In a renal transplant patient with worsening renal function, should transplant medications, such as immunosuppressants (e.g. tacrolimus, mycophenolate mofetil), be continued?

Management of Immunosuppressive Medications in Renal Transplant Patients with Worsening Creatinine

In renal transplant patients with worsening creatinine, immunosuppressive medications should be continued but with appropriate modifications based on the cause of renal dysfunction, rather than completely discontinued. 1

Diagnostic Approach for Worsening Creatinine

Before making any medication changes, it's essential to determine the cause of worsening renal function:

1. Kidney allograft biopsy is strongly recommended for all patients with declining kidney function of unclear cause to detect potentially reversible causes. 1

   • Biopsy should be performed before treating suspected acute rejection unless it would substantially delay treatment.

2. Monitor CNI blood levels whenever there is a decline in kidney function that may indicate nephrotoxicity or rejection. 1

3. Check for other potential causes:

   • Dehydration
   • Medication interactions
   • Urinary obstruction
   • Infection
   • Recurrent primary disease

Management Algorithm Based on Cause of Renal Dysfunction

1. If CNI Toxicity is Confirmed:

• For patients with chronic allograft injury (CAI) and histological evidence of CNI toxicity:
  • Reduce, withdraw, or replace the CNI 1
  • For patients with CAI, eGFR >40 ml/min/1.73 m² and urine protein <500 mg/g creatinine, consider replacing CNI with an mTOR inhibitor 1
  • Maintain tacrolimus trough in the low therapeutic range 1

2. If Acute Rejection is Confirmed:

• Continue all immunosuppressive medications
• Add corticosteroids for initial treatment of acute cellular rejection 1
• For steroid-resistant or recurrent rejections, consider lymphocyte-depleting antibodies 1
• Consider adding or restoring maintenance prednisone in patients not on steroids 1

3. For Failing Allograft with Residual Function:

• Maintain CNI as the main immunosuppressive medication to minimize risk of new donor-specific antibodies 1
• Consider reduction in anti-metabolite (mycophenolate mofetil) by 50% 1
• Adjust mycophenolate mofetil dose based on severity of renal dysfunction:
  • For severe chronic renal impairment (GFR <25 mL/min/1.73 m²), avoid doses greater than 1g twice daily 2

4. For Failed Allograft Requiring Dialysis:

• Taper immunosuppression gradually rather than abrupt discontinuation 1
• Recommended tapering schedule:
  1. First: Reduce anti-metabolite (MMF/AZA) by 50%
  2. Later: Stop anti-metabolite
  3. At 6 months post-dialysis: Reduce CNI by 50%
  4. Consider maintaining low-dose CNI and/or prednisone for patients who are candidates for re-transplantation 1

Monitoring Recommendations

• Measure serum creatinine at appropriate intervals based on time post-transplant 1
• Monitor CNI levels whenever there is a change in medication or patient status 1
• Monitor MMF levels when available 1
• Measure urine protein excretion regularly 1

Common Pitfalls to Avoid

1. Abrupt discontinuation of all immunosuppressants can lead to acute rejection and graft intolerance syndrome
2. Failure to adjust CNI dose when renal function declines can worsen nephrotoxicity
3. Overlooking drug interactions that may increase CNI levels and toxicity
4. Delaying biopsy when the cause of worsening renal function is unclear
5. Not considering CNI-sparing strategies when CNI toxicity is confirmed

Special Considerations

• Lower tacrolimus levels and higher MMF doses are associated with better renal function in transplant patients 3
• Even after prolonged hemodialysis (e.g., 4 months), some recipients may still recover renal function if immunosuppression is not completely withdrawn 4
• For patients with progressively deteriorating renal function due to chronic allograft nephropathy, addition of MMF followed by withdrawal of cyclosporine can result in significant improvement in transplant function 5

Remember that maintaining some level of immunosuppression is crucial for preserving residual graft function and minimizing sensitization for future transplants, even when renal function is significantly compromised.