Cetuximab & Panitumumab
Erbitux · Vectibix · Anti-EGFR antibody
TRPM6 magnesium wasting.
LYTE
MildOpen →
Adrenolytic
Mitotane
Lysodren · MTT
Adrenolytic for adrenocortical carcinoma; renal risk is indirect — adrenal insufficiency drives hyponatremia and prerenal azotemia, compounded by cisplatin in EDP-M.
Moderateestablished · approved 1970
Advanced/metastatic adrenocortical carcinomaAdjuvant therapy after resection of adrenocortical carcinoma (high recurrence risk)Component of the EDP-M regimen (etoposide, doxorubicin, cisplatin + mitotane) for advanced diseaseControl of cortisol hypersecretion in Cushing syndrome (off-label)
Signature kidney injury
Electrolyte Wasting
Intrinsic mitotane nephrotoxicity is not characteristically quantified. Clinically important renal events are indirect (adrenal insufficiency-related electrolyte/volume disturbance) or attributable to co-administered cisplatin in EDP-M; incidence not reliably enumerated for mitotane alone.
Source: Turla et al., Endocrine 2022 (indirect: hypoadrenalism + cisplatin in EDP-M)
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityModerate
ReversibilityReversible
Evidence0 refs
Nephron map
Vasculature / Endothelium
Distal Tubule / Collecting DuctFine-tuning of Na, K, Mg, acid & water
Electrolyte Wasting
Renal loss of magnesium, potassium or calcium — cisplatin and the anti-EGFR antibodies.
Mechanism of kidney injury
Mitotane has no well-established direct tubular nephrotoxicity; its renal relevance is indirect and endocrine. By inducing adrenal insufficiency (hypoadrenalism) and accelerating cortisol/aldosterone metabolism, it can produce hyponatremia, volume depletion, and prerenal azotemia, particularly when glucocorticoid/mineralocorticoid replacement is inadequate. Persistent nausea, vomiting, and asthenia signal hypoadrenalism and worsen prerenal physiology. Critically, mitotane is given within the EDP-M regimen alongside cisplatin, a directly nephrotoxic agent — so AKI in these patients is frequently attributable to cisplatin and to the volume/electrolyte derangements of adrenal insufficiency rather than to mitotane itself.
Clinical presentation
Hyponatremia, hypotension, fatigue, nausea/vomiting and prerenal azotemia in the setting of under-replaced adrenal insufficiency; superimposed cisplatin-type AKI when EDP-M is used. Frank intrinsic kidney injury directly from mitotane is not a typical presentation.
Onset
Adrenal insufficiency and its electrolyte/volume consequences develop over weeks of therapy as adrenolytic effect accrues; cisplatin-associated AKI in EDP-M is acute, within days of chemotherapy cycles.
Reversibility
Reversible
Anticancer mechanism
Adrenolytic agent (an o,p'-DDD isomer related to the insecticide DDT) that is selectively cytotoxic to adrenocortical cells, causing focal degeneration of the zona fasciculata and reticularis; it suppresses cortisol production and exerts direct antitumor activity against adrenocortical carcinoma, while also accelerating peripheral steroid metabolism.
Management
Treat the underlying adrenal insufficiency with adequate steroid replacement and restore volume/electrolytes; correct hyponatremia per cause and rate-safe guidelines. For AKI during EDP-M, manage as cisplatin-associated injury (hydration, nephrotoxin avoidance, dose/schedule modification). Mitotane itself is rarely the direct culprit for kidney injury.
Risk factors
- Inadequate glucocorticoid/mineralocorticoid replacement
- Concurrent cisplatin (EDP-M regimen)
- Pre-existing mild renal impairment
- Poor performance status with poor oral intake
- Persistent vomiting causing volume depletion
Prevention
- Mandatory glucocorticoid (and mineralocorticoid as needed) replacement to prevent adrenal crisis and resultant prerenal/electrolyte derangement
- Aggressive antiemesis and maintenance of hydration
- For patients with mild renal impairment receiving EDP-M, consider 24-hour continuous-infusion cisplatin to reduce nephrotoxicity risk
- Monitor and replace sodium; assess volume status regularly
Note · A key onconephrology teaching point: the kidney threat with mitotane is endocrine and regimen-driven (hypoadrenalism + cisplatin), not direct tubular toxicity. Mitotane plasma level monitoring (target therapeutic window) is also standard for efficacy/toxicity balance.
Clinical depth
Renal dose adjustment
Mitotane dosing is guided by plasma-level monitoring and tolerability rather than by renal function; there is no standardized renal dose reduction. In EDP-M with mild renal impairment, cisplatin scheduling (e.g., continuous infusion) is modified to mitigate nephrotoxicity.
Dialyzability & ESKD dosing
Dialyzability not characterized/clinically relevant; mitotane is highly lipophilic and tissue-distributed, making dialysis removal unlikely to be useful.
Differential diagnosis
In a mitotane-treated patient with AKI/hyponatremia, distinguish (1) adrenal insufficiency with prerenal azotemia/volume depletion, (2) cisplatin-induced tubular injury from EDP-M, and (3) SIADH or other causes — rather than attributing injury to direct mitotane tubular toxicity.
Monitoring
- Serum sodium and other electrolytes
- Volume/blood pressure status and signs of adrenal insufficiency
- Renal function (especially during cisplatin-containing cycles)
- Mitotane plasma concentrations (therapeutic monitoring)
- Cortisol/ACTH and adequacy of steroid replacement
Key trials & series
- Turla et al. (Endocrine 2022): supportive-care guidance for the EDP-M regimen, explicitly addressing mitotane-induced hypoadrenalism and management of patients with mild renal impairment (cisplatin scheduling)
- EDP-M established as standard first-line cytotoxic regimen for advanced adrenocortical carcinoma
Clinical pearls
- The renal danger of mitotane is indirect: hypoadrenalism leads to hyponatremia/volume depletion/prerenal azotemia.
- Always ensure adequate steroid replacement; persistent nausea/vomiting and asthenia are red flags for hypoadrenalism.
- In EDP-M, cisplatin is the directly nephrotoxic partner — consider continuous-infusion cisplatin in mild renal impairment.
- Mitotane requires therapeutic plasma-level monitoring, not renal dose adjustment.
Where it strikes
Nephron segments
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Electrolyte WastingPrerenal / Hemodynamic AKISIADH / Hyponatremia
Evidence
3 peer-reviewed references. Citation metadata via PubMed / NLM.
PMIDSupportive therapies in patients with advanced adrenocortical carcinoma submitted to standard EDP-M regimen.Turla A et al. · Endocrine 2022 · PMID 35567656Directly addresses management of mitotane-induced hypoadrenalism and of patients with mild renal impairment on EDP-M (including continuous-infusion cisplatin to reduce nephrotoxicity).PMIDConventional Chemotherapy Nephrotoxicity.Gupta S et al. · Adv Chronic Kidney Dis 2021 · PMID 35190107Reviews cisplatin nephrotoxicity and chemotherapy-associated electrolyte disturbances/hyponatremia — context for the cisplatin and electrolyte risks accompanying mitotane in EDP-M.LandmarkAcute Kidney Injury in Patients with Cancer.Rosner MH et al. · N Engl J Med 2017 · PMID 28467867Onconephrology overview supporting the framing of prerenal/electrolyte (indirect) injury versus direct tubular toxicity in this setting.