Skip to content
IgG Kappa Multiple Myeloma with Cutaneous Plasmacytoma and Hypereosinophilic Leukocytosis in a Young Patient: A Rare Case Report
Back to full profile

BRAF inhibitor

Dabrafenib

Tafinlar · DAB

BRAF inhibitor · approved 2013 · 8 references

The gentler BRAF inhibitor — mostly pyrexia-driven, reversible AKI, with granulomatous interstitial nephritis as its rare histologic signature.

Signature injury
Acute Interstitial Nephritis
Severity
Mild
Reversibility
Reversible
Onset
Variable and biphasic. Pyrexia-associated AKI clusters early, in the first weeks to months of therapy and coincides with febrile episodes. Biopsy-proven granulomatous/acute interstitial nephritis has appeared anywhere from a few weeks to as late as ~5 years into treatment.

Signature kidney injury & incidence

Acute Interstitial Nephritis — representative incidence ~21%.

AKI is relatively common on dabrafenib-based therapy but usually mild and reversible. In the largest cohort, 42/199 (21%) of patients on dabrafenib/trametinib developed AKI within 12 months, and roughly 24% of those episodes occurred during the drug-induced febrile (pyrexia) syndrome (Seethapathy 2022). Pharmacovigilance places dabrafenib well below vemurafenib: FAERS acute-kidney-injury reporting-odds-ratio approximately 1.35 (95% CI 1.15–1.60) for dabrafenib versus approximately 3.28 for vemurafenib (Sanagawa 2021). Biopsy-proven granulomatous/acute interstitial nephritis and clinically significant electrolyte disorders (hyponatremia, hypokalemia, hypophosphatemia) are each individually rare — documented mainly in case reports and small FAERS counts. Registrational trials did not flag renal toxicity; the signal emerged post-marketing.

Source: Seethapathy et al., Nephrol Dial Transplant 2022 (PMID 33355659): 42/199 (21%) of dabrafenib/trametinib patients developed AKI within 12 months in a single-center retrospective cohort, with ~24% of AKI episodes occurring during the drug-induced pyrexia/febrile syndrome. This is all-cause AKI on combination therapy and largely mild/reversible; drug-specific granulomatous interstitial nephritis is far rarer.

Reported injury signatures: Acute Interstitial Nephritis, Prerenal / Hemodynamic AKI, Electrolyte Disturbance, SIADH / Hyponatremia, Acute Tubular Necrosis.

Renal toxicity profile

  1. Acute Interstitial NephritisPrimary
  2. Prerenal / Hemodynamic AKISecondary
  3. Electrolyte DisturbanceSecondary
  4. SIADH / HyponatremiaSecondary
  5. Acute Tubular NecrosisSecondary

Onset timing & rechallenge

Variable / unpredictable — Biphasic: pyrexia-associated AKI clusters in the first weeks to months, while granulomatous/acute interstitial nephritis has appeared from a few weeks to as late as ~5 years.

Mechanism of kidney injury

Two dominant routes, both indirect. (1) Pre-renal/hemodynamic: dabrafenib — especially combined with trametinib — provokes a systemic pyrexia/febrile syndrome (fever, chills, rigors, GI losses, transaminitis) that causes volume depletion and hemodynamic AKI, sometimes progressing to ischemic tubular injury; about one in four AKI episodes in the largest cohort occurred during this febrile syndrome. (2) Immunoallergic tubulointerstitial: biopsy-proven acute — often granulomatous — interstitial nephritis, at times with concurrent granulomatous dermatitis, implying a T-cell/hypersensitivity mechanism rather than direct nephrotoxicity. Unlike vemurafenib, dabrafenib shows little direct proximal-tubular or glomerular-epithelial cytotoxicity in vitro, consistent with its lower FAERS AKI signal. Electrolyte wasting (hyponatremia including an SIADH-like pattern, hypokalemia, hypophosphatemia) reflects disturbed tubular handling. Rare glomerular lesions have been reported but are confounded by concomitant immune-checkpoint-inhibitor exposure.

Clinical presentation

Most often an asymptomatic serum creatinine rise found on surveillance labs. When tied to the pyrexia syndrome, patients have fever, chills, rigors, GI symptoms, and transaminitis accompanying the creatinine rise. Interstitial nephritis cases may show sterile pyuria, low-grade proteinuria/microalbuminuria, peripheral edema, and sometimes a concurrent granulomatous skin rash; the classic AIN triad (fever/rash/eosinophilia) is usually incomplete. Electrolyte abnormalities — low sodium, potassium, or phosphate — can be the presenting clue.

Management

Pyrexia-associated AKI: hold dabrafenib (and usually trametinib), give IV/oral fluids and antipyretics, and resume at the same or a reduced dose once fever and creatinine recover; corticosteroids are used for recurrent/refractory pyrexia. Suspected interstitial nephritis: discontinue the drug, refer to nephrology, and consider kidney biopsy if AKI is persistent or unexplained — biopsy-proven granulomatous/acute interstitial nephritis is treated with corticosteroids (e.g., prednisone ~1 mg/kg with a slow taper) and is generally steroid-responsive, though relapse on premature taper is described. Electrolytes: replete potassium, phosphate, and magnesium; evaluate hyponatremia for SIADH versus volume depletion and treat by cause. Rechallenge is often feasible after pyrexia-driven AKI resolves, but should be avoided after biopsy-proven granulomatous interstitial nephritis.

Risk factors

  • Pre-existing liver disease (the only significant baseline predictor of AKI in the largest cohort)
  • Drug-induced pyrexia/febrile syndrome (fever, chills, GI losses, transaminitis) with volume depletion
  • Combination with trametinib (pyrexia and febrile-syndrome AKI are more frequent with the doublet)
  • Prior or concurrent immune-checkpoint-inhibitor therapy (adds interstitial and glomerular injury risk; confounds attribution)
  • Volume depletion from GI toxicity, diuretics, RAAS blockade, or intercurrent nephrotoxins/NSAIDs
  • Male sex (FAERS reports skew male, though this likely reflects melanoma epidemiology)

Prevention

  • Baseline and periodic serum creatinine, eGFR, and electrolytes (sodium, potassium, phosphate, magnesium)
  • Recognize the pyrexia syndrome early — interrupt dabrafenib (per label at temperature >=38.5 C), hydrate, and give antipyretics before AKI develops
  • Maintain volume during febrile episodes and GI losses; avoid unnecessary nephrotoxins/NSAIDs and iodinated contrast when febrile
  • Correct volume depletion promptly and review concomitant nephrotoxic or ADH-active medications
  • Surveillance urinalysis when creatinine rises to screen for interstitial nephritis

Renal dose adjustment

No dedicated renal dose adjustment is specified in the FDA label. Dabrafenib is cleared predominantly by hepatobiliary metabolism (CYP2C8/CYP3A4) and fecal excretion with a minority renal route, so no adjustment is recommended for mild-to-moderate renal impairment. It has not been formally studied in severe renal impairment or ESRD — use with caution and monitor. In practice, dose interruptions/reductions are driven by pyrexia, transaminitis, and other toxicities rather than by eGFR.

Dialyzability & ESKD dosing

Not expected to be removed by dialysis and not established as dialyzable. Dabrafenib is highly protein-bound (~99.7%) with a large volume of distribution and hepatic metabolism, so hemodialysis is unlikely to clear meaningful drug; no data support supplemental dosing around dialysis.

Differential diagnosis

Distinguish pyrexia/febrile-syndrome pre-renal azotemia and volume depletion (most common, fully reversible with fluids and drug hold) from intrinsic drug-induced granulomatous/acute interstitial nephritis (biopsy-confirmed, steroid-responsive). Consider concomitant or sequenced immune-checkpoint-inhibitor nephritis or glomerulonephritis — a rare atypical anti-GBM glomerulonephritis has been reported in a patient on MAPK plus checkpoint inhibitors (Kyriazis 2021), so glomerular presentations are confounded. Exclude other nephrotoxins (NSAIDs, contrast, PPIs), sepsis, and tumor-related causes (obstruction, hypercalcemia). If therapy was switched from vemurafenib, note vemurafenib carries a higher intrinsic tubular-toxicity signal.

Monitoring

  • Serum creatinine and eGFR at baseline and periodically, and during any febrile episode
  • Electrolytes — sodium, potassium, phosphate, and magnesium
  • Temperature/pyrexia surveillance (the febrile syndrome is the leading trigger for AKI)
  • Urinalysis when creatinine rises — sterile pyuria, WBC casts, and low-grade proteinuria suggest interstitial nephritis
  • Liver enzymes (transaminitis accompanies the febrile syndrome and pre-existing liver disease predicts AKI)

Key trials & series

  • COMBI-v (Robert et al., N Engl J Med 2014; PMID 25399551): dabrafenib plus trametinib improved overall survival versus vemurafenib in BRAF V600 metastatic melanoma; renal toxicity was not flagged in the pivotal data.
  • 5-year outcomes of dabrafenib plus trametinib in metastatic melanoma (Robert et al., N Engl J Med 2019; PMID 31166680): durable long-term benefit of the doublet.
  • COMBI-AD (Long et al., N Engl J Med 2017; PMID 28891408): adjuvant dabrafenib plus trametinib in resected stage III BRAF-mutant melanoma.

Clinical pearls

  • Dabrafenib is the 'kinder-to-kidney' BRAF inhibitor: FAERS AKI reporting-odds-ratio is ~1.35 versus ~3.28 for vemurafenib, and in vitro it lacks vemurafenib's direct tubular cytotoxicity.
  • Most AKI on dabrafenib/trametinib is pyrexia-driven and pre-renal — think fever plus volume depletion and hold/hydrate before reaching for a biopsy.
  • The one true histologic signature is granulomatous/acute interstitial nephritis, sometimes paired with a granulomatous dermatitis; it is steroid-responsive but relapses if steroids are tapered too quickly.
  • Check electrolytes — hyponatremia (including an SIADH-like pattern), hypokalemia, and hypophosphatemia are reported.
  • Pre-existing liver disease was the only baseline predictor of AKI in the largest cohort — flag these patients for closer monitoring.
  • Renal signals were essentially absent in the registrational trials and emerged from post-marketing case reports and FAERS, so incidence figures should be hedged accordingly.

Anticancer mechanism

Selective ATP-competitive inhibitor of mutant BRAF V600E/K kinase that shuts down constitutive RAF–MEK–ERK (MAPK) signaling driving BRAF-mutant tumor proliferation. Almost always paired with the MEK inhibitor trametinib to deepen and prolong response and blunt paradoxical MAPK reactivation (fewer cutaneous squamous lesions than single-agent BRAF inhibition).

Note

Dabrafenib is almost always given with trametinib, so much of the renal data reflects the combination and all-cause AKI in melanoma patients rather than a pure single-agent, drug-attributable effect. Reported incidence should be read as combination, real-world, largely mild and reversible AKI.

Guidelines & consensus

  • ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.Nat Rev Nephrol · PMID 41361704
  • SIRM (2022) — SIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.Radiol Med · PMID 35303246
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.Kidney Int · PMID 33126977
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.Kidney Int · PMID 33276867
  • ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.EClinicalMedicine · PMID 40290844
  • ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.EClinicalMedicine · PMID 40290845
  • ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.EClinicalMedicine · PMID 40290846
  • KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.Crit Care · PMID 23394211
  • KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.Kidney Int · PMID 34556300
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.Kidney Int · PMID 38388147
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.Kidney Int · PMID 38182299
  • KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.Kidney Int · PMID 40975525

References

8 peer-reviewed references. Citation metadata via PubMed / NLM.

  1. 1.Clinical features of acute kidney injury in patients receiving dabrafenib and trametinib.Seethapathy H, et al. · Nephrol Dial Transplant · 2022 · PMID 33355659
  2. 2.Nephrotoxicity of the BRAF Inhibitors Vemurafenib and Dabrafenib.Jhaveri KD, et al. · JAMA Oncol · 2015 · PMID 26182194
  3. 3.Renal effects of BRAF inhibitors: a systematic review by the Cancer and the Kidney International Network.Wanchoo R, et al. · Clin Kidney J · 2016 · PMID 26985376
  4. 4.BRAF/MEK inhibitor-associated nephrotoxicity in a real-world setting and human kidney cells.Sanagawa A, et al. · Anticancer Drugs · 2021 · PMID 34232935
  5. 5.Acute granulomatous interstitial nephritis in a patient with metastatic melanoma on targeted therapy with dabrafenib and trametinib-A case report.Krelle A, et al. · Cancer Rep (Hoboken) · 2021 · PMID 34350734
  6. 6.Granulomatous nephritis and dermatitis in a patient with BRAF V600E mutant metastatic melanoma treated with dabrafenib and trametinib.Jansen YJ, et al. · Melanoma Res · 2015 · PMID 26512791
  7. 7.Atypical anti-glomerular basement membrane glomerulonephritis in a patient with metastatic melanoma treated with mitogen-activated protein kinase and immune checkpoint inhibitors: a case report.Kyriazis P, et al. · J Med Case Rep · 2021 · PMID 33810799
  8. 8.Improved overall survival in melanoma with combined dabrafenib and trametinib.Robert C, et al. · N Engl J Med · 2014 · PMID 25399551
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.