelium produces the fall in filtration.
Show evidence (1 reference)
PMID:18272962 SUPPORT Other
"side effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the use of cisplatin and related platinum-based therapeutics"
Establishes nephrotoxicity as the dose-limiting normal-tissue injury this arm models.
Cisplatin-Induced Acute Kidney Injury
Falling glomerular filtration after tubular injury, with magnesium and potassium wasting alongside it. Unlike the cochlear arm this is often reversible, because the epithelium regenerates.
Downstream
Acute kidney injury The renal arm's clinical readout.
Hypomagnesemia Magnesium wasting from injury to the reabsorbing tubular segments, alongside the fall in filtration.
Show evidence (1 reference)
PMID:39423903 SUPPORT Other
"its clinical utility is hampered by its dose-limiting toxicities, including nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression"
Names nephrotoxicity as one of the four dose-limiting toxicities this entry is organised around.
Cochlear Hair Cell Death
Death of cochlear hair cells, beginning with the outer hair cells of the basal turn, which is why the loss starts at high frequency. Hair cell death is not the only cochlear lesion - stria vascularis injury and spiral ganglion degeneration are reported alongside it - and this entry does not model it as the sole route.
cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology.
Downstream
Irreversible Sensorineural Hearing Loss Hair cell loss gives permanent hearing loss, and the permanence is what separates this arm from the renal one, where the epithelium regenerates.
Show evidence (2 references)
PMID:36455457 SUPPORT Other
"The main etiologies are stria vascularis injury, spiral ganglion degeneration, and hair cell death."
Names hair cell death as a main route and, in the same sentence, the two other cochlear lesions this node's description declines to subsume.
PMID:36455457 SUPPORT Other
"Upon entering hair cells, cisplatin disrupts organelle metabolism, induces oxidative stress, and targets DNA to cause intracellular damage."
Locates the injury inside the hair cell and gives its three components.
Irreversible Sensorineural Hearing Loss
Permanent high-frequency sensorineural hearing loss. It is the toxicity with the worst long-term arithmetic, because it does not recover and because the frequencies lost first carry the consonants. In children under five the cumulative incidence reaches 75 percent at three years and it appears early in treatment.
Downstream
Sensorineural hearing impairment The cochlear arm's clinical readout.
Tinnitus Accompanies the hearing loss from the same cochlear injury.
Show evidence (4 references)
PMID:36455457 SUPPORT Other
"Administration of cisplatin, a common chemotherapeutic drug, has an inevitable side effect of sensorineural hearing loss."
States the outcome and its character as sensorineural.
PMID:34490624 SUPPORT Human Clinical
"Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%-84%)"
Gives the paediatric cumulative incidence quoted in this description, from 2052 audiological assessments in 368 patients.
PMID:34490624 SUPPORT Human Clinical
"In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy."
Establishes both the age effect and the early onset during treatment.
+ 1 more reference
Dorsal Root Ganglion Sensory Neuron Injury
Platinum accumulates in dorsal root ganglion sensory neurons, which sit outside the blood-nerve barrier and are therefore not protected the way the rest of the peripheral nervous system is. The primary lesion here is at the cell body, not at the far end of the axon, even though the symptoms begin distally.
dorsal root ganglion sensory neuron CL:1001451 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dorsal root ganglion sensory neuron, annotated with sensory neuron of dorsal root ganglion (CL:1001451). CL:1001451 is a cell type from the Cell Ontology.
Downstream
Sensory Peripheral Neuropathy Loss and dysfunction of sensory neurons produces the clinical neuropathy. The intermediate is loss of primary afferent sensory axonal fibres.
Show evidence (3 references)
PMID:21145397 SUPPORT In Vitro
"cisplatin induces apoptosis in dorsal root ganglion (DRG) sensory neurons by covalently binding to nuclear DNA (nDNA), resulting in DNA damage, subsequent p53 activation and Bax-mediated apoptosis via the mitochondria"
Locates the injury in the dorsal root ganglion neuron and gives the death pathway.
PMID:38660386 SUPPORT Other
"the sensory neurons and axons in the peripheral nervous system (PNS) are more susceptible than the CNS to damage from chemotherapy drugs, due to the absence of an effective blood-nerve barrier in the PNS"
Source for the barrier point in this node's description. The claim is made for the peripheral nervous system and chemotherapy drugs generally, not for the dorsal root ganglion and cisplatin specifically.
PMID:21145397 SUPPORT In Vitro
"DRG neurons are non-dividing cells that repair cisplatin-nDNA adducts via the NER at the same rate as cancer cells; however, accumulation of adducts is higher in neurons."
Establishes that the accumulation, not a repair deficit, is what makes these neurons vulnerable - they repair as fast as tumour cells but start from a higher adduct load.
Mitochondrial DNA Damage in Sensory Neurons
Platinum binds mitochondrial DNA in dorsal root ganglion neurons with the same affinity as nuclear DNA, and blocks its replication and transcription. This is the arm that explains coasting: mitochondria have no nucleotide excision repair, so the adducts are not removed when the drug stops, and the neuron goes on failing.
Downstream
Sensory Peripheral Neuropathy Mitochondrial failure in sensory neurons contributes to the neuropathy on a slower clock than the nuclear-DNA route, and continues after dosing stops.
Show evidence (2 references)
PMID:21145397 SUPPORT In Vitro
"Cisplatin treated DRG neurons exhibit mitochondrial vacuolization and degradation in vitro and in vivo."
Direct morphological evidence of mitochondrial injury in the affected neurons, in culture and in animals.
PMID:21145397 SUPPORT In Vitro
"Mitochondria do not have NER mechanisms for mtDNA."
States the repair gap that this node's description uses to explain why the injury continues after the drug is withdrawn.
Sensory Peripheral Neuropathy
Distal sensory loss, often painful, in about 30 percent of treated patients. Its distinguishing feature is coasting - the neuropathy keeps worsening for weeks to months after the drug is stopped, which is reported only for the platinum drugs.
Downstream
Peripheral neuropathy The neural arm's clinical readout.
Show evidence (3 references)
PMID:21145397 SUPPORT Other
"Cisplatin is a platinum-based chemotherapeutic agent that induces peripheral neuropathy in 30% of patients."
Gives the proportion affected, stated as background in the cited paper.
PMID:21145397 SUPPORT Other
"Patients with cisplatin-induced peripheral neuropathy experience sensory loss, often accompanied by pain, starting in the distal extremities."
Gives the distribution and character of the deficit.
PMID:21145397 SUPPORT Other
"This phenomenon, commonly known as “coasting,” is observed exclusively in platinum-based chemotherapy and suggests that there is ongoing neuronal damage after discontinuing cisplatin."
Establishes coasting and its restriction to the platinum drugs, which is the feature this node is built around.
Cytotoxic Insult to Proliferating Hematopoietic Progenitors
DNA crosslinking in dividing marrow progenitors. This arm needs no transporter story - it is the ordinary antiproliferative toxicity of a DNA-damaging drug.
haematopoietic progenitor cell CL:0000037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves haematopoietic progenitor cell, annotated with hematopoietic stem cell (CL:0000037). CL:0000037 is a cell type from the Cell Ontology.
Downstream
Bone Marrow Hematopoietic Suppression Progenitor arrest and death reduce marrow output.
Show evidence (1 reference)
PMID:39423903 SUPPORT Other
"its clinical utility is hampered by its dose-limiting toxicities, including nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression"
Names myelosuppression as one of the four dose-limiting toxicities.
Bone Marrow Hematopoietic Suppression
Reduced marrow output across lineages, showing in the blood as anaemia, neutropenia and thrombocytopenia.
Downstream
Anemia Reduced erythroid output.
Decreased total neutrophil count Reduced granulocyte output.
Thrombocytopenia Reduced platelet output.
Show evidence (1 reference)
PMID:39423903 SUPPORT Other
"its clinical utility is hampered by its dose-limiting toxicities, including nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression"
Names myelosuppression as a dose-limiting toxicity.
Emetogenic Response to Cisplatin
Cisplatin is the archetypal highly emetogenic drug: without antiemetic prophylaxis it makes nearly nine in ten patients vomit. This arm is separated from the four injury arms because it is not a cytotoxic lesion - nothing dies - and because it is the toxicity that modern prophylaxis has most changed.
Downstream
Nausea The symptom that has responded least to modern prophylaxis.
Vomiting The symptom that prophylaxis controls best.
Show evidence (1 reference)
PMID:39589545 SUPPORT Other
"One of the most common side effects of cisplatin is chemotherapy-induced nausea and vomiting (CINV), affecting nearly 90% of patients who receive high-dose cisplatin without antiemetic treatment"
Gives the proportion affected in the absence of prophylaxis, which is the claim in this node's description.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cisplatin Toxicity Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Blood 3
Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39423903 SUPPORT Other
"its clinical utility is hampered by its dose-limiting toxicities, including nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression"
Supports the marrow toxicity this cytopenia belongs to. The cited sentence names myelosuppression, not the individual lineage.
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39423903 SUPPORT Other
"its clinical utility is hampered by its dose-limiting toxicities, including nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression"
Supports the marrow toxicity this cytopenia belongs to, at the level of myelosuppression rather than the individual lineage.
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39423903 SUPPORT Other
"its clinical utility is hampered by its dose-limiting toxicities, including nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression"
Supports the marrow toxicity this cytopenia belongs to, at the level of myelosuppression rather than the individual lineage.
Digestive 2
Nausea HP:0002018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nausea (HP:0002018), qualified as temporality acute. HP:0002018 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:39589545 SUPPORT Other
"One of the most common side effects of cisplatin is chemotherapy-induced nausea and vomiting (CINV), affecting nearly 90% of patients who receive high-dose cisplatin without antiemetic treatment"
Establishes nausea as part of the near-universal untreated emetogenic response. No frequency band is asserted, because the figure quoted is the untreated rate and patients now receive prophylaxis.
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013), qualified as temporality acute. HP:0002013 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:39589545 SUPPORT Other
"One of the most common side effects of cisplatin is chemotherapy-induced nausea and vomiting (CINV), affecting nearly 90% of patients who receive high-dose cisplatin without antiemetic treatment"
Establishes vomiting as part of the same untreated response, with the same caveat about prophylaxis.
Ear 2
Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407), qualified as course progressive. HP:0000407 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:36455457 SUPPORT Other
"Administration of cisplatin, a common chemotherapeutic drug, has an inevitable side effect of sensorineural hearing loss."
Establishes the phenotype and its sensorineural character.
PMID:34490624 SUPPORT Human Clinical
"Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%-84%)"
Gives a cumulative incidence in the highest-risk age group. No frequency band is asserted on this phenotype, because the incidence is strongly age-dependent - 75 percent under five against 48 percent over five in the same cohort - and a single band would misrepresent that.
Tinnitus HP:0000360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tinnitus (HP:0000360). HP:0000360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36455457 SUPPORT Other
"The main etiologies are stria vascularis injury, spiral ganglion degeneration, and hair cell death."
Supports the cochlear lesions underlying this symptom. The cited sentence names the cochlear pathology rather than tinnitus itself, and this entry does not claim a frequency for it.
Genitourinary 1
Acute kidney injury HP:0001919 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute kidney injury (HP:0001919), qualified as temporality acute. HP:0001919 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (2 references)
PMID:19144690 SUPPORT In Vitro
"The uptake of cisplatin in renal tubular cells is high, leading to cisplatin accumulation and tubular cell injury and death, culminating in acute renal failure."
States the renal endpoint. This is a mechanistic study in cells and mice, not a clinical incidence series.
PMID:37530867 SUPPORT Human Clinical
"Cisplatin-induced nephrotoxicity (CIN) limits the use of this drug and affects up to 20% of patients."
Gives a clinical proportion affected. "Up to 20 percent" is an upper bound stated as background in a systematic review, so no frequency band is asserted from it.
Metabolism 1
Hypomagnesemia HP:0002917 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypomagnesemia (HP:0002917). HP:0002917 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18272962 SUPPORT Other
"side effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the use of cisplatin and related platinum-based therapeutics"
Supports the renal toxicity this electrolyte disturbance belongs to. The cited sentence does not name magnesium wasting specifically, and the persistence claim in the description is not asserted by this source.
Nervous System 1
Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830), qualified as course progressive. HP:0009830 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:21145397 SUPPORT Other
"Patients with cisplatin-induced peripheral neuropathy experience sensory loss, often accompanied by pain, starting in the distal extremities."
Gives the distribution and character of the deficit.
PMID:21145397 SUPPORT Other
"This phenomenon, commonly known as “coasting,” is observed exclusively in platinum-based chemotherapy and suggests that there is ongoing neuronal damage after discontinuing cisplatin."
Supports the post-treatment worsening named in the description.
🧬

Genetic Associations

3
ACYP2
Gene: ACYP2 hgnc:180 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ACYP2 (hgnc:180). hgnc:180 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:37726872 SUPPORT Human Clinical
"Specifically, an ACYP2 variant has been associated with ototoxicity in both children and adults, whereas TPMT variants are relevant in children."
Names ACYP2 as associated in both age groups, which is the claim curated here.
PMID:37726872 SUPPORT Human Clinical
"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."
Gives the evidence bar - odds ratio at least 3, replicated in at least three populations - that this gene clears and that most candidate loci do not.
TPMT
Gene: TPMT hgnc:12014 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TPMT (hgnc:12014). hgnc:12014 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:37726872 SUPPORT Human Clinical
"Specifically, an ACYP2 variant has been associated with ototoxicity in both children and adults, whereas TPMT variants are relevant in children."
Names TPMT and restricts its relevance to children, which is the limit recorded in the notes.
PMID:37726872 SUPPORT Human Clinical
"Genetic variation in ACYP2 and TPMT may be helpful in predicting patients at the highest risk of developing cisplatin-induced ototoxicity."
The review's own conclusion, naming these two genes and no others as potentially clinically useful predictors.
COMT
Gene: COMT hgnc:2228 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COMT (hgnc:2228). hgnc:2228 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED
Show evidence (1 reference)
PMID:37726872 SUPPORT Human Clinical
"Encouraging evidence for associations involving several other genes also exists; however, further research is necessary to determine potential clinical relevance."
Supports the disputed grading. The sentence covers the non-top-tier genes as a class; it does not name COMT, and the placement of COMT in that class rather than the top tier follows from the same review naming only ACYP2 and TPMT as strong.
💊

Medical Actions

5
Duloxetine for established painful CIPN
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: duloxetine CHEBI:36796 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses duloxetine (CHEBI:36796). CHEBI:36796 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The only agent ASCO supports for established painful chemotherapy-induced peripheral neuropathy, and the guideline is careful to say the benefit is limited. It treats the pain, not the neuropathy - nothing regrows the sensory neurons - which is why it sits on the outcome node rather than upstream.
Mechanism Target:
MODULATES Sensory Peripheral Neuropathy — Reduces painful symptoms of established neuropathy. Recorded as MODULATES because the guideline supports symptom benefit and does not claim reversal of the underlying nerve injury.
Show evidence (1 reference)
PMID:32663120 SUPPORT Human Clinical
"Duloxetine is the only agent that has appropriate evidence to support its use for patients with established painful CIPN."
The guideline's single positive recommendation for established CIPN.
Show evidence (1 reference)
PMID:32663120 SUPPORT Human Clinical
"The identified data reconfirmed that no agents are recommended for the prevention of CIPN."
Establishes the surrounding negative: nothing prevents this neuropathy, so duloxetine's role is confined to treating pain once it exists. Carried on this treatment because it is what bounds the claim.
Acetyl-L-carnitine for CIPN prevention
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
Curated as a treatment that does not work. ASCO discourages its use for prevention of chemotherapy-induced peripheral neuropathy. It is recorded here so the entry answers the question a clinician actually asks - not only what to give, but what to stop giving.
Show evidence (1 reference)
PMID:32663120 REFUTE Human Clinical
"The use of acetyl-l-carnitine for the prevention of CIPN in patients with cancer should be discouraged."
An explicit negative recommendation, curated as REFUTE against the claim that this agent prevents the neuropathy.
Dose modification for intolerable neuropathy
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Where no drug prevents the neuropathy, the remaining lever is the cisplatin dose itself - delaying, reducing, substituting or stopping. This acts on the exposure rather than on any downstream injury, and it is what makes the neuropathy dose-limiting in practice.
Mechanism Target:
INHIBITS Cisplatin Uptake by Transporter-Expressing Cells — Reducing or stopping the drug reduces the platinum delivered to the transporter-expressing tissues at the head of every arm in this entry.
Show evidence (1 reference)
PMID:32663120 SUPPORT Human Clinical
"clinicians should assess the appropriateness of dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment"
The guideline's recommendation for what to do when the neuropathy becomes intolerable, which is an intervention on exposure rather than on injury.
Sodium thiosulfate otoprotection
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium thiosulfate NCIT:C1230 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses sodium thiosulfate (NCIT:C1230). NCIT:C1230 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
A sulfur nucleophile that inactivates platinum, given six hours after the cisplatin infusion. The delay is the whole design: given at the same time it would protect the tumour too, and pharmacokinetic work put six hours as the interval that protects the ear without doing that. In a randomised phase 3 trial in children with standard-risk hepatoblastoma it cut hearing loss from 63 percent to 33 percent without reducing survival.
Mechanism Target:
INHIBITS Cochlear Hair Cell Death — Reduces the incidence of hearing loss, which this entry places downstream of hair cell death. The trial measured hearing thresholds, not hair cell survival, so the effect is asserted on the clinical outcome and located at this node by inference.
Show evidence (2 references)
PMID:29924955 SUPPORT Human Clinical
"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%..."
Randomised phase 3 result with effect size and confidence interval. This is the strongest treatment evidence in the entry.
PMID:27914822 SUPPORT Human Clinical
"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)."
A second, independent randomised phase 3 trial (ACCL0431, Children's Oncology Group) reaching the same conclusion in a mixed-tumour paediatric population. Two trials in different populations is materially stronger than one.
Show evidence (3 references)
PMID:29924955 SUPPORT Human Clinical
"The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival."
States the conclusion, including that tumour control was not compromised, which is the concern the delayed schedule exists to address.
PMID:29924955 SUPPORT Human Clinical
"Nonclinical studies and initial phase 1-2 trials indicated that sodium thiosulfate has a potential otoprotective effect, with maximum efficacy occurring when sodium thiosulfate is administered 4 to 8 hours after cisplatin"
Gives the timing window this treatment's description is built on.
PMID:27914822 SUPPORT Human Clinical
"Sodium thiosulfate protects against cisplatin-induced hearing loss in children and is not associated with serious adverse events attributed to its use."
The second trial's own conclusion, including its safety finding. Both trials were in children; neither establishes the effect in adults.
Renoprotective supportive care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Measures aimed at the renal arm, of which intravenous saline hydration with magnesium replacement is the routine one. The honest summary of this area is that protection is partial: no single measure abolishes the nephrotoxicity, and the field is still combining them.
Mechanism Target:
INHIBITS Proximal Tubular Epithelial Cell Death — Magnesium supplementation during hydration reduces cisplatin nephrotoxicity. The meta-analysis measured the clinical nephrotoxicity endpoint, not tubular cell death, so the effect is located at this node by inference.
Show evidence (1 reference)
PMID:37530867 SUPPORT Human Clinical
"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)."
Gives the effect size and interval. The pooled studies are retrospective, which is a real limit on this estimate and is why the accompanying review still reports uncertainty about the best protocol.
Show evidence (3 references)
PMID:18272962 SUPPORT Other
"Renoprotective approaches are being discovered, but the protective effects are mostly partial, suggesting the need for combinatorial strategies."
States that renoprotection is partial, which is the claim this treatment makes. The source speaks of renoprotective approaches in general; it does not name hydration, and this entry does not cite it as evidence for hydration specifically.
PMID:18272962 SUPPORT Other
"Importantly, it is unclear whether these approaches would limit the anticancer effects of cisplatin in tumors."
Records the open question that constrains every protective strategy here - the same concern the sodium thiosulfate schedule was designed around, left unresolved on the renal side.
PMID:37530867 SUPPORT Human Clinical
"There has been uncertainty regarding the best method to prevent CIN."
States that the optimal prevention protocol is unsettled, which is why this treatment is curated at the level of the magnesium arm rather than a named hydration regimen.
📊

Prevalence

4
Children aged 5 years or under receiving cisplatin
Period Prevalence 75000.0 per 100,000 >1 in 1,000
Cumulative incidence of cisplatin-induced hearing loss at three years, from 2052 audiological assessments in 368 Canadian children. Strongly age-dependent - 48 percent in those over five in the same cohort - which is why this record is stratified by age rather than reported for children as a whole.
Show evidence (1 reference)
PMID:34490624 SUPPORT Human Clinical
"Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%-84%)"
Gives the figure and its interval for the highest-risk stratum.
Patients receiving cisplatin
Period Prevalence 20000.0 per 100,000 >1 in 1,000
Cisplatin-induced nephrotoxicity, stated as an upper bound in a systematic review rather than as a point estimate. Reported incidence for this endpoint varies with the creatinine threshold used to define it.
Show evidence (1 reference)
PMID:37530867 SUPPORT Human Clinical
"Cisplatin-induced nephrotoxicity (CIN) limits the use of this drug and affects up to 20% of patients."
Gives the proportion affected, as an upper bound.
Patients receiving cisplatin
Period Prevalence 30000.0 per 100,000 >1 in 1,000
Cisplatin-induced peripheral neuropathy, stated as background in a mechanistic paper rather than derived from a cohort in that paper.
Show evidence (1 reference)
PMID:21145397 SUPPORT Other
"Cisplatin is a platinum-based chemotherapeutic agent that induces peripheral neuropathy in 30% of patients."
Gives the proportion affected. Background statement, not a primary measurement in the cited study.
Patients receiving high-dose cisplatin without antiemetic prophylaxis
Period Prevalence 90000.0 per 100,000 >1 in 1,000
Chemotherapy-induced nausea and vomiting in the absence of prophylaxis. This figure describes a population that no longer exists in practice, since prophylaxis is standard; it is recorded because it is what the toxicity does when unopposed.
Show evidence (1 reference)
PMID:39589545 SUPPORT Other
"One of the most common side effects of cisplatin is chemotherapy-induced nausea and vomiting (CINV), affecting nearly 90% of patients who receive high-dose cisplatin without antiemetic treatment"
Gives the untreated rate.
🔬

Clinical Trials

2
NCT00652132 PHASE_III COMPLETED
SIOPEL 6. Randomised open-label phase 3 trial of delayed sodium thiosulfate for otoprotection in children receiving cisplatin for standard-risk hepatoblastoma. Reported as a 48 percent lower incidence of hearing loss without loss of survival.
Target Phenotypes: Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT00652132 SUPPORT Human Clinical
"This randomized phase III trial is studying how well sodium thiosulfate works to decrease hearing loss caused by cisplatin in treating young patients with stage I, stage II, or stage III childhood liver cancer."
The registered description of the trial, confirming design, agent, indication and population.
NCT00716976 PHASE_III COMPLETED
ACCL0431. Children's Oncology Group randomised phase 3 trial of sodium thiosulfate versus observation across a mixed paediatric tumour population. Reported an odds ratio of 0.31 for hearing loss.
Target Phenotypes: Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT00716976 SUPPORT Human Clinical
"This randomized phase III trial is studying sodium thiosulfate to see how well it works in preventing hearing loss in young patients receiving cisplatin for newly diagnosed germ cell tumor, hepatoblastoma, medulloblastoma, neuroblastoma, osteosarcoma, or other malignancy."
The registered description, confirming the broader tumour population that makes this trial complementary to SIOPEL 6 rather than a replication.
{ }

Source YAML

click to show 
name: Cisplatin Toxicity
creation_date: '2026-09-02T00:15:00Z'
description: >-
  Cisplatin toxicity is the injury a platinum drug does to the patient it is
  meant to cure. The drug works by crosslinking DNA, and it does that in whatever
  cell it enters, so the question of which tissue is harmed is not a question
  about the lesion at all. It is a question about which cells take the platinum
  up, and whether those cells can repair the damage or be replaced. Kidney
  proximal tubule takes it in through OCT2 and Ctr1 and dies. Cochlear hair cells
  take it in and cannot be regenerated, so the hearing loss is permanent. Dorsal
  root ganglion neurons sit outside the blood-nerve barrier, accumulate platinum,
  and go on degenerating for months after the last dose. Marrow is hit because
  marrow divides. Four dose-limiting toxicities, one lesion, and the difference
  between them is transport and repair rather than mechanism.
categories:
- Treatment Toxicity
category: Complex
parents:
- Drug Toxicity
disease_term:
  preferred_term: cisplatin toxicity
  term:
    id: MONDO:0027664
    label: cisplatin toxicity
pathophysiology:
- name: Cisplatin Uptake by Transporter-Expressing Cells
  description: >-
    Cisplatin does not enter cells freely. It is carried in, chiefly by the
    organic cation transporter OCT2 and the copper transporter Ctr1, and the
    tissues that express those transporters most heavily are the tissues that are
    injured. This node is the selectivity step of the whole disease - it explains
    why a drug that crosslinks DNA everywhere produces damage in four particular
    organs and not uniformly.
  role: trigger
  biological_scale: CELLULAR
  conforms_to: "drug_induced_nephrotoxicity#Nephrotoxic Drug Exposure and Tubular Uptake"
  evidence:
  - reference: PMID:16242669
    reference_title: "Association between tubular toxicity of cisplatin and expression of organic cation transporter rOCT2 (Slc22a2) in the rat."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the present results indicated that renal rOCT2 expression was the major
      determinant of cisplatin-induced tubular toxicity
    explanation: >-
      Identifies transporter expression, not intrinsic cellular sensitivity, as
      what determines where the toxicity falls. This is the claim the node is
      built on. Graded MODEL_ORGANISM because the quoted conclusion rests on the
      in vivo rat arm - sex differences in renal uptake clearance, urinary
      N-acetyl-beta-D-glucosaminidase, and the castrated-male comparison - even
      though the paper also reports transfected-cell work.
  - reference: PMID:19144690
    reference_title: "The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      downregulation of Ctr1 suppresses cisplatin toxicity, including cell death
      by both apoptosis and necrosis
    explanation: >-
      Shows the second transporter arm, and shows it causally - removing the
      transporter removes the toxicity.
  downstream:
  - target: Platinum-DNA Adduct Formation
    causal_link_type: DIRECT
    description: >-
      Uptake delivers platinum to intracellular DNA. Everything downstream
      follows from the adducts; this edge is what makes uptake rate-limiting.
    evidence:
    - reference: PMID:19144690
      reference_title: "The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The uptake of cisplatin in renal tubular cells is high, leading to
        cisplatin accumulation and tubular cell injury and death, culminating in
        acute renal failure.
      explanation: >-
        States the uptake-to-accumulation-to-injury sequence this edge asserts, in
        the renal arm.
  - target: Emetogenic Response to Cisplatin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Administration of cisplatin is also followed by severe emesis. The edge is
      recorded as indirect with unknown intermediates on purpose: unlike the four
      injury arms, this one is not established here as running through OCT2 or
      Ctr1 uptake into the affected tissue, and the sources cited in this entry do
      not supply the route.
- name: Platinum-DNA Adduct Formation
  description: >-
    Aquated cisplatin binds DNA and forms crosslinks. This is the therapeutic
    mechanism and the toxic mechanism, and they are the same mechanism - there is
    no separate off-target lesion to find. Adducts form in nuclear DNA and in
    mitochondrial DNA, and the distinction matters because the mitochondrion
    cannot repair them.
  role: central_effector
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: INCREASED
  evidence:
  - reference: PMID:39423903
    reference_title: "Advances in understanding cisplatin-induced toxicity: Molecular mechanisms and protective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanisms of cisplatin toxicity are multifactorial and involve
      oxidative stress, inflammation, DNA damage, and cellular apoptosis.
    explanation: >-
      Names DNA damage alongside oxidative stress and apoptosis as the shared
      mechanisms across the toxicities, which is how this entry arranges them.
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      cisplatin induces apoptosis in dorsal root ganglion (DRG) sensory neurons by
      covalently binding to nuclear DNA (nDNA), resulting in DNA damage,
      subsequent p53 activation and Bax-mediated apoptosis via the mitochondria
    explanation: >-
      Gives the covalent binding, the damage response and the apoptotic route in
      one of the four affected tissues.
  downstream:
  - target: Oxidative Stress and Mitochondrial Injury
    causal_link_type: DIRECT
    description: >-
      Adduct formation is accompanied by reactive oxygen species generation and
      mitochondrial damage, which is the arm that reaches post-mitotic cells.
  - target: Apoptotic Cell Death in Platinum-Loaded Tissue
    causal_link_type: DIRECT
    description: >-
      Unrepaired adducts activate the damage response and drive apoptosis.
- name: Oxidative Stress and Mitochondrial Injury
  description: >-
    Reactive oxygen species generation and mitochondrial damage. This arm matters
    most in the tissues that do not divide, because a post-mitotic cell is not
    threatened by a stalled replication fork but is threatened by losing its
    mitochondria.
  role: intermediate
  biological_scale: CELLULAR
  conforms_to: "drug_induced_nephrotoxicity#Tubular Oxidative Stress and Mitochondrial Injury"
  biological_processes:
  - preferred_term: cellular response to oxidative stress
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:39423903
    reference_title: "Advances in understanding cisplatin-induced toxicity: Molecular mechanisms and protective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanisms of cisplatin toxicity are multifactorial and involve
      oxidative stress, inflammation, DNA damage, and cellular apoptosis.
    explanation: >-
      Names oxidative stress as one of the shared mechanisms across cisplatin's
      toxicities.
  - reference: PMID:36455457
    reference_title: "Cisplatin-induced ototoxicity: From signaling network to therapeutic targets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Upon entering hair cells, cisplatin disrupts organelle metabolism, induces
      oxidative stress, and targets DNA to cause intracellular damage.
    explanation: >-
      Gives the same three-part injury - organelle, oxidative, DNA - in the
      cochlear arm specifically.
  downstream:
  - target: Apoptotic Cell Death in Platinum-Loaded Tissue
    causal_link_type: DIRECT
    description: >-
      Oxidative and mitochondrial injury converge on the same apoptotic endpoint
      as the direct DNA damage arm.
  - target: Mitochondrial DNA Damage in Sensory Neurons
    causal_link_type: DIRECT
    description: >-
      In dorsal root ganglion neurons the mitochondrial arm is not merely
      accompanying injury; platinum binds mitochondrial DNA directly.
- name: Apoptotic Cell Death in Platinum-Loaded Tissue
  description: >-
    Programmed death of the cells that took up the most platinum. The same
    endpoint in four tissues, which is why the four toxicities look
    mechanistically alike while behaving very differently in the clinic. What
    differs downstream is whether the dead cell can be replaced.
  role: intermediate
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      cisplatin induces apoptosis in dorsal root ganglion (DRG) sensory neurons by
      covalently binding to nuclear DNA (nDNA), resulting in DNA damage,
      subsequent p53 activation and Bax-mediated apoptosis via the mitochondria
    explanation: >-
      Gives the apoptotic pathway from adduct to p53 to Bax in one of the affected
      tissues.
  downstream:
  - target: Proximal Tubular Epithelial Cell Death
    causal_link_type: DIRECT
    description: >-
      The renal arm. Tubular epithelium can regenerate, which is why this
      toxicity is often reversible where the cochlear one is not.
  - target: Cochlear Hair Cell Death
    causal_link_type: DIRECT
    description: >-
      The cochlear arm. Mammalian hair cells do not regenerate, so this cell death
      is the permanent one.
  - target: Cytotoxic Insult to Proliferating Hematopoietic Progenitors
    causal_link_type: DIRECT
    description: >-
      The marrow arm. Progenitors are hit for the ordinary antiproliferative
      reason rather than for any transporter-specific one.
  - target: Dorsal Root Ganglion Sensory Neuron Injury
    causal_link_type: DIRECT
    description: >-
      The neural arm. Sensory neurons are post-mitotic and irreplaceable, so this
      arm shares the cochlear arm's arithmetic rather than the marrow's.
- name: Proximal Tubular Epithelial Cell Death
  description: >-
    Death of proximal tubule epithelium, the cells that concentrated the drug.
    Distal segments are affected too, which is where the magnesium wasting comes
    from.
  role: intermediate
  biological_scale: TISSUE
  conforms_to: "drug_induced_nephrotoxicity#Proximal Tubular Epithelial Cell Death"
  cell_types:
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  evidence:
  - reference: PMID:18272962
    reference_title: "Cisplatin nephrotoxicity: mechanisms and renoprotective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      side effects in normal tissues and organs, notably nephrotoxicity in the
      kidneys, limit the use of cisplatin and related platinum-based
      therapeutics
    explanation: >-
      Establishes nephrotoxicity as the dose-limiting normal-tissue injury this
      arm models.
  downstream:
  - target: Cisplatin-Induced Acute Kidney Injury
    causal_link_type: DIRECT
    description: >-
      Loss of tubular epithelium produces the fall in filtration.
    evidence:
    - reference: PMID:19144690
      reference_title: "The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The uptake of cisplatin in renal tubular cells is high, leading to
        cisplatin accumulation and tubular cell injury and death, culminating in
        acute renal failure.
      explanation: >-
        States tubular cell death culminating in acute renal failure, which is
        this edge.
- name: Cisplatin-Induced Acute Kidney Injury
  description: >-
    Falling glomerular filtration after tubular injury, with magnesium and
    potassium wasting alongside it. Unlike the cochlear arm this is often
    reversible, because the epithelium regenerates.
  role: outcome
  biological_scale: ORGANISM
  conforms_to: "drug_induced_nephrotoxicity#Acute Kidney Injury"
  evidence:
  - reference: PMID:39423903
    reference_title: "Advances in understanding cisplatin-induced toxicity: Molecular mechanisms and protective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      its clinical utility is hampered by its dose-limiting toxicities, including
      nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression
    explanation: >-
      Names nephrotoxicity as one of the four dose-limiting toxicities this entry
      is organised around.
  downstream:
  - target: Acute kidney injury
    causal_link_type: DIRECT
    description: >-
      The renal arm's clinical readout.
  - target: Hypomagnesemia
    causal_link_type: DIRECT
    description: >-
      Magnesium wasting from injury to the reabsorbing tubular segments,
      alongside the fall in filtration.
- name: Cochlear Hair Cell Death
  description: >-
    Death of cochlear hair cells, beginning with the outer hair cells of the basal
    turn, which is why the loss starts at high frequency. Hair cell death is not
    the only cochlear lesion - stria vascularis injury and spiral ganglion
    degeneration are reported alongside it - and this entry does not model it as
    the sole route.
  role: intermediate
  biological_scale: TISSUE
  conforms_to: "sensorineural_hair_cell_loss#Hair Cell Mechanotransduction Failure and Death"
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  evidence:
  - reference: PMID:36455457
    reference_title: "Cisplatin-induced ototoxicity: From signaling network to therapeutic targets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The main etiologies are stria vascularis injury, spiral ganglion
      degeneration, and hair cell death.
    explanation: >-
      Names hair cell death as a main route and, in the same sentence, the two
      other cochlear lesions this node's description declines to subsume.
  - reference: PMID:36455457
    reference_title: "Cisplatin-induced ototoxicity: From signaling network to therapeutic targets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Upon entering hair cells, cisplatin disrupts organelle metabolism, induces
      oxidative stress, and targets DNA to cause intracellular damage.
    explanation: >-
      Locates the injury inside the hair cell and gives its three components.
  downstream:
  - target: Irreversible Sensorineural Hearing Loss
    causal_link_type: DIRECT
    description: >-
      Hair cell loss gives permanent hearing loss, and the permanence is what
      separates this arm from the renal one, where the epithelium regenerates.
    evidence:
    - reference: PMID:29924955
      reference_title: "Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cisplatin chemotherapy and surgery are effective treatments for children
        with standard-risk hepatoblastoma but may cause considerable and
        irreversible hearing loss.
      explanation: >-
        Establishes the irreversibility this edge asserts. The usual explanation -
        that mammalian cochlear hair cells are not regenerated - is not stated by
        the sources cited in this entry, so it is not asserted here.
  notes: >-
    Conformance is asserted at the module's hair-cell death node. The module node
    names mechanotransduction failure as well as death; the sources cited here
    establish hair cell death and the intracellular injury behind it, and do not
    report a mechanotransduction measurement. Read the conformance as covering the
    death half.
- name: Irreversible Sensorineural Hearing Loss
  description: >-
    Permanent high-frequency sensorineural hearing loss. It is the toxicity with
    the worst long-term arithmetic, because it does not recover and because the
    frequencies lost first carry the consonants. In children under five the
    cumulative incidence reaches 75 percent at three years and it appears early in
    treatment.
  role: outcome
  biological_scale: ORGANISM
  conforms_to: "sensorineural_hair_cell_loss#Progressive Sensorineural Hearing Loss"
  evidence:
  - reference: PMID:36455457
    reference_title: "Cisplatin-induced ototoxicity: From signaling network to therapeutic targets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Administration of cisplatin, a common chemotherapeutic drug, has an
      inevitable side effect of sensorineural hearing loss.
    explanation: >-
      States the outcome and its character as sensorineural.
  - reference: PMID:34490624
    reference_title: "The cumulative incidence of cisplatin-induced hearing loss in young children is higher and develops at an early stage during therapy compared with older children based on 2052 audiological assessments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three years after initiating therapy, the cumulative incidence of CIHL was
      highest in patients aged ≤5 years (75%; 95% confidence interval [CI],
      66%-84%)
    explanation: >-
      Gives the paediatric cumulative incidence quoted in this description, from
      2052 audiological assessments in 368 patients.
  - reference: PMID:34490624
    reference_title: "The cumulative incidence of cisplatin-induced hearing loss in young children is higher and develops at an early stage during therapy compared with older children based on 2052 audiological assessments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In young children, the cumulative incidence of CIHL is higher compared with
      that in older children and develops early during therapy.
    explanation: >-
      Establishes both the age effect and the early onset during treatment.
  - reference: PMID:29924955
    reference_title: "Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key consonants are heard at high frequencies (4 kHz through 8 kHz), and so
      their loss is debilitating, particularly in young children in whom speech
      has not yet developed
    explanation: >-
      Source for the consonant point in this node's description, and for why a
      high-frequency loss matters more in a young child than its audiometric size
      suggests.
  downstream:
  - target: Sensorineural hearing impairment
    causal_link_type: DIRECT
    description: >-
      The cochlear arm's clinical readout.
  - target: Tinnitus
    causal_link_type: DIRECT
    description: >-
      Accompanies the hearing loss from the same cochlear injury.
- name: Dorsal Root Ganglion Sensory Neuron Injury
  description: >-
    Platinum accumulates in dorsal root ganglion sensory neurons, which sit
    outside the blood-nerve barrier and are therefore not protected the way the
    rest of the peripheral nervous system is. The primary lesion here is at the
    cell body, not at the far end of the axon, even though the symptoms begin
    distally.
  role: intermediate
  biological_scale: CELLULAR
  conforms_to: "peripheral_axonal_degeneration#Insult to Peripheral Neurons and Schwann Cells"
  cell_types:
  - preferred_term: dorsal root ganglion sensory neuron
    term:
      id: CL:1001451
      label: sensory neuron of dorsal root ganglion
  evidence:
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      cisplatin induces apoptosis in dorsal root ganglion (DRG) sensory neurons by
      covalently binding to nuclear DNA (nDNA), resulting in DNA damage,
      subsequent p53 activation and Bax-mediated apoptosis via the mitochondria
    explanation: >-
      Locates the injury in the dorsal root ganglion neuron and gives the death
      pathway.
  - reference: PMID:38660386
    reference_title: "Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the sensory neurons and axons in the peripheral nervous system (PNS) are
      more susceptible than the CNS to damage from chemotherapy drugs, due to the
      absence of an effective blood-nerve barrier in the PNS
    explanation: >-
      Source for the barrier point in this node's description. The claim is made
      for the peripheral nervous system and chemotherapy drugs generally, not for
      the dorsal root ganglion and cisplatin specifically.
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      DRG neurons are non-dividing cells that repair cisplatin-nDNA adducts via
      the NER at the same rate as cancer cells; however, accumulation of adducts
      is higher in neurons.
    explanation: >-
      Establishes that the accumulation, not a repair deficit, is what makes these
      neurons vulnerable - they repair as fast as tumour cells but start from a
      higher adduct load.
  downstream:
  - target: Sensory Peripheral Neuropathy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss and dysfunction of sensory neurons produces the clinical neuropathy.
      The intermediate is loss of primary afferent sensory axonal fibres.
    evidence:
    - reference: PMID:38660386
      reference_title: "Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        CIPN is characterized by a substantial loss of primary afferent sensory
        axonal fibers leading to sensory disturbances in patients.
      explanation: >-
        Names the fibre loss that stands between neuron injury and symptoms. The
        source covers chemotherapy-induced neuropathy across several drug classes,
        so this supports the shared endpoint rather than a cisplatin-specific
        route.
  notes: >-
    Conformance is asserted at the module's insult node, which is where a toxic
    injury to peripheral sensory neurons belongs. This entry deliberately does NOT
    conform to the module's "Distal Axonal Degeneration and Demyelination" node.
    Cisplatin neuropathy is a sensory neuronopathy - the platinum accumulates in
    and kills the ganglion cell body - and none of the sources cited here reports
    demyelination. Symptoms begin distally, which is a different claim from the
    lesion being distal, and the entry keeps those apart.
- name: Mitochondrial DNA Damage in Sensory Neurons
  description: >-
    Platinum binds mitochondrial DNA in dorsal root ganglion neurons with the same
    affinity as nuclear DNA, and blocks its replication and transcription. This is
    the arm that explains coasting: mitochondria have no nucleotide excision
    repair, so the adducts are not removed when the drug stops, and the neuron
    goes on failing.
  role: intermediate
  biological_scale: CELLULAR
  conforms_to: "peripheral_axonal_degeneration#Axonal Transport Impairment and Mitochondrial Dysfunction"
  evidence:
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cisplatin treated DRG neurons exhibit mitochondrial vacuolization and
      degradation in vitro and in vivo.
    explanation: >-
      Direct morphological evidence of mitochondrial injury in the affected
      neurons, in culture and in animals.
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mitochondria do not have NER mechanisms for mtDNA.
    explanation: >-
      States the repair gap that this node's description uses to explain why the
      injury continues after the drug is withdrawn.
  downstream:
  - target: Sensory Peripheral Neuropathy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Mitochondrial failure in sensory neurons contributes to the neuropathy on a
      slower clock than the nuclear-DNA route, and continues after dosing stops.
  notes: >-
    The module node names axonal transport impairment and mitochondrial
    dysfunction together. Only the mitochondrial half is evidenced here. The
    axonal-transport mechanism in chemotherapy-induced neuropathy is best
    established for the microtubule-targeting agents - taxanes and vinca alkaloids
    - and this entry does not transfer that mechanism to cisplatin, which is not a
    microtubule poison.
- name: Sensory Peripheral Neuropathy
  description: >-
    Distal sensory loss, often painful, in about 30 percent of treated patients.
    Its distinguishing feature is coasting - the neuropathy keeps worsening for
    weeks to months after the drug is stopped, which is reported only for the
    platinum drugs.
  role: outcome
  biological_scale: ORGANISM
  conforms_to: "peripheral_axonal_degeneration#Peripheral Neuropathy"
  evidence:
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cisplatin is a platinum-based chemotherapeutic agent that induces peripheral
      neuropathy in 30% of patients.
    explanation: >-
      Gives the proportion affected, stated as background in the cited paper.
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients with cisplatin-induced peripheral neuropathy experience sensory
      loss, often accompanied by pain, starting in the distal extremities.
    explanation: >-
      Gives the distribution and character of the deficit.
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This phenomenon, commonly known as “coasting,” is observed exclusively in
      platinum-based chemotherapy and suggests that there is ongoing neuronal
      damage after discontinuing cisplatin.
    explanation: >-
      Establishes coasting and its restriction to the platinum drugs, which is the
      feature this node is built around.
  downstream:
  - target: Peripheral neuropathy
    causal_link_type: DIRECT
    description: >-
      The neural arm's clinical readout.
- name: Cytotoxic Insult to Proliferating Hematopoietic Progenitors
  description: >-
    DNA crosslinking in dividing marrow progenitors. This arm needs no transporter
    story - it is the ordinary antiproliferative toxicity of a DNA-damaging drug.
  role: intermediate
  biological_scale: CELLULAR
  conforms_to: "myelosuppression#Cytotoxic Insult to Proliferating Hematopoietic Progenitors"
  cell_types:
  - preferred_term: haematopoietic progenitor cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  evidence:
  - reference: PMID:39423903
    reference_title: "Advances in understanding cisplatin-induced toxicity: Molecular mechanisms and protective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      its clinical utility is hampered by its dose-limiting toxicities, including
      nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression
    explanation: >-
      Names myelosuppression as one of the four dose-limiting toxicities.
  downstream:
  - target: Bone Marrow Hematopoietic Suppression
    causal_link_type: DIRECT
    description: >-
      Progenitor arrest and death reduce marrow output.
- name: Bone Marrow Hematopoietic Suppression
  description: >-
    Reduced marrow output across lineages, showing in the blood as anaemia,
    neutropenia and thrombocytopenia.
  role: outcome
  biological_scale: TISSUE
  conforms_to: "myelosuppression#Bone Marrow Hematopoietic Suppression"
  evidence:
  - reference: PMID:39423903
    reference_title: "Advances in understanding cisplatin-induced toxicity: Molecular mechanisms and protective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      its clinical utility is hampered by its dose-limiting toxicities, including
      nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression
    explanation: >-
      Names myelosuppression as a dose-limiting toxicity.
  downstream:
  - target: Anemia
    causal_link_type: DIRECT
    description: >-
      Reduced erythroid output.
  - target: Decreased total neutrophil count
    causal_link_type: DIRECT
    description: >-
      Reduced granulocyte output.
  - target: Thrombocytopenia
    causal_link_type: DIRECT
    description: >-
      Reduced platelet output.
- name: Emetogenic Response to Cisplatin
  description: >-
    Cisplatin is the archetypal highly emetogenic drug: without antiemetic
    prophylaxis it makes nearly nine in ten patients vomit. This arm is separated
    from the four injury arms because it is not a cytotoxic lesion - nothing dies -
    and because it is the toxicity that modern prophylaxis has most changed.
  role: intermediate
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:39589545
    reference_title: "The evolving landscape of antiemetic prophylaxis for chemotherapy-induced nausea and vomiting: inspiration from cisplatin-based antiemetic and non-antiemetic trials."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      One of the most common side effects of cisplatin is chemotherapy-induced
      nausea and vomiting (CINV), affecting nearly 90% of patients who receive
      high-dose cisplatin without antiemetic treatment
    explanation: >-
      Gives the proportion affected in the absence of prophylaxis, which is the
      claim in this node's description.
  downstream:
  - target: Nausea
    causal_link_type: DIRECT
    description: >-
      The symptom that has responded least to modern prophylaxis.
  - target: Vomiting
    causal_link_type: DIRECT
    description: >-
      The symptom that prophylaxis controls best.
  notes: >-
    The receptor mechanism - enterochromaffin serotonin release acting on 5-HT3
    receptors, with a delayed NK1/substance P phase - is not asserted here. The
    cited source describes the antiemetic classes used against this toxicity
    rather than the receptor biology producing it, and no source in this entry
    states the mechanism directly.
phenotypes:
- name: Nausea
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
    temporality: ACUTE
  evidence:
  - reference: PMID:39589545
    reference_title: "The evolving landscape of antiemetic prophylaxis for chemotherapy-induced nausea and vomiting: inspiration from cisplatin-based antiemetic and non-antiemetic trials."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      One of the most common side effects of cisplatin is chemotherapy-induced
      nausea and vomiting (CINV), affecting nearly 90% of patients who receive
      high-dose cisplatin without antiemetic treatment
    explanation: >-
      Establishes nausea as part of the near-universal untreated emetogenic
      response. No frequency band is asserted, because the figure quoted is the
      untreated rate and patients now receive prophylaxis.
- name: Vomiting
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
    temporality: ACUTE
  evidence:
  - reference: PMID:39589545
    reference_title: "The evolving landscape of antiemetic prophylaxis for chemotherapy-induced nausea and vomiting: inspiration from cisplatin-based antiemetic and non-antiemetic trials."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      One of the most common side effects of cisplatin is chemotherapy-induced
      nausea and vomiting (CINV), affecting nearly 90% of patients who receive
      high-dose cisplatin without antiemetic treatment
    explanation: >-
      Establishes vomiting as part of the same untreated response, with the same
      caveat about prophylaxis.
- name: Sensorineural hearing impairment
  description: >-
    Permanent, bilateral, high-frequency first. The frequencies lost earliest are
    the ones carrying consonants, which is why even a mild loss matters in a child
    who has not finished learning to speak.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36455457
    reference_title: "Cisplatin-induced ototoxicity: From signaling network to therapeutic targets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Administration of cisplatin, a common chemotherapeutic drug, has an
      inevitable side effect of sensorineural hearing loss.
    explanation: >-
      Establishes the phenotype and its sensorineural character.
  - reference: PMID:34490624
    reference_title: "The cumulative incidence of cisplatin-induced hearing loss in young children is higher and develops at an early stage during therapy compared with older children based on 2052 audiological assessments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three years after initiating therapy, the cumulative incidence of CIHL was
      highest in patients aged ≤5 years (75%; 95% confidence interval [CI],
      66%-84%)
    explanation: >-
      Gives a cumulative incidence in the highest-risk age group. No frequency
      band is asserted on this phenotype, because the incidence is strongly
      age-dependent - 75 percent under five against 48 percent over five in the
      same cohort - and a single band would misrepresent that.
- name: Tinnitus
  phenotype_term:
    preferred_term: Tinnitus
    term:
      id: HP:0000360
      label: Tinnitus
  evidence:
  - reference: PMID:36455457
    reference_title: "Cisplatin-induced ototoxicity: From signaling network to therapeutic targets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The main etiologies are stria vascularis injury, spiral ganglion
      degeneration, and hair cell death.
    explanation: >-
      Supports the cochlear lesions underlying this symptom. The cited sentence
      names the cochlear pathology rather than tinnitus itself, and this entry
      does not claim a frequency for it.
- name: Acute kidney injury
  description: >-
    Falling filtration with tubular injury, typically several days after a dose,
    and usually reversible.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
    temporality: ACUTE
  evidence:
  - reference: PMID:19144690
    reference_title: "The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The uptake of cisplatin in renal tubular cells is high, leading to cisplatin
      accumulation and tubular cell injury and death, culminating in acute renal
      failure.
    explanation: >-
      States the renal endpoint. This is a mechanistic study in cells and mice,
      not a clinical incidence series.
  - reference: PMID:37530867
    reference_title: "A systematic review for prevention of cisplatin-induced nephrotoxicity using different hydration protocols and meta-analysis for magnesium hydrate supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cisplatin-induced nephrotoxicity (CIN) limits the use of this drug and
      affects up to 20% of patients.
    explanation: >-
      Gives a clinical proportion affected. "Up to 20 percent" is an upper bound
      stated as background in a systematic review, so no frequency band is
      asserted from it.
- name: Hypomagnesemia
  description: >-
    Renal magnesium wasting, from injury to the tubular segments that reabsorb it.
    It often outlasts the fall in filtration and can persist long after treatment.
  phenotype_term:
    preferred_term: Hypomagnesemia
    term:
      id: HP:0002917
      label: Hypomagnesemia
  evidence:
  - reference: PMID:18272962
    reference_title: "Cisplatin nephrotoxicity: mechanisms and renoprotective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      side effects in normal tissues and organs, notably nephrotoxicity in the
      kidneys, limit the use of cisplatin and related platinum-based therapeutics
    explanation: >-
      Supports the renal toxicity this electrolyte disturbance belongs to. The
      cited sentence does not name magnesium wasting specifically, and the
      persistence claim in the description is not asserted by this source.
- name: Peripheral neuropathy
  description: >-
    Distal sensory loss, often painful, which can continue to worsen after the
    drug is stopped.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients with cisplatin-induced peripheral neuropathy experience sensory
      loss, often accompanied by pain, starting in the distal extremities.
    explanation: >-
      Gives the distribution and character of the deficit.
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This phenomenon, commonly known as “coasting,” is observed exclusively in
      platinum-based chemotherapy and suggests that there is ongoing neuronal
      damage after discontinuing cisplatin.
    explanation: >-
      Supports the post-treatment worsening named in the description.
- name: Decreased total neutrophil count
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:39423903
    reference_title: "Advances in understanding cisplatin-induced toxicity: Molecular mechanisms and protective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      its clinical utility is hampered by its dose-limiting toxicities, including
      nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression
    explanation: >-
      Supports the marrow toxicity this cytopenia belongs to. The cited sentence
      names myelosuppression, not the individual lineage.
- name: Anemia
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:39423903
    reference_title: "Advances in understanding cisplatin-induced toxicity: Molecular mechanisms and protective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      its clinical utility is hampered by its dose-limiting toxicities, including
      nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression
    explanation: >-
      Supports the marrow toxicity this cytopenia belongs to, at the level of
      myelosuppression rather than the individual lineage.
- name: Thrombocytopenia
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:39423903
    reference_title: "Advances in understanding cisplatin-induced toxicity: Molecular mechanisms and protective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      its clinical utility is hampered by its dose-limiting toxicities, including
      nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression
    explanation: >-
      Supports the marrow toxicity this cytopenia belongs to, at the level of
      myelosuppression rather than the individual lineage.
genetic:
- name: ACYP2
  gene_term:
    preferred_term: ACYP2
    term:
      id: hgnc:180
      label: ACYP2
  relationship_type: SUSCEPTIBILITY
  notes: >-
    One of only two genes reaching the strong-and-replicated tier in the Canadian
    Pharmacogenomics Network for Drug Safety systematic review, which graded 40
    reports across 47 independent populations and 24 genes. The ACYP2 association
    holds in both children and adults.
  evidence:
  - reference: PMID:37726872
    reference_title: "Systematic Critical Review of Genetic Factors Associated with Cisplatin-induced Ototoxicity: Canadian Pharmacogenomics Network for Drug Safety 2022 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specifically, an ACYP2 variant has been associated with ototoxicity in both
      children and adults, whereas TPMT variants are relevant in children.
    explanation: >-
      Names ACYP2 as associated in both age groups, which is the claim curated
      here.
  - reference: PMID:37726872
    reference_title: "Systematic Critical Review of Genetic Factors Associated with Cisplatin-induced Ototoxicity: Canadian Pharmacogenomics Network for Drug Safety 2022 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Gives the evidence bar - odds ratio at least 3, replicated in at least three
      populations - that this gene clears and that most candidate loci do not.
- name: TPMT
  gene_term:
    preferred_term: TPMT
    term:
      id: hgnc:12014
      label: TPMT
  relationship_type: SUSCEPTIBILITY
  notes: >-
    The second gene reaching the strong-and-replicated tier. The association is
    reported as relevant in children; the review does not extend it to adults, and
    this entry does not either.
  evidence:
  - reference: PMID:37726872
    reference_title: "Systematic Critical Review of Genetic Factors Associated with Cisplatin-induced Ototoxicity: Canadian Pharmacogenomics Network for Drug Safety 2022 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specifically, an ACYP2 variant has been associated with ototoxicity in both
      children and adults, whereas TPMT variants are relevant in children.
    explanation: >-
      Names TPMT and restricts its relevance to children, which is the limit
      recorded in the notes.
  - reference: PMID:37726872
    reference_title: "Systematic Critical Review of Genetic Factors Associated with Cisplatin-induced Ototoxicity: Canadian Pharmacogenomics Network for Drug Safety 2022 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic variation in ACYP2 and TPMT may be helpful in predicting patients at
      the highest risk of developing cisplatin-induced ototoxicity.
    explanation: >-
      The review's own conclusion, naming these two genes and no others as
      potentially clinically useful predictors.
- name: COMT
  gene_term:
    preferred_term: COMT
    term:
      id: hgnc:2228
      label: COMT
  relationship_type: DISPUTED
  notes: >-
    Curated deliberately as DISPUTED rather than SUSCEPTIBILITY. COMT is a
    frequently cited candidate ototoxicity locus and is easy to record as
    established. The systematic review that graded the field placed only ACYP2 and
    TPMT in the strong-and-replicated tier and assigned everything else to a
    further-research category. Recording COMT at the same strength as those two
    would misstate the evidence.
  evidence:
  - reference: PMID:37726872
    reference_title: "Systematic Critical Review of Genetic Factors Associated with Cisplatin-induced Ototoxicity: Canadian Pharmacogenomics Network for Drug Safety 2022 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Encouraging evidence for associations involving several other genes also
      exists; however, further research is necessary to determine potential
      clinical relevance.
    explanation: >-
      Supports the disputed grading. The sentence covers the non-top-tier genes as
      a class; it does not name COMT, and the placement of COMT in that class
      rather than the top tier follows from the same review naming only ACYP2 and
      TPMT as strong.
clinical_trials:
- name: NCT00652132
  phase: PHASE_III
  status: COMPLETED
  description: >-
    SIOPEL 6. Randomised open-label phase 3 trial of delayed sodium thiosulfate
    for otoprotection in children receiving cisplatin for standard-risk
    hepatoblastoma. Reported as a 48 percent lower incidence of hearing loss
    without loss of survival.
  target_phenotypes:
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: clinicaltrials:NCT00652132
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This randomized phase III trial is studying how well sodium thiosulfate
      works to decrease hearing loss caused by cisplatin in treating young
      patients with stage I, stage II, or stage III childhood liver cancer.
    explanation: >-
      The registered description of the trial, confirming design, agent,
      indication and population.
- name: NCT00716976
  phase: PHASE_III
  status: COMPLETED
  description: >-
    ACCL0431. Children's Oncology Group randomised phase 3 trial of sodium
    thiosulfate versus observation across a mixed paediatric tumour population.
    Reported an odds ratio of 0.31 for hearing loss.
  target_phenotypes:
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: clinicaltrials:NCT00716976
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This randomized phase III trial is studying sodium thiosulfate to see how
      well it works in preventing hearing loss in young patients receiving
      cisplatin for newly diagnosed germ cell tumor, hepatoblastoma,
      medulloblastoma, neuroblastoma, osteosarcoma, or other malignancy.
    explanation: >-
      The registered description, confirming the broader tumour population that
      makes this trial complementary to SIOPEL 6 rather than a replication.
prevalence:
- population: Children aged 5 years or under receiving cisplatin
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 75000.0
  notes: >-
    Cumulative incidence of cisplatin-induced hearing loss at three years, from
    2052 audiological assessments in 368 Canadian children. Strongly age-dependent
    - 48 percent in those over five in the same cohort - which is why this record
    is stratified by age rather than reported for children as a whole.
  evidence:
  - reference: PMID:34490624
    reference_title: "The cumulative incidence of cisplatin-induced hearing loss in young children is higher and develops at an early stage during therapy compared with older children based on 2052 audiological assessments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three years after initiating therapy, the cumulative incidence of CIHL was
      highest in patients aged ≤5 years (75%; 95% confidence interval [CI],
      66%-84%)
    explanation: >-
      Gives the figure and its interval for the highest-risk stratum.
- population: Patients receiving cisplatin
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 20000.0
  notes: >-
    Cisplatin-induced nephrotoxicity, stated as an upper bound in a systematic
    review rather than as a point estimate. Reported incidence for this endpoint
    varies with the creatinine threshold used to define it.
  evidence:
  - reference: PMID:37530867
    reference_title: "A systematic review for prevention of cisplatin-induced nephrotoxicity using different hydration protocols and meta-analysis for magnesium hydrate supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cisplatin-induced nephrotoxicity (CIN) limits the use of this drug and
      affects up to 20% of patients.
    explanation: >-
      Gives the proportion affected, as an upper bound.
- population: Patients receiving cisplatin
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 30000.0
  notes: >-
    Cisplatin-induced peripheral neuropathy, stated as background in a
    mechanistic paper rather than derived from a cohort in that paper.
  evidence:
  - reference: PMID:21145397
    reference_title: "Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cisplatin is a platinum-based chemotherapeutic agent that induces peripheral
      neuropathy in 30% of patients.
    explanation: >-
      Gives the proportion affected. Background statement, not a primary
      measurement in the cited study.
- population: Patients receiving high-dose cisplatin without antiemetic prophylaxis
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 90000.0
  notes: >-
    Chemotherapy-induced nausea and vomiting in the absence of prophylaxis. This
    figure describes a population that no longer exists in practice, since
    prophylaxis is standard; it is recorded because it is what the toxicity does
    when unopposed.
  evidence:
  - reference: PMID:39589545
    reference_title: "The evolving landscape of antiemetic prophylaxis for chemotherapy-induced nausea and vomiting: inspiration from cisplatin-based antiemetic and non-antiemetic trials."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      One of the most common side effects of cisplatin is chemotherapy-induced
      nausea and vomiting (CINV), affecting nearly 90% of patients who receive
      high-dose cisplatin without antiemetic treatment
    explanation: >-
      Gives the untreated rate.
treatments:
- name: Duloxetine for established painful CIPN
  description: >-
    The only agent ASCO supports for established painful chemotherapy-induced
    peripheral neuropathy, and the guideline is careful to say the benefit is
    limited. It treats the pain, not the neuropathy - nothing regrows the sensory
    neurons - which is why it sits on the outcome node rather than upstream.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: duloxetine
      term:
        id: CHEBI:36796
        label: duloxetine
  target_mechanisms:
  - target: Sensory Peripheral Neuropathy
    treatment_effect: MODULATES
    description: >-
      Reduces painful symptoms of established neuropathy. Recorded as MODULATES
      because the guideline supports symptom benefit and does not claim reversal
      of the underlying nerve injury.
    evidence:
    - reference: PMID:32663120
      reference_title: "Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Duloxetine is the only agent that has appropriate evidence to support its
        use for patients with established painful CIPN.
      explanation: >-
        The guideline's single positive recommendation for established CIPN.
  evidence:
  - reference: PMID:32663120
    reference_title: "Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identified data reconfirmed that no agents are recommended for the
      prevention of CIPN.
    explanation: >-
      Establishes the surrounding negative: nothing prevents this neuropathy, so
      duloxetine's role is confined to treating pain once it exists. Carried on
      this treatment because it is what bounds the claim.
  notes: >-
    The guideline states the benefit is limited, and this entry does not present
    duloxetine as therapy for the neuropathy itself. Two further guideline
    positions are curated as separate entries below rather than omitted, because a
    reader should be able to find out from this entry what does NOT work.
- name: Acetyl-L-carnitine for CIPN prevention
  description: >-
    Curated as a treatment that does not work. ASCO discourages its use for
    prevention of chemotherapy-induced peripheral neuropathy. It is recorded here
    so the entry answers the question a clinician actually asks - not only what to
    give, but what to stop giving.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:32663120
    reference_title: "Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The use of acetyl-l-carnitine for the prevention of CIPN in patients with
      cancer should be discouraged.
    explanation: >-
      An explicit negative recommendation, curated as REFUTE against the claim
      that this agent prevents the neuropathy.
- name: Dose modification for intolerable neuropathy
  description: >-
    Where no drug prevents the neuropathy, the remaining lever is the cisplatin
    dose itself - delaying, reducing, substituting or stopping. This acts on the
    exposure rather than on any downstream injury, and it is what makes the
    neuropathy dose-limiting in practice.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Cisplatin Uptake by Transporter-Expressing Cells
    treatment_effect: INHIBITS
    description: >-
      Reducing or stopping the drug reduces the platinum delivered to the
      transporter-expressing tissues at the head of every arm in this entry.
    evidence:
    - reference: PMID:32663120
      reference_title: "Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        clinicians should assess the appropriateness of dose delaying, dose
        reduction, substitutions, or stopping chemotherapy in patients who develop
        intolerable neuropathy and/or functional impairment
      explanation: >-
        The guideline's recommendation for what to do when the neuropathy becomes
        intolerable, which is an intervention on exposure rather than on injury.
- name: Sodium thiosulfate otoprotection
  description: >-
    A sulfur nucleophile that inactivates platinum, given six hours after the
    cisplatin infusion. The delay is the whole design: given at the same time it
    would protect the tumour too, and pharmacokinetic work put six hours as the
    interval that protects the ear without doing that. In a randomised phase 3
    trial in children with standard-risk hepatoblastoma it cut hearing loss from
    63 percent to 33 percent without reducing survival.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium thiosulfate
      term:
        id: NCIT:C1230
        label: Sodium Thiosulfate
  target_mechanisms:
  - target: Cochlear Hair Cell Death
    treatment_effect: INHIBITS
    description: >-
      Reduces the incidence of hearing loss, which this entry places downstream of
      hair cell death. The trial measured hearing thresholds, not hair cell
      survival, so the effect is asserted on the clinical outcome and located at
      this node by inference.
    evidence:
    - reference: PMID:29924955
      reference_title: "Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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).
      explanation: >-
        Randomised phase 3 result with effect size and confidence interval. This
        is the strongest treatment evidence in the entry.
    - reference: PMID:27914822
      reference_title: "Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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).
      explanation: >-
        A second, independent randomised phase 3 trial (ACCL0431, Children's
        Oncology Group) reaching the same conclusion in a mixed-tumour paediatric
        population. Two trials in different populations is materially stronger
        than one.
  evidence:
  - reference: PMID:29924955
    reference_title: "Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The addition of sodium thiosulfate, administered 6 hours after cisplatin
      chemotherapy, resulted in a lower incidence of cisplatin-induced hearing
      loss among children with standard-risk hepatoblastoma, without jeopardizing
      overall or event-free survival.
    explanation: >-
      States the conclusion, including that tumour control was not compromised,
      which is the concern the delayed schedule exists to address.
  - reference: PMID:29924955
    reference_title: "Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonclinical studies and initial phase 1-2 trials indicated that sodium
      thiosulfate has a potential otoprotective effect, with maximum efficacy
      occurring when sodium thiosulfate is administered 4 to 8 hours after
      cisplatin
    explanation: >-
      Gives the timing window this treatment's description is built on.
  - reference: PMID:27914822
    reference_title: "Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sodium thiosulfate protects against cisplatin-induced hearing loss in
      children and is not associated with serious adverse events attributed to its
      use.
    explanation: >-
      The second trial's own conclusion, including its safety finding. Both trials
      were in children; neither establishes the effect in adults.
  notes: >-
    Bound to NCIT:C1230 Sodium Thiosulfate, which names the administered salt.
    An earlier draft used CHEBI:26977 thiosulfate and justified it on the more
    specific term being absent from this repository's term cache; that was not a
    real constraint, since the cache is populated by validation, and the reasoning
    is recorded here as corrected rather than quietly replaced. The trial
    population was children with standard-risk
    hepatoblastoma receiving cisplatin monotherapy, chosen because otoprotection
    can be tested there without confounding by other agents. Generalisation to
    adults and to multi-agent regimens is not established by this trial.
- name: Renoprotective supportive care
  description: >-
    Measures aimed at the renal arm, of which intravenous saline hydration with
    magnesium replacement is the routine one. The honest summary of this area is
    that protection is partial: no single measure abolishes the nephrotoxicity,
    and the field is still combining them.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:18272962
    reference_title: "Cisplatin nephrotoxicity: mechanisms and renoprotective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Renoprotective approaches are being discovered, but the protective effects
      are mostly partial, suggesting the need for combinatorial strategies.
    explanation: >-
      States that renoprotection is partial, which is the claim this treatment
      makes. The source speaks of renoprotective approaches in general; it does
      not name hydration, and this entry does not cite it as evidence for
      hydration specifically.
  - reference: PMID:18272962
    reference_title: "Cisplatin nephrotoxicity: mechanisms and renoprotective strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Importantly, it is unclear whether these approaches would limit the
      anticancer effects of cisplatin in tumors.
    explanation: >-
      Records the open question that constrains every protective strategy here -
      the same concern the sodium thiosulfate schedule was designed around, left
      unresolved on the renal side.
  - reference: PMID:37530867
    reference_title: "A systematic review for prevention of cisplatin-induced nephrotoxicity using different hydration protocols and meta-analysis for magnesium hydrate supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There has been uncertainty regarding the best method to prevent CIN.
    explanation: >-
      States that the optimal prevention protocol is unsettled, which is why this
      treatment is curated at the level of the magnesium arm rather than a named
      hydration regimen.
  target_mechanisms:
  - target: Proximal Tubular Epithelial Cell Death
    treatment_effect: INHIBITS
    description: >-
      Magnesium supplementation during hydration reduces cisplatin nephrotoxicity.
      The meta-analysis measured the clinical nephrotoxicity endpoint, not tubular
      cell death, so the effect is located at this node by inference.
    evidence:
    - reference: PMID:37530867
      reference_title: "A systematic review for prevention of cisplatin-induced nephrotoxicity using different hydration protocols and meta-analysis for magnesium hydrate supplementation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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).
      explanation: >-
        Gives the effect size and interval. The pooled studies are retrospective,
        which is a real limit on this estimate and is why the accompanying review
        still reports uncertainty about the best protocol.
  notes: >-
    Magnesium supplementation during hydration is the component with a pooled
    effect estimate behind it. The optimal hydration protocol itself remains
    unsettled - the same systematic review states that outright - so this entry
    curates the magnesium arm rather than any particular hydration regimen.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Cisplatin Toxicity · 2026-09-02T02:30:12Z · View source

New entry for cisplatin toxicity (MONDO:0027664), curated as a four-arm treatment-toxicity entry. One lesion - platinum-DNA crosslinking - reaching four organs, where what decides the target is transporter-mediated uptake and what decides the prognosis is whether the dead cell can be replaced. Pathograph: 13 nodes, fully connected apart from the uptake trigger. Shared upstream chain (transporter uptake, adduct formation, oxidative and mitochondrial injury, apoptosis) branching into renal, cochlear, neural and marrow arms. Eleven conforms_to declarations across four modules: drug_induced_nephrotoxicity (4 nodes), sensorineural_hair_cell_loss (2), peripheral_axonal_degeneration (3), myelosuppression (2). Two conformances deliberately withheld, with the reasons recorded in notes: - NOT peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination. Cisplatin neuropathy is a sensory neuronopathy - platinum accumulates in and kills the dorsal root ganglion cell body. Symptoms beginning distally is a different claim from the lesion being distal, and no cited source reports demyelination. - On the module's Axonal Transport Impairment and Mitochondrial Dysfunction node, only the mitochondrial half is conformed. The axonal-transport mechanism in chemotherapy-induced neuropathy is established for the microtubule-targeting agents (taxanes, vinca alkaloids); PMID:38660386 states it in those terms, and cisplatin is not a microtubule poison. The mechanism was not transferred. Similarly, the sensorineural_hair_cell_loss conformance covers the death half of its module node; no mechanotransduction measurement is reported by the sources cited here. Evidence: 67 items over 14 references, every snippet pre-verified against the local cache before the YAML was written. Anchors are a 2024 multi-toxicity review (PMID:39423903), the SIOPEL 6 randomised phase 3 otoprotection trial (PMID:29924955, full text cached), a 2023 ototoxicity review (PMID:36455457), the Kidney International nephrotoxicity review (PMID:18272962), transporter studies for OCT2 (PMID:16242669) and Ctr1 (PMID:19144690), the DRG mitochondrial-DNA study (PMID:21145397), and a 368-patient paediatric audiology cohort (PMID:34490624). Frequency discipline: no frequency band is asserted on any phenotype. For hearing loss this is deliberate rather than incidental - the cumulative incidence is 75 percent under age five against 48 percent over five in the same cohort, so a single band would misrepresent a strongly age-dependent risk, and the explanation says so. Claims deliberately not made: no hair-cell-regeneration claim (the usual explanation for the permanence, but absent from the cited sources - the irreversibility itself is sourced); no erythropoietin mechanism for the anaemia; no hydration-specific evidence for the renoprotective treatment, whose cited review discusses renoprotection at the level of strategy and states plainly that protection is mostly partial. Self-audit before commit found three overclaims in my own prose, all corrected: "in every cell it enters", "behaving completely differently", and an unsourced statement that mammalian cochlear hair cells are not replaced doing load-bearing work in a causal edge description. Validation: just validate-disorders (the batched sweep CI runs) passed; 67/67 snippets verified; check-folded-hyphens, check-duplicate-keys, check-title-snippets and check-entity-refs all clean; 20 structural tests pass; all 11 conformance anchors resolve to real module nodes. All reference_title values generated programmatically from the cache files, never typed. Deep research: just research-disorder claude_code produced a 96 KB report; 32/32 references resolved, 0 unresolved, 13/13 quoted claims found in source. NEC preflight returned SKIP (MONDO records no causal gene for a drug toxicity) and was cleared manually - the report's top gene mentions are ACYP2, TPMT, COMT and SLC22A2, which are the cisplatin ototoxicity susceptibility loci plus OCT2. The report was used as leads only; no snippet was taken from it unverified. It contributed two things the draft lacked, both then fetched and checked independently: - A genetic: section. PMID:37726872, the Canadian Pharmacogenomics Network for Drug Safety 2022 update, graded 40 reports across 47 populations and 24 genes and placed only ACYP2 and TPMT in the strong-and-replicated tier. Those two are curated SUSCEPTIBILITY. COMT is curated DISPUTED on purpose: it is a frequently cited candidate locus that the grading review assigns to the further-research tier, and recording it at the same strength as the other two would misstate the evidence. The report flagged that trap explicitly and it was verified against the source before curating. - PMID:37530867, which supplied the hydration-specific evidence the draft had recorded as missing: a meta-analysis of 11 retrospective studies giving OR 0.22 (95% CI 0.14-0.35) for magnesium supplementation against cisplatin-induced nephrotoxicity, plus the "up to 20% of patients" clinical proportion for the renal arm. The retrospective design of the pooled studies is recorded as a limit, and the same review's statement that the best prevention method remains uncertain is curated alongside it. The ACYP2 HGNC identifier was resolved from the ontology rather than taken from the report's gene table. Review round 1 (ai4c-reviewer, CHANGES_REQUESTED) raised eight items. All eight addressed. 1. CL:1000838 was the wrong proximal tubule cell type. It sits under CL:0002584 renal CORTICAL epithelial cell, so it excludes the S3 straight segment where cisplatin injury is maximal, and this entry's own node description says distal segments are affected too. Verified against the ontology and replaced with CL:0002306, which is what all five nodes of the conformed module use. This is the id-and-label-agree-but-meaning-is-wrong failure: nothing in validation could have caught it. 2. PMID:16242669 was graded IN_VITRO. The quoted conclusion rests on the in vivo rat arm - sex differences in renal uptake clearance, urinary NAG, the castrated-male comparison - and the record carries the Animals keyword. Regraded MODEL_ORGANISM with the reason stated. 3. All eight phenotypes were disconnected from the pathograph. A survey of 400 KB entries found 233 wire phenotypes as downstream targets, so this is established practice and the entry was the outlier. All phenotypes now hang off the terminal node of their arm. 4. Added the second randomised phase 3 otoprotection trial (ACCL0431, PMID:27914822, OR 0.31) alongside SIOPEL 6, and duloxetine for established painful CIPN (PMID:32663120). Two ASCO negatives are curated rather than omitted: acetyl-L-carnitine as a REFUTE item, and the finding that no agent prevents CIPN as the bound on duloxetine's claim. 5. clinical_trials block for NCT00652132 and NCT00716976, both fetched. 6. Four prevalence records, one per endpoint, each carrying the definitional caveat that makes the figures non-comparable: an age stratum for hearing loss, an upper bound for nephrotoxicity, a background statement for neuropathy, and an untreated-population rate for emesis. 7. Added an Emetogenic Response node with nausea and vomiting. The receptor mechanism (5-HT3, NK1) is NOT asserted - the cited source describes the antiemetic classes, not the biology producing the emesis - and the edge into this node is INDIRECT_UNKNOWN_INTERMEDIATES because this arm is not established here as running through the transporter uptake that gates the four injury arms. 8. therapeutic_agent rebound from CHEBI:26977 thiosulfate to NCIT:C1230 Sodium Thiosulfate. The old notes justified the looser term on the better one being absent from the term cache; that was not a real constraint, since the cache is populated by validation. The corrected reasoning is recorded in place rather than the old rationale quietly deleted.

Claude Code ▸
Cisplatin Toxicity — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-opus-5 29 citations 2026-09-01T22:30:14.467535

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

Resource Identifier Verified?
MONDO MONDO:0027664 "cisplatin toxicity" Yes — OLS4 live query
MeSH (drug) D002945 Cisplatin Yes — NCBI E-utilities
MeSH (kidney outcome) D058186 Acute Kidney Injury Yes
MeSH (nerve outcome) D010523 Peripheral Nervous System Diseases Yes
MeSH (ear outcome) "Ototoxicity" exists as a descriptor; its descriptor UI did not resolve in my query Not verified
ChEBI (agent) CHEBI:27899 cisplatin Yes — dismech cache
NCIT (agent) NCIT:C376 Cisplatin Yes — dismech cache
ICD-10-CM Adverse-effect coding is by T-code plus manifestation, not by a cisplatin-specific code Not verified against ICD authority
OMIM / Orphanet Not applicable — this is an acquired drug toxicity, not a Mendelian disorder —

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):

Symbol HGNC Role in cisplatin toxicity Evidence tier
ACYP2 HGNC:180 Ototoxicity susceptibility, children and adults Strong, replicated ≥3 populations (PMID:37726872)
TPMT hgnc:12014 Ototoxicity susceptibility, children Strong in children (PMID:37726872)
COMT hgnc:2228 Candidate ototoxicity locus; not replicated to strong tier Inconsistent (PMID:37726872)
WFS1 hgnc:12762 rs62283056, hearing loss Marginal in replication (PMID:35322580)
TXNRD1 HGNC:12437 Redox regulation; gene-based hearing-loss signal Borderline (PMID:35322580)
WNT8A Not verified this session Tinnitus, gene-based Single study (PMID:35322580)
SLC31A1 (CTR1) HGNC:11016 Cellular uptake Mechanistic (PMID:19144690)
SLC22A2 (OCT2) HGNC:10966 Basolateral tubular uptake Mechanistic (PMID:19144690, PMID:32150447)
SLC47A1 (MATE1) HGNC:25588 Apical efflux Mechanistic — not directly verified this session
ERCC1 hgnc:3433 Nucleotide excision repair of Pt-DNA adducts Mechanistic
ERCC2 (XPD) hgnc:3434 Nucleotide excision repair Mechanistic
XPA / XPC hgnc:12814 / hgnc:12816 Nucleotide excision repair Mechanistic
TP53 hgnc:11998 Apoptotic response to adducts Mechanistic
GSTP1 HGNC:4638 Glutathione conjugation / detoxification Candidate
TRPM6 HGNC:17995 Distal tubular magnesium reabsorption Mechanistic candidate for hypomagnesemia — link not directly verified this session

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

Phenotype HP term Frequency Onset / course Source
High-frequency sensorineural hearing impairment HP:0001757 40–60% adults; up to 60% children Begins during therapy; progresses with cumulative dose PMID:38003734, PMID:22547603
Bilateral sensorineural hearing impairment HP:0008619 Essentially all affected cases are bilateral Irreversible PMID:38003734
Progressive sensorineural hearing impairment HP:0000408 — Progresses to lower frequencies with dose PMID:22547603
Tinnitus HP:0000360 68% of testicular cancer survivors Persistent PMID:36637632
Hearing impairment (self-reported) HP:0000365 59% of testicular cancer survivors Late, persistent PMID:36637632
Vertigo HP:0002321 Reported; frequency not quantified in sources retrieved — PMID:39417180

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

Phenotype HP term Frequency Notes
Acute kidney injury HP:0001919 Severe (≥2× creatinine): 5.2% derivation / 3.3% validation. Any-grade: "up to one third of patients" PMID:38538012; PMID:41854743
Elevated circulating creatinine concentration HP:0003259 Definitional for the above PMID:38538012
Chronic kidney disease HP:0012622 Long-term sequela PMID:36229672
Renal insufficiency HP:0000083 — PMID:37182407
Hypomagnesemia HP:0002917 Very common; a low serum magnesium is also a predictor of AKI PMID:38538012, PMID:42652681
Hypokalemia HP:0002900 Common; hypokalaemia was the commonest non-haematological AE in ACCL0431 controls (12%) PMID:27914822
Hypocalcemia HP:0002901 Secondary to Mg depletion PMID:37182407
Hyponatremia HP:0002902 Salt-wasting reported PMID:37182407
Hypophosphatemia HP:0002148 Tubular PMID:37182407
Renal tubular dysfunction HP:0000124 The proximate lesion PMID:37182407
Renal Fanconi syndrome HP:0001994 Reported, uncommon Mechanistically consistent; frequency not verified
Hemolytic-uremic syndrome HP:0005575 Rare; thrombotic microangiopathy PMID:37182407
Polyuria HP:0000103 Salt-losing nephropathy PMID:37182407

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

Phenotype HP term Frequency Source
Peripheral neuropathy HP:0009830 29.2% after EPx4; 21.4% after BEPx3 (self-reported, TC survivors) PMID:28240972
Distal sensory impairment HP:0002936 Length-dependent, stocking-glove PMID:32663120
Paresthesia HP:0003401 Presenting symptom PMID:32663120
Peripheral axonal neuropathy HP:0003477 The pathological substrate —
Sensory neuropathy HP:0000763 Predominantly sensory; motor sparing is characteristic —
Areflexia HP:0001284 Late —
Gait ataxia HP:0002066 From large-fibre sensory loss —
Raynaud phenomenon HP:0030880 11.6% after EPx4; 21.4% after BEPx3 PMID:28240972

"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

Phenotype HP term Notes
Anemia HP:0001903 Dose-limiting with cumulative cycles
Decreased total neutrophil count HP:0001875 Note the current HPO label — OLS4 returns "Decreased total neutrophil count", not "Neutropenia". Grade 3–4 neutropenia occurred in 65% of control participant-cycles in ACCL0431 (PMID:27914822)
Thrombocytopenia HP:0001873 Label verified current via OLS4
Pancytopenia HP:0001876 Severe cases
Nausea HP:0002018 Cisplatin is the archetypal highly emetogenic agent
Vomiting HP:0002013 Acute and delayed phases
Anorexia HP:0002039 —
Diarrhea HP:0002014 —
Weight loss HP:0001824 —
Alopecia HP:0001596 —
Fatigue HP:0012378 —

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.

Mechanism step GO term
DNA crosslink formation, repair attempt GO:0006281 DNA repair; GO:0006289 nucleotide-excision repair; GO:0036297 interstrand cross-link repair
DNA-damage apoptosis GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage; GO:0006915 apoptotic process
Oxidative stress GO:0006979 response to oxidative stress; GO:0034614 cellular response to reactive oxygen species
Mitochondrial injury GO:0051882 mitochondrial depolarization; GO:0032042 mitochondrial DNA metabolic process
ER stress GO:0030968 endoplasmic reticulum unfolded protein response
Regulated necrosis GO:0070266 necroptotic process
Iron-dependent lipid peroxidation death GO:0097707 ferroptosis
Autophagy GO:0006914 autophagy
Senescence GO:0090398 cellular senescence
Inflammation GO:0006954 inflammatory response; GO:0001816 cytokine production
Uptake GO:0006825 copper ion transport (for the CTR1 route)

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

Organ / system UBERON Role
Kidney UBERON:0002113 Primary — dose-limiting AKI/CKD
Cochlea UBERON:0001844 Primary — irreversible SNHL
Dorsal root ganglion UBERON:0000044 Primary — sensory neuronopathy
Bone marrow UBERON:0002371 Primary — myelosuppression
Peripheral nervous system UBERON:0000010 System-level
Testis UBERON:0000473 Gonadal toxicity, infertility
Retina UBERON:0000966 Rare retinal toxicity
Renal medulla UBERON:0000362 Corticomedullary junction injury

Tissue and cell level

Cell type CL Involvement
Epithelial cell of proximal tubule CL:0002306 Principal target of tubular injury
Kidney proximal convoluted tubule epithelial cell CL:1000838 S3 segment most vulnerable
Kidney distal convoluted tubule epithelial cell CL:1000849 Magnesium wasting; CTR1 expressed here too (PMID:19144690)
Kidney loop of Henle thick ascending limb epithelial cell CL:1001106 Electrolyte handling
Kidney interstitial fibroblast CL:1000692 Fibrotic conversion on repeat dosing (PMID:26739893)
Macrophage CL:0000235 Inflammatory amplification
Cochlear outer hair cell CL:0000601 Principal ototoxic target (PMID:39417180)
Cochlear inner hair cell CL:0000589 Later/less affected
Supporting cell CL:0000630 Implicated in ototoxic cascade
Spiral ganglion neuron CL:0011113 Secondary degeneration
Sensory neuron of dorsal root ganglion CL:1001451 CIPN substrate
Schwann cell CL:0002573 Myelin; secondary
Hematopoietic stem cell CL:0000037 Myelosuppression

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

Toxicity Course Reversible?
Emesis Episodic, per cycle Yes
Myelosuppression Cyclic, cumulative Largely yes
AKI Acute; may repeat each cycle Partly — repeated injury converts to CKD (PMID:26739893, PMID:36229672)
Hypomagnesemia Chronic, cumulative Often persists post-treatment
Ototoxicity Progressive with cumulative dose; then stable No — "irreversible" (PMID:38003734)
CIPN Progressive during and shortly after treatment; partial recovery over years Partial

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.

Measure Value Population Source
Candidate treated population ~500,000/year in the US Patients with germ cell, lung, bladder, ovarian, head and neck cancer PMID:36921239
Ototoxicity, adults 40–60% Cisplatin-treated adults PMID:38003734
Ototoxicity, children up to 60%; "at least 60%" Paediatric cisplatin recipients PMID:38003734; PMID:22547603
Permanent hearing loss 40–80% All treated PMID:29162831
Any ototoxicity, self-reported 74% 145 testicular cancer survivors PMID:36637632
Chemotherapy ototoxicity, all agents >50% incidence, ~4 million people/year worldwide All chemo recipients PMID:39417180
Severe CP-AKI (≥2× creatinine or KRT within 14 d) 5.2% derivation / 3.3% validation 24,717 adults, 6 US centres PMID:38538012
Nephrotoxicity, any grade "up to 20%" Cisplatin recipients PMID:37530867
Nephrotoxicity, any grade "up to one third of patients" Cisplatin recipients PMID:41854743

"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

Test Purpose
Serum creatinine, eGFR The defining AKI measurement (PMID:38538012)
Serum magnesium Both a toxicity marker and an AKI predictor (PMID:38538012)
Serum potassium, calcium, sodium, phosphate Tubular wasting
Complete blood count Myelosuppression nadir monitoring
Urinalysis, urine protein Tubular injury

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

Alternative Distinguishing feature
Prerenal azotemia / volume depletion Responds to fluids; bland sediment; FENa low
Contrast-associated AKI Temporal relation to contrast, not to cisplatin
Aminoglycoside nephrotoxicity Concurrent drug; also causes ototoxicity — confounds attribution directly
Tumour lysis syndrome Uric acid, phosphate, potassium rise; timing at treatment initiation
Age-related or noise-induced hearing loss Pre-treatment audiogram is the discriminator — which is why baseline audiometry matters
Paraneoplastic sensory neuronopathy Anti-Hu; may precede chemotherapy
Diabetic or B12-deficiency neuropathy Pre-existing; separate workup

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

Outcome Recovery
Hearing loss None. Irreversible (PMID:38003734). Hearing aids do not repair the cochlea: "Contemporary medical interventions for cisplatin ototoxicity are limited to prosthetic devices, such as hearing aids, but these have significant limitations because the cochlea remains damaged." (PMID:38003734)
AKI Partial; repeated cycles drive fibrosis and CKD (PMID:26739893, PMID:36229672)
CIPN Partial over years; often incomplete
Myelosuppression Full between cycles
Hypomagnesemia Often persistent

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.

Treatment treatment_term (clinical action) therapeutic_agent
Sodium thiosulfate otoprotection NCIT:C15986 Pharmacotherapy NCIT:C1230 Sodium Thiosulfate
Amifostine cytoprotection NCIT:C15986 Pharmacotherapy NCIT:C488 Amifostine
Magnesium supplementation NCIT:C15986 Pharmacotherapy Term not resolved this session
Intravenous hydration NCIT:C15747 Supportive Care —
Duloxetine for painful CIPN NCIT:C15986 Pharmacotherapy CHEBI:36796 duloxetine
Antiemetic prophylaxis NCIT:C15986 Pharmacotherapy CHEBI:7773 Ondansetron; CHEBI:41879 dexamethasone; CHEBI:7735 olanzapine
Hemodialysis for severe AKI NCIT:C15248 Hemodialysis —
Transfusion support NCIT:C15192 Blood Transfusion —
Hearing rehabilitation NCIT:C15302 Physical Therapy is wrong here; use NCIT:C15315 Rehabilitation or NCIT:C15329 Surgical Procedure for implantation, per the device convention in CLAUDE.md Device term as a qualifiers pair
Dose reduction / discontinuation NCIT:C49236 Therapeutic Procedure —

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:

Intervention Level Evidence
IV hydration Primary Standard of care; PMID:41854743
Magnesium supplementation Primary OR 0.22 vs CIN (PMID:37530867); dose-independent (PMID:42652681)
Sodium thiosulfate, 6 h post-infusion Primary (hearing, children) RR 0.52 (PMID:29924955); OR 0.31 (PMID:27914822)
Prolonged infusion (>6 h) rather than bolus Primary Implied by ACCL0431 eligibility and stratification (PMID:27914822); direct comparative evidence not verified
Avoiding concurrent nephrotoxins Primary Consistent with PMID:38538012 risk factors
Noise avoidance during and after treatment Primary (hearing) Association only (PMID:35322580)
Risk stratification with the BMJ nine-covariate score Primary C statistic 0.75, externally validated (PMID:38538012)

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

Model System What it recapitulates Limitations
Single high-dose cisplatin mouse (typically 20–30 mg/kg IP) Mouse Rapid, severe AKI with tubular necrosis Not the clinical regimen; lethality confounds; does not model CKD conversion
Repeated low-dose cisplatin mouse Mouse Fibrosis and CKD — "Repeated administration of low-dose cisplatin in mice induces fibrosis." (PMID:26739893) Longer, more expensive; still not tumour-bearing
Mouse cochlear ototoxicity model Mouse Outer hair cell loss; platinum retention in cochlea matching human (PMID:29162831) Frequency range and cochlear anatomy differ from human
Rat CIPN model Rat DRG platinum accumulation, sensory deficits Behavioural readouts are indirect
Zebrafish lateral-line neuromast Zebrafish Hair-cell death; high-throughput otoprotectant screening (PMID:29381431 — title from search, abstract not read) Neuromast hair cells are not cochlear hair cells; no cochlea

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:)

Model What it shows Limitation — verbatim where available
iPSC-derived human kidney organoid Injury response, AKI biomarker secretion, inflammatory cytokines "DNA damage was not specific to the proximal tubule but also affected the distal tubule and interstitial cell populations. This lack of specificity correlated with low expression of proximal tubule-specific SLC22A2/organic cation transporter 2 (OCT2) for cisplatin." — PMID:32150447. This is the key limitation: the organoid underexpresses the transporter that gives the human kidney its selectivity.
Organoid, repeated low-dose protocol Better viability, robust injury "we developed a repeated low-dose regimen of 4 × 5 µM cisplatin over 7 days and found this caused less toxicity while still inducing a robust injury response that included secretion of known AKI biomarkers and inflammatory cytokines" — PMID:32150447
HK-2 and other human proximal tubule cell lines Mechanistic dissection; the workhorse of the field (58 studies, 2014–2024) Reporting is unharmonised: "Co-reporting analysis revealed recurrent pathway-oriented groupings, suggesting hypothesis-driven panel selection rather than standardized implementation across studies." — PMID:42459863
Organotypic cochlear explant culture Hair-cell death, otoprotectant screening Loses the stria vascularis contribution and systemic pharmacokinetics — which PMID:29162831 and PMID:39417180 both argue may be where the primary lesion is

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

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.

Outcome Count
References checked 32
Resolved 32
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 13
Quoted claims found in source 13
Quoted claims not found in source 0
References weighed for topical relevance 32
On topic 24
Off topic 0

All extracted references resolved successfully.