Patient selection critical for calcineurin inhibitor withdrawal in pediatric kidney transplantation

Abstract

CNI withdrawal may be employed as a "rescue" strategy for patients with established renal allograft injury and/or declining allograft function, with the aim at eliminating CNI-associated nephrotoxic effects. This analysis reviews outcomes in a pediatric population and identifies risk factors for adverse events post-CNI withdrawal. We performed a retrospective analysis of 17 pediatric renal transplants who underwent CNI withdrawal, with conversion to sirolimus and MMF. Mean CrCl decreased from 64.3 +/- 22 to 59.38 +/- 28.6 mL/min/1.73 m(2) (p = 0.04) at six months and 57.46 +/- 31.1 mL/min/1.73 m(2) (p = 0.02) at 12 months post-withdrawal. Forty-one percent of patients experienced AR. Increased risk for AR was associated with prior AR history, lower sirolimus trough levels, and lower CNIT biopsy scores. Graft loss (24%) was associated with worse CrCl, proteinuria, and histologic chronicity. Proteinuria (spot protein/creatinine ratio) increased from 0.75 +/- 1.0 to 1.71 +/- 2.0 (p = 0.03), unrelated to de novo sirolimus use. Four patients returned to CNI-based immunosuppression due to AR (n = 3) and gastrointestinal side effects (n = 1). Careful selection of pediatric candidates for CNI withdrawal is recommended. Worsening graft function and graft loss may be minimized by selecting patients with high CNIT scores and low biopsy chronicity and excluding patients with prior AR history.

Pediatric renal transplantation: an overview and update

“…Calcineurin-sparing regimens, with the aim to limit nonimmune fibrosing injury from calcineurin inhibitor graft toxicity, have not shown much success in pediatric patients. Early calcineurin inhibitor avoidance CNO1 [25] had higher rates of early acute rejection, and late calcineurin inhibitor switch to sirolimus was associated with greater risk of graft functional decline and proteinuria [26]. For this reason, calcineurin inhibitor dose minimization, rather than avoidance or withdrawal, is the generally practiced approach for children.…”

Calcineurin Inhibitor-Free Immunosuppression in Pediatric Renal Transplantation

“…[38,[65][66][67][70][71][72] One prospective, randomized trial encompassed 84 adult renal transplant patients with biopsy-proven chronic allograft nephropathy who were randomly assigned to receive a 40% reduction of their calcineurin inhibitor dose (n = 50) or to withdraw calcineurin inhibitor therapy using sirolimus as a substitute (n = 34) [table IV]. [65] Concomitant immunosuppression consisted of mycophenolate mofetil and corticosteroids.…”

“…[38,[70][71][72] A small-scale, prospective trial involved eight pediatric renal transplant patients with chronic allograft nephropathy and declining eGFR (table V). [70] Calcineurin inhibitor withdrawal took place and sirolimus treatment started at a median timepoint of 32 months post-transplant.…”

Pediatric kidney transplantation: a review

“…Weintraub et al used calcineurin inhibitor withdrawal in 17 children with renal allograft injury due to calcineurin inhibitor nephrotoxicity by substituting with sirolimus and mycophenolate mofetil. 55 Although they achieved improvement in renal function, 41% of patients experienced an episode of acute rejection. While early calcineurin inhibitor avoidance is associated with higher rates of early acute rejection, late calcineurin inhibitor switch to sirolimus has been associated with a greater risk of decline in graft function with proteinuria.…”

“…While early calcineurin inhibitor avoidance is associated with higher rates of early acute rejection, late calcineurin inhibitor switch to sirolimus has been associated with a greater risk of decline in graft function with proteinuria. 54,55 For this reason, minimization of the calcineurin inhibitor dose, rather than avoidance or withdrawal, is the generally practiced approach for children. In addition to calcineurin inhibitors, maintenance regimens in children also commonly include an antimetabolite.…”