Can selpercatinib (Retevmo) cause proteinuria in a patient with RET‑positive disease who is taking 160 mg twice daily and has rising serum creatinine and decreasing eGFR?

Can Selpercatinib Cause Proteinuria?

Selpercatinib does not cause proteinuria as a recognized adverse effect. The most common treatment-related adverse events are hypertension, elevated liver enzymes (ALT/AST), increased creatinine, diarrhea, and edema, but proteinuria is not listed among the documented toxicities in the pivotal trials or FDA-approved labeling. 1, 2, 3

Evidence from Clinical Trials and Guidelines

Safety Profile from LIBRETTO Studies

The comprehensive safety analysis of selpercatinib across 702 patients with RET-altered solid tumors in the LIBRETTO-001 study documented the following most common adverse events (occurring in ≥25% of patients): 1

• Increased AST or ALT
• Elevated glucose
• Decreased leukocytes
• Decreased albumin
• Decreased calcium
• Dry mouth
• Diarrhea
• Increased creatinine
• Increased alkaline phosphatase
• Hypertension
• Fatigue
• Edema
• Decreased platelets
• Increased total cholesterol
• Rash
• Decreased sodium
• Constipation

Proteinuria is notably absent from this comprehensive list. 1

Grade 3 or Higher Adverse Events

The most common grade 3 treatment-related adverse events were: 1, 2, 3

• Hypertension (14-21%)
• Increased ALT (9-12%)
• Increased AST (8-10%)
• Hyponatremia (6-8%)
• Diarrhea (6%)
• Lymphopenia (6%)

Again, proteinuria does not appear among the serious adverse events. 1, 2, 3

Distinguishing Creatinine Elevation from Proteinuria

Creatinine Rise Without Proteinuria

The increased creatinine observed with selpercatinib (listed as a common adverse event) does not indicate proteinuria or glomerular injury. 1 This distinction is critical:

• Creatinine elevation can occur through non-injurious mechanisms, such as inhibition of tubular creatinine secretion (similar to ALK inhibitors like crizotinib and CDK4/6 inhibitors like abemaciclib), which should be differentiated from genuine renal toxicity. 1

• Proteinuria, in contrast, typically indicates glomerular barrier dysfunction and is a distinct adverse effect seen with anti-angiogenesis drugs (VEGF inhibitors), which cause hypertension, proteinuria (sometimes nephrotic-range), and lesions such as thrombotic microangiopathy or focal segmental glomerulosclerosis. 1

Mechanism of Selpercatinib-Related Creatinine Changes

Selpercatinib may cause a non-injurious increase in serum creatinine owing to inhibitory effects on creatinine secretion rather than true nephrotoxicity. 1 This mechanism parallels other tyrosine kinase inhibitors and does not involve:

• Glomerular injury
• Proteinuria
• Tubular damage
• Thrombotic microangiopathy

Clinical Management of Rising Creatinine on Selpercatinib

When to Investigate Further

If a patient on selpercatinib 160 mg twice daily develops rising serum creatinine and decreasing eGFR, the evaluation should focus on: 1

1. Exclude volume depletion – assess hydration status, recent diuretic use, or intercurrent illness
2. Review concomitant nephrotoxins – NSAIDs, contrast agents, other medications
3. Check for renovascular disease – especially if creatinine rise exceeds 30% or is progressive
4. Measure urine protein-to-creatinine ratio – to definitively rule out proteinuria as the cause

Expected vs. Pathologic Creatinine Rise

• Creatinine increases ≤30% from baseline within the first 2-4 weeks may represent a benign hemodynamic or secretory effect and do not indicate acute kidney injury. 4
• Creatinine rises >30% or progressive decline in eGFR warrant investigation for true renal toxicity, volume depletion, or drug-drug interactions. 4

Comparison with Other Targeted Therapies

Anti-Angiogenesis Drugs (VEGF Inhibitors)

Unlike VEGF inhibitors (e.g., lenvatinib, sorafenib), selpercatinib is not associated with proteinuria. 1 VEGF inhibitors commonly cause:

• New or worsened hypertension
• Proteinuria (sometimes nephrotic-range)
• Thrombotic microangiopathy
• Minimal change disease/focal segmental glomerulosclerosis

Other Tyrosine Kinase Inhibitors

Selpercatinib's renal safety profile resembles ALK and CDK4/6 inhibitors, which cause non-injurious creatinine elevation without proteinuria. 1 This contrasts with:

• B-Raf inhibitors – cause acute kidney injury (acute tubular injury and acute interstitial nephritis) less commonly 1
• Proteasome inhibitors – may be associated with thrombotic microangiopathy 1

Common Pitfalls to Avoid

1. Do not assume creatinine elevation equals proteinuria – these are distinct adverse effects with different mechanisms and clinical significance. 1

2. Do not discontinue selpercatinib reflexively for modest creatinine rises – investigate reversible causes (volume depletion, drug interactions) first. 4

3. Do not overlook hypertension management – hypertension is a common adverse effect of selpercatinib (14-21% grade 3+) and requires monitoring and treatment to prevent secondary renal injury. 1, 2, 3

4. Always measure urine protein – if renal function declines on selpercatinib, obtain a spot urine protein-to-creatinine ratio to definitively assess for proteinuria rather than assuming its presence. 1

Monitoring Recommendations

For patients on selpercatinib with rising creatinine: 1, 4

• Measure serum creatinine and eGFR at baseline and periodically during treatment
• Check blood pressure at each visit (hypertension is common)
• Obtain spot urine protein-to-creatinine ratio if eGFR declines >30% or creatinine rises progressively
• Assess volume status and review all concomitant medications
• Consider dose interruption (42% of patients required dose interruptions for treatment-related adverse events, most commonly for elevated ALT/AST) 1