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Drug-Induced Nephrotoxicity Module

Toxicology Pharmacology Module drug_induced_nephrotoxicity 1 disorder Pathograph 5
A conserved treatment-toxicity module representing the final common pathway by which nephrotoxic drugs injure the renal tubule and cause acute kidney injury. The culprit agent varies — cisplatin and other platinums, aminoglycosides, vancomycin, tenofovir, amphotericin B, iodinated contrast, NSAIDs — but because the kidney concentrates, transports, and excretes these compounds, the downstream sequence repeatedly converges on proximal tubular drug accumulation, oxidative and mitochondrial stress, tubular epithelial cell death (apoptosis and acute tubular necrosis), tubulointerstitial inflammation, and a fall in glomerular filtration rate. This is a "side effect as mechanism" module: it captures the adverse-drug-reaction pathophysiology shared across nephrotoxic drugs, so a drug-toxicity entry can declare conformance rather than re-deriving the chain. It models the dose-dependent acute-tubular-injury arm; crystal/cast obstruction and immune-mediated interstitial nephritis are distinct arms noted in the literature but not the focus here.
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Pathophysiology Nodes

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5 shared nodes are defined in this module.
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Cell Types

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proximal tubule epithelial cell CL:0002306 Cell Ontology (CL) Relation: this mechanism module involves this cell type This mechanism module involves proximal tubule epithelial cell (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
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Biological Processes

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xenobiotic transport GO:0042908 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased xenobiotic transport (GO:0042908). GO:0042908 is a biological process from the Gene Ontology. INCREASED response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. INCREASED cell death GO:0008219 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased cell death (GO:0008219). GO:0008219 is a biological process from the Gene Ontology. INCREASED apoptotic process GO:0006915 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. INCREASED inflammatory response GO:0006954 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. INCREASED renal system process GO:0003014 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves decreased renal system process (GO:0003014). GO:0003014 is a biological process from the Gene Ontology. DECREASED
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Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "drug_induced_nephrotoxicity#Proximal Tubular Epithelial Cell Death"). Conforming nodes should substitute the drug-specific uptake/transport route (e.g. OCT2/cisplatin, megalin-endocytosis/aminoglycosides) while preserving the conserved uptake → oxidative/mitochondrial stress → tubular cell death → inflammation → AKI chain. The key conformance / central-effector target is "drug_induced_nephrotoxicity#Proximal Tubular Epithelial Cell Death".
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Used By Disorder Entries

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Hospital-Acquired Acute Kidney Injury via Nephrotoxic Injury → Proximal Tubular Epithelial Cell Death
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Pathograph

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Pathograph: causal mechanism network for Drug-Induced Nephrotoxicity Module Interactive directed graph showing how this shared module's pathophysiology nodes connect.
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Pathophysiology

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Nephrotoxic Drug Exposure and Tubular Uptake
trigger
The conserved initiating lesion is renal handling of the drug: the proximal tubule is exposed to filtered and secreted compounds and takes them up via apical endocytosis or basolateral organic anion/cation transporters, leading to intracellular accumulation. This renal handling, combined with the drug's inherent toxicity, concentrates the insult in tubular epithelial cells.
proximal tubule epithelial cell CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves proximal tubule epithelial cell, annotated with epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
xenobiotic transport GO:0042908 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased xenobiotic transport (GO:0042908). GO:0042908 is a biological process from the Gene Ontology. INCREASED
Downstream
  • Tubular Oxidative Stress and Mitochondrial Injury Accumulated drug provokes oxidative and mitochondrial stress in tubular cells.
Tubular Oxidative Stress and Mitochondrial Injury
amplifier
Intracellular drug accumulation generates reactive oxygen species and damages mitochondria in the metabolically active proximal tubule, the major amplifying event linking drug uptake to tubular cell death.
proximal tubule epithelial cell CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves proximal tubule epithelial cell, annotated with epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. INCREASED
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrion (GO:0005739). GO:0005739 is a cellular component from the Gene Ontology.
Downstream
  • Proximal Tubular Epithelial Cell Death Oxidative and mitochondrial injury precipitate tubular epithelial cell death.
Proximal Tubular Epithelial Cell Death
central effector
Oxidative and mitochondrial injury precipitate proximal tubular epithelial cell death by apoptosis and acute tubular necrosis (ATN). This is the central effector lesion and the key conformance target; conforming disorder nodes substitute the drug-specific upstream driver but converge here.
proximal tubule epithelial cell CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves proximal tubule epithelial cell, annotated with epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
cell death GO:0008219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell death (GO:0008219). GO:0008219 is a biological process from the Gene Ontology. INCREASED 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
Used by disorders
Hospital-Acquired Acute Kidney Injury as Nephrotoxic Injury
Downstream
  • Tubulointerstitial Inflammation Dying tubular cells release signals that recruit inflammatory cells.
  • Acute Kidney Injury Loss of functional tubular epithelium reduces kidney function.
Tubulointerstitial Inflammation
amplifier
Tubular cell death releases damage-associated signals that drive tubulointerstitial inflammation, which amplifies and extends the tubular injury.
proximal tubule epithelial cell CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves proximal tubule epithelial cell, annotated with epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. INCREASED
Downstream
  • Acute Kidney Injury Sustained inflammatory injury extends nephron loss toward clinical AKI.
Acute Kidney Injury
consequence
Accumulated tubular cell loss and inflammation reduce the glomerular filtration rate, producing acute kidney injury — the defining clinical consequence and frequently a dose-limiting toxicity that necessitates dose reduction or drug withdrawal.
proximal tubule epithelial cell CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves proximal tubule epithelial cell, annotated with epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
renal system process GO:0003014 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased renal system process (GO:0003014). GO:0003014 is a biological process from the Gene Ontology. DECREASED