How should hematuria be managed in a patient receiving dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for melanoma?

Management of Hematuria in Patients on Dabrafenib and Trametinib

Hematuria is not a recognized adverse effect of dabrafenib and trametinib combination therapy, but if it occurs, immediately evaluate for renal injury including acute interstitial nephritis, nephrotic syndrome, or granulomatous nephritis—all rare but documented renal complications of BRAF/MEK inhibitor therapy.

Initial Evaluation

When hematuria develops in a patient receiving dabrafenib and trametinib:

• Obtain urgent serum creatinine, eGFR, urinalysis with microscopy, and urine protein-to-creatinine ratio to assess for acute kidney injury and proteinuria 1, 2, 3

• Check for accompanying symptoms including peripheral edema, oliguria, fever, rash, or constitutional symptoms that may indicate systemic drug reaction 3

• Review baseline renal function as kidney impairment was rarely reported in pivotal trials, making any new renal abnormality potentially drug-related 1

Documented Renal Toxicities with BRAF/MEK Inhibitors

While hematuria specifically is not listed among common adverse events in major trials 4, 5, several serious renal complications have been documented:

Acute Interstitial Nephritis

• Biopsy-proven acute interstitial nephritis has been reported in patients on dabrafenib and trametinib, presenting with acute kidney injury (creatinine 3.34 mg/dL, eGFR 20.3 mL/min/m²) 1

• This requires permanent discontinuation of both drugs and corticosteroid therapy (methylprednisolone 16 mg daily) for recovery 1

• Renal biopsy is mandatory in the absence of clear explanation or rapid recovery of renal failure 1

Nephrotic Syndrome

• Podocyte injury with nephrotic syndrome has been documented, showing diffuse loss of podocyte cytoarchitecture, extensive foot-process effacement, and glomerular endothelial injury on biopsy 2

• BRAF inhibition decreases PLCε1 and nephrin expression in podocytes and inhibits the podocyte-VEGF system, leading to increased albumin permeability 2

• Full recovery occurred after drug withdrawal, indicating reversibility if caught early 2

Granulomatous Nephritis

• Granulomatous inflammation affecting kidneys has been reported, presenting with acute kidney injury (RIFLE category failure), bilateral leg edema, and rash 3

• This required permanent discontinuation and prolonged corticosteroid therapy (tapered over 6 months) for complete resolution 3

Management Algorithm

If Hematuria with Normal Renal Function

• Continue close monitoring with weekly serum creatinine, urinalysis, and urine protein checks for 2-3 weeks 1, 2

• Evaluate for alternative causes including urinary tract infection, nephrolithiasis, or bladder pathology unrelated to therapy

If Hematuria with Elevated Creatinine or Proteinuria

• Immediately hold both dabrafenib and trametinib pending further evaluation 1, 2, 3

• Perform renal biopsy to establish diagnosis, as this directly impacts management decisions 1, 3

• Initiate corticosteroids (methylprednisolone 16 mg daily or equivalent) if interstitial nephritis or granulomatous nephritis is confirmed 1, 3

After Recovery

• If complete renal function recovery occurs and limited treatment options exist, switching to an alternative BRAF/MEK inhibitor combination (encorafenib plus binimetinib) can be considered 1

• This switch has been successful in maintaining disease control while preserving kidney function in documented cases 1

• Do not rechallenge with the same drugs if biopsy-proven drug-induced nephritis occurred 1, 3

Critical Monitoring Recommendations

Patients on dabrafenib and trametinib should be monitored closely for potential glomerular damage given the documented podocyte injury mechanism 2

• Baseline and periodic urinalysis should be performed, though this is not emphasized in standard toxicity monitoring protocols 5

• Any unexplained decline in renal function warrants immediate investigation rather than assuming it is unrelated to therapy 1

Common Pitfalls to Avoid

• Do not dismiss renal symptoms as unrelated to therapy simply because kidney toxicity was rare in pivotal trials—case reports demonstrate serious renal complications do occur 1, 2, 3

• Do not delay renal biopsy if kidney injury persists or worsens, as histologic diagnosis determines appropriate management 1, 3

• Do not attempt to continue therapy at reduced doses if drug-induced nephritis is confirmed—permanent discontinuation is required 1, 3

• Do not stop corticosteroids prematurely in granulomatous or interstitial nephritis, as rapid decline can occur with early cessation 3