Is it recommended to use steroids with calcineurin inhibitors (CNI) simultaneously in the treatment of membranous nephropathy?

Use of Steroids with CNIs in Membranous Nephropathy

The necessity of combining low-dose steroids with calcineurin inhibitors (CNIs) in membranous nephropathy is not clearly established, and CNIs can be used as monotherapy without steroids. 1

Evidence for CNI Monotherapy vs. Combination Therapy

The KDIGO guideline commentary explicitly states that "the necessity of low-dose steroids in combination with CNIs in the treatment of MN is not clear." 1 The evidence base shows divergent practices:

• Tacrolimus studies did not use concurrent steroids, while earlier cyclosporine studies did include low-dose prednisone (every other day or daily). 1
• Some clinicians choose to avoid steroids entirely when using CNIs for membranous nephropathy. 1

Clinical Decision Algorithm

For patients choosing CNI therapy:

Option 1: CNI Monotherapy (Preferred for tacrolimus)

• Use tacrolimus alone targeting trough levels of 8-10 ng/mL for at least 6 months. 1
• This approach is supported by studies demonstrating efficacy without steroid co-administration. 1
• Particularly appropriate when trying to minimize steroid-related toxicity in patients with contraindications (obesity, diabetes, advanced age). 1

Option 2: CNI + Low-Dose Steroids (Historical approach for cyclosporine)

• If using cyclosporine, consider adding low-dose prednisone every other day based on earlier study protocols. 1
• This combination was used in older cyclosporine trials but is not mandatory. 1

Important Mechanistic Considerations

CNIs have dual mechanisms that affect treatment duration decisions:

• Rapid hemodynamic effect: Decreases proteinuria quickly through glomerular perfusion pressure reduction and podocyte cytoprotection. 1
• Delayed immunologic effect: Takes months to achieve and represents the true disease-modifying action. 1

This distinction is critical because early proteinuria reduction should not be assumed to represent complete immunologic response, necessitating prolonged therapy regardless of steroid use. 1

Treatment Duration and Monitoring

Continue CNI therapy for at least 12 months after achieving remission, with gradual dose reduction at 4-8 week intervals to approximately 50% of starting dose. 1, 2 Most complete remissions occur after at least 6 months of therapy, with increasing numbers as treatment extends beyond 12 months. 1, 2

Common Pitfalls to Avoid

• Do not discontinue CNIs prematurely at 6 months if substantial proteinuria reduction (30-50%) is occurring but complete remission not yet achieved, particularly in patients with high-grade baseline proteinuria. 1
• Monitor closely for nephrotoxicity: Check serum creatinine for any unexplained rise >20% during therapy. 1
• Recognize high relapse rates: CNI-containing regimens have similar efficacy to alkylating agents for remission but higher relapse rates after discontinuation. 1

Adverse Effect Profile

CNIs carry risks including nephrotoxicity with prolonged use, hypertension, sodium retention, neurotoxicity, hyperglycemia, gingival hyperplasia (cyclosporine), or hair loss (tacrolimus). 1 These risks must be weighed against steroid-related toxicity when deciding whether to add corticosteroids.

Contraindications for CNI Use

Exercise caution with CNIs in patients with significant vascular or interstitial disease on renal biopsy and those with decreased eGFR. 1