Calcineurin inhibitor toxicity in children with nephrotic syndrome: a retrospective cohort study

Aims/Purpose: International guidelines currently recommend kidney biopsy for the assessment of calcineurin inhibitor (CNI) toxicity after prolonged exposure (2-3 years). However, the incidence of biopsy proven CNI toxicity is unknown in children treated with CNI for nephrotic syndrome, and the procedure has risks and attendant costs to the healthcare system.
We sought to describe the proportion of children with nephrotic syndrome who had CNI toxicity, the type of histopathological injury and complications of their biopsy.
Methods: We conducted a s retrospective review of kidney biopsies performed in an Australian tertiary paediatric hospital between 2016-2023. We included all children with frequently relapsing or steroid dependent nephrotic syndrome aged 0-17 years who had a native kidney biopsy to check for CNI toxicity after treatment with either cyclosporin or tacrolimus. Demographic and clinical data was extracted from electronic medical records, including details of the procedure, type of CNI, levels and duration of exposure, type and severity of histological changes, any complications and change in management. CNI toxicity was defined as a presence of tubular vacuolisation, arterial hyalinosis, interstitial fibrosis and/or tubular atrophy, fibrinoid necrosis or thrombotic microangiopathy. Descriptive statistics was used for data analysis. Hospital ethics board approval was obtained.
Results: 29 native kidney biopsies were performed for CNI toxicity using a 16G TruCore instrument. 14(48%) patients were treated with cyclosporine alone, 8 (27.5%) treated with tacrolimus, and 7 (24%) with both. Age range was 2-19 years (mean 9 +/- 3.7years) and majority (76%, 22) were male. Biopsy was performed on average at 40 months(+/-21) from commencement of CNI. Mean 1.55 (1-4) passes were performed to obtain the samples; all biopsies had an adequate sample (mean 22+/- 9.6 glomeruli). Toxicity was found in 3 cases(10%) (cyclosporin 3, tacrolimus 0) and could not be excluded in additional 3(10%). Isometric epithelial cytoplasmic vacuolation was most frequently reported, followed by tubular atrophy. The average drug level prior to the biopsy was in the therapeutic range in all cases where toxicity was reported. Most frequent procedural complication was haematoma. It was reported as small in 41% (12) of cases, or moderate in 17% (5). There was no serious bleeding, transfusion or other complications reported. Only 6% of patients required repeated biopsy with the same indication. Of those patients with CNI toxicity, management was changed in a single one after the biopsy, and in another CNI were stopped prior to procedure. Remainder of the patients continued therapy due to inability to achieve disease control on alternative treatment.
Conclusions: In children with nephrotic syndrome treated with either cyclosporin or tacrolimus, CNI toxicity was uncommon and even when observed, lead to a change in management in a small proportion of patients. CNI toxicity occurred despite average drug levels being in the therapeutic range. Complications from biopsy were more frequent but minor.