Functional and histological improvement after everolimus rescue of chronic allograft dysfunction in renal transplant recipients

Abstract

Background

We tested the strategy of mTOR inhibitors with calcineurin inhibitor minimization in renal transplant recipients with known chronic allograft dysfunction.

Methods

In this open-label, single-arm study, renal transplant patients were recruited after biopsy-confirmed chronic allograft dysfunction in the absence of acute rejection episode within 2 months, with proteinuria <0.8 g/day, and serum creatinine <220 μmol/L or estimated glomerular filtration rate >40 mL/min/1.73 m². They were converted to everolimus (aiming for trough everolimus level 3–8 ng/mL) with cyclosporine minimization, to assess the effect on renal function, rate of glomerular filtration rate decline, and longitudinal transplant biopsy at 12 months.

Results

Seventeen Chinese patients (median transplant duration, 4.2 years) were recruited; no patients discontinued study medication. The mean slope of the glomerular filtration rate over time was −4.31±6.65 mL/min/1.73 m² per year in the year before everolimus, as compared with 1.29±5.84 mL/min/1.73 m² per year in the 12 months of everolimus therapy, a difference of 5.61 mL/min/1.73 m² per year (95% confidence interval [CI], 0.40–10.8) favoring everolimus therapy (P=0.036). Serial renal biopsy histology showed significant decrease of tubular atrophy (15.7%±11.3% versus 7.1%±7.3%, P=0.005) and interstitial fibrosis (14.8%±11.5% versus 7.2%±8.2%, P=0.013). Intrarenal expression of TGF-β1 mRNA showed a nonsignificant decrease after everolimus treatment.

Conclusion

In renal transplant recipients with biopsy-confirmed chronic allograft dysfunction, we found a significant beneficial effect of everolimus rescue therapy and calcineurin inhibitor minimization strategy on the improvement of glomerular filtration rate decline rate. In secondary analysis, everolimus was shown to slow down the disease progression by reducing the tubular atrophy and interstitial fibrosis scoring.

Keywords:

• cyclosporine
• calcineurin inhibitor
• everolimus
• glomerular filtration rate
• renal transplantation
• mTOR inhibitor
• immunosuppression

Acknowledgments

The study was supported in part by the Hong Kong Society of Nephrology Research Grant and the Chinese University of Hong Kong Research Grant Account 6900570.

Disclosure

The authors report no conflicts of interest in this work.