Should Jynarque (Tolvaptan) be discontinued in a patient with OFD1 and CFI mutations, without PKD1, and with worsening renal function, and is further complement testing and kidney biopsy warranted?

Management of Polycystic Kidney Disease with OFD1 Mutation and Worsening Renal Function

Jynarque (tolvaptan) should be discontinued in this patient because she lacks PKD1 or PKD2 mutations, and the available evidence demonstrates that patients without these mutations show significantly less improvement or even worsening with tolvaptan therapy. 1

Question 1: Should Jynarque Be Stopped?

Evidence Against Continuing Tolvaptan

• Tolvaptan is FDA-approved specifically for ADPKD caused by PKD1 or PKD2 mutations, and the Mayo Imaging Classification used to predict treatment response should not be applied to patients with pathogenic variants in genes other than PKD1 or PKD2 2

• A 2020 study directly addressing this question found that patients with ADPKD lacking PKD1/2 mutations showed significantly less improvement in eGFR decline with tolvaptan (median improvement -0.7 mL/min/1.73 m² vs. 0.6 mL/min/1.73 m² in those with PKD1/2 mutations, p=0.01) 1

• The same study demonstrated that patients without PKD1/2 mutations had significantly less improvement in total kidney volume growth rate with tolvaptan (-1.1% vs. -6.7% in mutation-positive patients, p=0.02) 1

Your Patient's Specific Context

• OFD1 (Oral-Facial-Digital Syndrome Type 1) is explicitly listed as a distinct syndromic ciliopathy that mimics ADPKD but is X-linked, not caused by PKD1/2 mutations 2

• Her worsening renal function (creatinine rising from 1.2 to 2.3 mg/dL) while on Jynarque suggests lack of therapeutic benefit, which aligns with the evidence that tolvaptan effectiveness requires PKD1/2 mutations 1

• The persistent pyuria and hematuria (6-10 RBC, 10-20 WBC) may indicate alternative pathology beyond simple cyst expansion, warranting investigation rather than continued empiric tolvaptan therapy 2

Recommendation for Tolvaptan

Discontinue Jynarque immediately. The drug was designed for and proven effective only in PKD1/2-mediated disease, and continuing it exposes her to unnecessary aquaretic side effects, hepatotoxicity risk, and medication costs without expected benefit 3, 1, 4

Question 2: CFI Mutation and Need for Further Testing

Understanding CFI and Complement-Mediated Disease

• CFI (Complement Factor I) mutations are associated with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, both of which can cause progressive renal dysfunction 2

• Her heterozygous CFI mutation represents a risk factor but does not guarantee disease manifestation, as complement-mediated diseases often require additional triggers or second hits 2

Clinical Assessment of Complement Activity

Normal C3 and C4 levels from 2019 do not exclude complement-mediated kidney disease, as these are screening tests that can be normal even with active complement dysregulation 2

The absence of thrombocytopenia and anemia argues against active aHUS, but does not exclude C3 glomerulopathy or chronic complement-mediated injury 2

The persistent urinary abnormalities (hematuria, pyuria, squamous cells) with minimal proteinuria suggest glomerular pathology that could be complement-mediated 2

Specific Testing Recommendations

Yes, she requires comprehensive complement testing including:

• Alternative pathway functional assays (CH50, AH50) to assess complement pathway activity beyond static C3/C4 levels 2

• Complement Factor I functional assays to determine if her CFI variant causes functional deficiency 2

• Complement Factor H levels and anti-Factor H antibodies to evaluate for additional complement dysregulation 2

• Soluble C5b-9 (membrane attack complex) to assess for ongoing complement activation 2

Kidney Biopsy Indication

A kidney biopsy is strongly indicated in this patient for the following reasons:

• Progressive renal dysfunction (creatinine 1.2→2.3 mg/dL) with uncertain etiology requires tissue diagnosis to guide management and prevent further deterioration 2

• The combination of OFD1-related cystic disease and CFI mutation creates diagnostic uncertainty that cannot be resolved without histopathology 2

• Persistent urinary abnormalities (hematuria, pyuria) suggest active glomerular or tubulointerstitial disease beyond simple cyst expansion 2

• Biopsy can identify C3 glomerulopathy (characterized by isolated C3 deposition on immunofluorescence with electron-dense deposits), which would dramatically change management 2

• If complement-mediated disease is confirmed, targeted therapies (complement inhibitors like eculizumab or avacopan) may be available, making tissue diagnosis critical for treatment decisions 2

Biopsy Timing and Technique

Perform the biopsy urgently given the rate of creatinine rise (nearly doubling over approximately 4 years suggests accelerating disease) 2

Ensure adequate tissue sampling with:

• Light microscopy for structural assessment
• Immunofluorescence specifically evaluating for isolated C3 deposition (hallmark of C3 glomerulopathy)
• Electron microscopy to characterize deposit location and morphology 2

Critical Pitfalls to Avoid

• Do not continue tolvaptan based solely on a clinical diagnosis of "polycystic kidney disease" without confirmed PKD1/2 mutations 2, 1

• Do not assume normal C3/C4 levels exclude complement-mediated disease—functional assays and biopsy are required 2

• Do not delay biopsy waiting for complement testing results—the procedures should proceed in parallel given progressive renal dysfunction 2

• Do not attribute all renal dysfunction to cystic disease when genetic testing reveals alternative pathogenic mechanisms (CFI mutation) 2

Immediate Management Steps

1. Discontinue Jynarque immediately 1
2. Order comprehensive complement testing (functional assays, Factor I activity, Factor H levels, sC5b-9) 2
3. Schedule kidney biopsy within 1-2 weeks with appropriate immunofluorescence and electron microscopy protocols 2
4. Continue losartan for blood pressure control and renoprotection 2
5. Refer to medical genetics for comprehensive counseling regarding OFD1 and CFI implications 2
6. Consider nephrology subspecialty consultation (glomerular disease expert) if C3 glomerulopathy or aHUS is confirmed 2