Platinum & the proximal tubule
Cisplatin acute tubular necrosis & hypomagnesemia
The drug that cures testicular cancer poisons its own portal of entry — pumped into the kidney's S3 tubule by OCT2, cisplatin necroses the proximal tubule and, downstream, silences the distal magnesium channel, leaving patients wasting magnesium long after the last dose.
- ~1 in 3
- Develop AKI after cisplatin31.5% of 821 adults across tumor types had acute kidney injury within 30 days of the first cyclePMID 27073199
- 1969
- Platinum's antitumor power revealedRosenberg's Nature report turned a bacterial curiosity into a cancer drug — and into nephrology's archetypal tubular toxinPMID 5782119
- OR 0.24
- Magnesium's protective oddsMeta-analysis of 15 studies (1841 patients): magnesium supplementation cut cisplatin AKI odds by about 76%PMID 31429065
- 23 / 44
- Hypomagnesemia on cisplatinSchilsky's 1979 series first tied cisplatin to inappropriate renal magnesium wastingPMID 375794
- 56 vs 79
- Mannitol backfired (mL/min CrCl)In a randomized trial, adding mannitol to saline left worse creatinine clearance than saline alonePMID 12719883
Teaching case · illustrative composite, not a real patient
A 58-year-old man with locally advanced head and neck squamous cell carcinoma receives his second cycle of high-dose cisplatin (100 mg/m²) with concurrent radiotherapy. He presents on about day 8 with fatigue, muscle cramps, and mild nausea. Labs show a nonoliguric rise in serum creatinine (roughly a 40% increase from baseline), magnesium 1.0 mg/dL, potassium 3.0 mmol/L, and mild hypocalcemia; urine studies show renal magnesium wasting with an inappropriately high fractional excretion of magnesium.
He had received isotonic saline hydration but no magnesium supplementation. The hypokalemia and hypocalcemia stay refractory to potassium and calcium replacement until magnesium is aggressively repleted, after which they correct. Mannitol is deliberately not added. Creatinine partially recovers over the next two weeks but settles at a new, slightly reduced baseline eGFR. Magnesium continues to run low for weeks, requiring ongoing oral (and intermittent IV) supplementation between cycles; subsequent cycles use pre-emptive magnesium loading and careful volume expansion.
Teaching point — Cisplatin injures the kidney at two distinct sites: OCT2-driven uptake concentrates drug in the S3 proximal segment causing acute tubular necrosis, while downstream suppression of distal TRPM6 causes renal magnesium wasting. The hypomagnesemia is often the more persistent problem and drives refractory hypokalemia and hypocalcemia — correct magnesium first. Volume-expand with isotonic saline (not mannitol), supplement magnesium pre-emptively, and keep monitoring magnesium and eGFR for weeks to months after the last dose.
How it happens
The pathophysiology as a cascade — select a step to follow the mechanism.
Cisplatin, a small neutral-then-reactive molecule, enters proximal tubule cells across the basolateral membrane via the organic cation transporter OCT2, which is densely expressed in the S3 segment — concentrating drug where toxicity is greatest.
PMID 16314463 (opens PubMed in a new tab)Inside the low-chloride cytosol, cisplatin loses chloride and becomes a reactive, positively charged aquated species that binds nucleophilic cellular targets. OCT2-deficient tubules accumulate less drug and are protected.
PMID 19625999 (opens PubMed in a new tab)Reactive cisplatin forms intrastrand DNA crosslinks (predominantly at guanine N7), damaging nuclear and mitochondrial DNA and triggering the DNA-damage response in post-mitotic tubular cells.
Platinum adducts and reactive oxygen species disrupt mitochondria in the metabolically active proximal tubule, activating p53 and stress-kinase (p38/JNK) pathways toward cell death.
PMID 32150448 (opens PubMed in a new tab)S3 tubular cells undergo apoptosis and necrosis, producing acute tubular necrosis and a fall in GFR; blocking OCT2 uptake with cimetidine prevents the apoptosis in human tubules.
PMID 16314463 (opens PubMed in a new tab)In the distal convoluted tubule, cisplatin suppresses epidermal growth factor and the apical magnesium channel TRPM6, the final gate for active Mg²⁺ reabsorption.
PMID 23457647 (opens PubMed in a new tab)Impaired distal Mg²⁺ reabsorption raises fractional magnesium excretion, producing inappropriate renal magnesium wasting and often refractory hypomagnesemia (with secondary hypokalemia and hypocalcemia).
PMID 375794 (opens PubMed in a new tab)
See it happen
How cisplatin injures the proximal tubule
The archetypal nephrotoxin traces a defined path: filtration, active transporter uptake, mitochondrial injury, and downstream electrolyte wasting. Scroll to follow the lesion from the S3 segment to the distal tubule.
How we learned it
- 1967
Rosenberg observes that platinum electrolysis products halt cell division in E. coli, causing filamentous growth.
The serendipitous discovery that a platinum compound has potent biological activity — the seed of cisplatin as a drug.
PMID 5335970 (opens PubMed in a new tab) - 1969
Rosenberg and colleagues report in Nature that cis-platinum compounds cause dramatic regression of transplanted mouse tumors.
Established platinum as a potent antitumor agent and launched cisplatin's path to the clinic — along with its dose-limiting kidney problem.
PMID 5782119 (opens PubMed in a new tab) - 1977
Hayes and Cvitkovic show mannitol-induced osmotic diuresis blunts cisplatin's renal toxicity, enabling high-dose therapy.
The Cvitkovic-era breakthrough that made cisplatin clinically usable — hydration/diuresis converted a nephrotoxin into a curative drug.
PMID 856437 (opens PubMed in a new tab) - 1978
Cisplatin receives FDA approval for testicular and ovarian cancer.
Cemented cisplatin in oncology and made its nephrotoxicity and magnesium wasting an everyday clinical management problem.
- 1979
Schilsky and Anderson describe hypomagnesemia and inappropriate renal magnesium wasting in cisplatin patients.
First systematic description of the distinct distal-tubule magnesium-wasting syndrome, separate from the proximal AKI.
PMID 375794 (opens PubMed in a new tab) - 2003
Santoso randomized trial finds adding mannitol to saline yields worse creatinine clearance than saline alone.
Challenged reflexive forced diuresis — isotonic saline, not mannitol, is the safe hydration backbone.
PMID 12719883 (opens PubMed in a new tab) - 2005
Ciarimboli identifies human OCT2 (SLC22A2) as the critical basolateral transporter carrying cisplatin into proximal tubule cells.
Explained cisplatin's organ-specific toxicity mechanistically and pointed to transporter competition as a renoprotective strategy.
PMID 16314463 (opens PubMed in a new tab) - 2009
Filipski shows Oct1/Oct2-null mice are protected and links the SLC22A2 SNP rs316019 to reduced nephrotoxicity in patients.
Nailed OCT2 as the pharmacogenetic gatekeeper of cisplatin nephrotoxicity, bridging bench to bedside.
PMID 19625999 (opens PubMed in a new tab) - 2013
Ledeganck demonstrates cisplatin downregulates distal-tubule EGF and the TRPM6 magnesium channel in rats.
Provided the molecular mechanism of cisplatin's distal magnesium wasting, decades after Schilsky's clinical description.
PMID 23457647 (opens PubMed in a new tab) - 2016
Latcha reports the largest long-term outcome study (821 adults): AKI is common but ESRD is rare.
Reframed cisplatin nephrotoxicity as mostly small, permanent eGFR loss rather than dialysis-requiring failure.
PMID 27073199 (opens PubMed in a new tab) - 2020
Song shows the SGLT2 inhibitor canagliflozin reduces renal cisplatin uptake and protects mice without blunting anticancer effect.
Opened a current renoprotection frontier — repurposing SGLT2 inhibitors against cisplatin AKI and magnesium wasting.
PMID 32150448 (opens PubMed in a new tab)
The landmark studies
Platinum compounds: a new class of potent antitumour agents
Rosenberg B, et al. · Nature 1969 · PMID 5782119
cis-Platinum(II) diamminedichloride produced dramatic regression of transplanted mouse tumors, defining platinum as a potent antitumor agent and launching cisplatin's clinical development.
Marked regression of Sarcoma 180 and L1210 leukemia in mice; the foundational report that made cisplatin a drug.
High dose cis-platinum diammine dichloride: amelioration of renal toxicity by mannitol diuresis
Hayes DM, Cvitkovic E, et al. · Cancer 1977 · PMID 856437
Concurrent mannitol-induced osmotic diuresis allowed high-dose cisplatin to be delivered with renal toxicity limited mostly to transient creatinine elevation — the practice that made high-dose cisplatin feasible.
60 heavily pretreated patients; doses 3–5 mg/kg; overall response rate 42%; renal injury reduced to transient creatinine rises in most, with dose-limiting renal toxicity only at 5 mg/kg.
Hypomagnesemia and renal magnesium wasting in patients receiving cisplatin
Schilsky RL, Anderson T. · Annals of Internal Medicine 1979 · PMID 375794
Cisplatin induces an intrinsic renal tubular defect in magnesium conservation, producing symptomatic hypomagnesemia distinct from its proximal azotemia.
Hypomagnesemia in 23 of 44 evaluable patients; inappropriate renal magnesium wasting documented in 4; 2 hospitalized for symptomatic magnesium deficiency.
Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2
Ciarimboli G, et al. · American Journal of Pathology 2005 · PMID 16314463
Human OCT2 (hOCT2) is the critical basolateral transporter for cisplatin uptake into proximal tubule cells, explaining its organ-specific toxicity; competing at hOCT2 prevents cisplatin-induced apoptosis.
Cisplatin 100 µmol/L inhibited transport via hOCT2 but not hepatic hOCT1; co-incubation with the hOCT2 substrate cimetidine (100 µmol/L) completely suppressed cisplatin-induced apoptosis.
Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity
Filipski KK, et al. · Clinical Pharmacology & Therapeutics 2009 · PMID 19625999
Oct1/Oct2-deficient mice are protected from severe cisplatin tubular damage, and a nonsynonymous SLC22A2 SNP (rs316019) is associated with reduced cisplatin nephrotoxicity in patients — establishing OCT2 as the pharmacogenetic gatekeeper.
Dose-limiting nephrotoxicity occurs in about one-third of patients despite prophylaxis; Oct1/Oct2 deletion impaired urinary cisplatin excretion (without changing plasma levels) and prevented severe renal tubular damage.
The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity
Ledeganck KJ, et al. · PLoS One 2013 · PMID 23457647
Cisplatin downregulates distal-tubule EGF and the magnesium channel TRPM6, impairing distal Mg²⁺ reabsorption — the molecular basis of cisplatin's renal magnesium wasting.
Fractional excretion of Mg²⁺ significantly increased after cisplatin; renal TRPM6 and EGF mRNA significantly decreased, while TRPM7 and claudin-16 remained stable.
Long-Term Renal Outcomes after Cisplatin Treatment
Latcha S, et al. · Clinical Journal of the American Society of Nephrology (CJASN) 2016 · PMID 27073199
AKI after cisplatin is common but progression to end-stage disease is rare; most patients sustain small, permanent declines in eGFR, and older age raises AKI risk.
AKI in 31.5%; median initial eGFR decline ~10 mL/min/1.73 m²; <3% ever reached eGFR <29 and none required dialysis; age >66 vs <25 carried an OR of 2.96 (95% CI 1.4–6.1) for AKI.
What the data says now
How disproportionately each agent's FAERS reports name these phenotypes vs. all other drugs (reporting odds ratio; significant signals only, 95% CI lower bound > 1; as of 2026-08-23). A reporting signal, not incidence or proven causation. A dash means tested without reaching significance, not a phenotype that never occurs — ATN and AIN undercount badly, most true cases filing as generic “acute kidney injury”. Computed by this atlas on the current snapshot — a published disproportionality analysis will not match cell for cell (different window, different term set).
| Agent | ATN | LYTE |
|---|---|---|
| Cisplatin | Cisplatin, Acute Tubular Necrosis: ROR 5.17, 185 reports | Cisplatin, Electrolyte Disturbance: ROR 5.41, 3,625 reports |
| Carboplatin | Carboplatin, Acute Tubular Necrosis: ROR 4.88, 282 reports | Carboplatin, Electrolyte Disturbance: ROR 3.69, 4,084 reports |
| Oxaliplatin | Oxaliplatin, Acute Tubular Necrosis: ROR 1.89, 65 reports | Oxaliplatin, Electrolyte Disturbance: ROR 3.31, 2,161 reports |
Acute kidney injury after cisplatin
821 adults across tumor types, ≥5-year survivors (retrospective cohort); AKI within 30 days of first cycle
PMID 27073199 (opens PubMed in a new tab)Cisplatin-induced AKI (cited as background, not pooled here)
Adults receiving cisplatin despite prophylaxis. This range is the opening context sentence of a systematic review, NOT a figure that review pooled — its meta-analysis could only be run on 15 observational studies of magnesium supplementation (1,841 patients)
PMID 31429065 (opens PubMed in a new tab)Hypomagnesemia on cisplatin
Patients receiving cisplatin chemotherapy (case series)
PMID 375794 (opens PubMed in a new tab)Nephrotoxicity despite intensive prophylaxis
Patients on cisplatin with intensive prophylactic hydration
PMID 19625999 (opens PubMed in a new tab)Progression to advanced CKD / dialysis long-term
821 adults, mean 6-year follow-up after cisplatin
PMID 27073199 (opens PubMed in a new tab)How it's managed
- 1
Isotonic (0.9%) saline hydration / volume expansion
Vigorous isotonic saline before and after cisplatin is the cornerstone renoprotective measure, diluting tubular drug concentration and maintaining urine flow — the practice descended from the Cvitkovic-era diuresis studies.
Established standard of care; historical foundation · PMID 856437 (opens PubMed in a new tab)
- 2
Magnesium supplementation
Adding magnesium to hydration both treats the wasting syndrome and independently lowers AKI risk; pooled observational data show a large protective effect.
Meta-analysis: AKI odds ratio 0.24 (95% CI 0.19–0.32) across 15 studies / 1841 patients · PMID 31429065 (opens PubMed in a new tab)
- 3
Magnesium supplementation (confirmatory meta-analysis)
A second independent meta-analysis of magnesium given during hydration found consistent protection against cisplatin-induced nephrotoxicity.
Meta-analysis: AKI odds ratio 0.22 (95% CI 0.14–0.35), 11 studies · PMID 37530867 (opens PubMed in a new tab)
- 4
Avoid routine mannitol / aggressive forced diuresis
Adding mannitol to saline did not help and was associated with worse creatinine clearance than saline alone; diuretics are not a substitute for volume expansion.
Randomized trial (n=49): post-cisplatin CrCl 56.4 (saline+mannitol) vs 79.1 mL/min (saline alone), P=0.02 · PMID 12719883 (opens PubMed in a new tab)
- 5
Limit cumulative dose, fractionate, and mitigate host risk
Cumulative cisplatin dose and older age drive long-term eGFR loss; dose-capping, fractionated dosing, avoiding concurrent nephrotoxins, and monitoring eGFR reduce permanent injury.
Large cohort: higher cumulative dose and age >66 (OR 2.96) associated with AKI/eGFR decline · PMID 27073199 (opens PubMed in a new tab)
- 6
Emerging: SGLT2 inhibitors and OCT2-directed strategies
Preclinically, canagliflozin cuts renal cisplatin uptake and protects tubules without blunting anticancer efficacy; OCT2 substrate competition (e.g., cimetidine) and amiloride/SGLT2 inhibitors are being explored for the magnesium wasting — currently investigational/off-label.
Preclinical (mouse) renoprotection signal; off-label clinical case reports/reviews · PMID 32150448 (opens PubMed in a new tab)
What the guidelines say
Society and consensus recommendations addressing this syndrome.
Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.
At the bedside
Magnesium wasting here is cumulative and often silent until it's severe. Grade the level to gauge urgency and route — oral repletion rarely keeps pace once IV territory is reached.
Magnesium grade & repletion
CTCAE v5.0Enter a serum magnesium level for its CTCAE grade and a directed-repletion frame. Drug-induced renal magnesium wasting (anti-EGFR antibodies, platinums) is cumulative — grade guides urgency and route.
Enter a level to see the CTCAE grade and repletion frame.
Educational aid only — not medical advice. Grades per NCI CTCAE v5.0, read directly from the column for the unit you enter. CTCAE defers to the reporting lab for the limits of normal; this tool assumes 1.7–2.6 mg/dL. Repletion route and dosing follow local protocol and clinical judgment.
Every citation on this page is a real, PubMed-verified reference. The teaching case is an illustrative composite, not a real patient. Medical-education content — not medical advice.