A randomized controlled trial of late conversion from calcineurin inhibitor (CNI)-based to sirolimus-based immunosuppression in liver transplant recipients with impaired renal function

Abstract

Renal impairment is common in patients after liver transplantation and is attributable in large part to the use of calcineurin inhibitor (CNI)-based immunosuppression. We sought to determine whether conversion to sirolimus-based immunosuppression was associated with improved renal function. In a single-center, randomized, controlled trial, 30 patients at least 6 months post liver transplantation were randomized to remain on CNI-based immunosuppression or to switch to sirolimus-based immunosuppression. The primary outcome measure was change in measured glomerular filtration rate (GFR) between baseline and 12 months. Of 30 patients randomized, 3 were withdrawn at randomization, leaving 14 patients on CNI and 13 on sirolimus. There was a significant improvement in delta GFR following conversion to sirolimus at 3 months (7.7 mL/minute/1.73 m 2 ; 95% confidence interval, 3.5-11.9) and 1 yr (6.1 mL/minute/1.73 m 2 ; 95% confidence interval, 0.9-11.4). The difference in absolute GFR between the 2 study groups was significant at 3 months (P ϭ 0.02), but not at 12 months (P ϭ 0.07). The principal adverse events following conversion were the development of skin rash (9 of 13 patients, 69%) and mouth ulcers (5 of 13 patients, 38%). Two patients developed acute rejection at 2 and 3 months following conversion, 1 in association with low sirolimus levels and 1 having stopped the drug inadvertently. In conclusion, overall, this study suggests that conversion to sirolimus immunosuppression is associated with a modest improvement in renal function. Side effects were common, but tolerable in most patients and controlled with dose reduction.

Sirolimus Conversion Regimen Versus Continued Calcineurin Inhibitors in Liver Allograft Recipients: A Randomized Trial

“…In addition, patients switched early after transplantation may have an increased ACR risk, whereas those switching later may have already experienced additional detrimental effects on kidney function. We also acknowledge the large loading dose of sirolimus mandated by the study protocol due to the abrupt withdrawal of calcineurin inhibitor immunosuppression (10-15 mg; mean loading dose 10.3 ± 2.1 mg [range, [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]), which may have impacted certain aspects of the results (e.g. TEAEs, discontinuations, etc).…”

“…One randomized, single-center trial observed improvements in creatinine clearance at 3 months following CNI withdrawal and conversion to SRL, but between-group differences were not significant at 12 months (17). A second single-center trial evaluating 27 patients ≥6 months post-LT showed that patients switched to SRL had improvement in GFR after 3 (p = 0.001) and 12 months (p = 0.02) compared with those continuing CNI-based immunosuppression (18).…”

Early Withdrawal of Calcineurin Inhibitors and Everolimus Monotherapy in de novo Liver Transplant Recipients Preserves Renal Function

“…(2,15,16) A potential concern with CNI withdrawal is the risk of under-immunosuppression and ensuing rejection, which has been described in several reports (6,17). (18)(19)(20)(21)(22)(23)(24)(25)(26) (23)(24)(25)(26), concurrent non-CNI-related renal disease (25) and interval from transplantation (25,26 in which there was little improvement in the renal function of LT recipients after nonnephrotoxic drug implementation maintenance (27). …”

Current Status of Immunosuppression in Liver Transplantation

“…The calcineurin inhibitors (Tacrolimus and Cyclosporine) are cornerstone of maintenance immunosuppression in liver transplantation and CNI free regimens had more chances of rejection as compared to regimens with CNI. 48,49 Calcineurin inhibitors are associated with nephrotoxicity which has both acute and chronic components. Acute reduction of GFR by CNIs is caused by afferent arteriolar vasoconstriction which is probably mediated by endothelin, rennin angiotensin aldosterone system and reduced activity of vasodilators.…”