Alteration of urinary neutrophil gelatinase-associated lipocalin as a predictor of tacrolimus-induced chronic renal allograft fibrosis in tacrolimus dose adjustments following kidney transplantation

Abstract

Despite tacrolimus (TAC) drug-level monitoring, TAC-induced chronic renal allograft fibrosis remains an important problem. This study investigated the potential of urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a chronic renal allograft fibrosis biomarker in a two-phase study (proof of concept and cohort). In the proof of concept stage of the study, increased TAC-doses at 3 days after dose adjustment compared with the baseline were associated with elevated uNGAL (+ΔuNGAL) and urinary interleukin 18 (IL-18), but normal serum creatinine (SCr), despite the therapeutic trough levels of TAC. In the cohort study, the patients with elevated uNGAL post-recruitment in comparison with the baseline (+ΔuNGAL) was associated with the more severe renal allograft fibrosis from renal pathology of the protocol biopsy at 12 months post kidney transplantation (post-KT). A cut-off value of uNGAL ≥ 125.2 ng/mL during a 3, 6, 9 and 12 months post-KT was associated with a higher fibrosis score, with an area under the receiver operating characteristics curve of 0.80 (95% confidence interval [CI] 0.72 to 0.88, p < 0.0001) and a hazard ratio (HR) of 2.54 (95% CI 1.45 to 9.33; p < 0.001). We conclude that uNGAL is a sensitive biomarker of TAC induced subtle renal injury and TAC-induced chronic renal allograft fibrosis. We propose that uNGAL measurements, in addition to trough levels of TAC, should be used to predict TAC-induced chronic renal allograft fibrosis in the recipients of KT.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Characteristics of the recipients.

CNI, calcineurin inhibitor; TAC, tacrolimus; uNGAL, urinary neutrophil gelatinase–associated lipocalin; Δ, change.

Fig 2. Comparison of renal injury markers before (D 0) and 3 days after (D +3) TAC dose adjustment in the -ΔTACdose and +ΔTACdose groups.

SCr and the alteration in SCr from the baseline were comparable between recipients in the decreased TAC dose (-ΔTACdose) and increased TAC dose (+ΔTACdose) groups (A and B). There were no differences in uNGAL and uNGAL/uCr between the -ΔTACdose and +ΔTACdose groups (C, E) but the alteration in absolute uNGAL (ΔuNGAL) and uNGAL/uCr from the baseline were higher in the +ΔTACdose group (D, F).

Fig 3. Comparison of urinary cytokines between the day before (D 0) and 3 days after (D +3) TAC dose adjustment in the -ΔTACdose and +ΔTACdose groups.

Both urinary IL-18 (A) and IL-6 (B) but not TNF-α were higher in recipients with increased TAC doses after dose adjustment.

Fig 4. Renal allograft histology, change in eGFR and percentage change in 24-h proteinuria during the study period.

A scatter plot showing eGFR and the percentage alteration in mean values of eGFR in the -ΔTACdose and +ΔTACdose groups at enrolment versus the values observed 12 months post-enrolment (A). The time course of changes in eGFR in all four subgroups (B, left side) (B, right side), in addition to the percentage change in 24-h urinary protein, in each group (C) *(p < 0.01), ***(p < 0.001).

Fig 5. Urinary NGAL was predictive of chronic renal allograft fibrosis at 12 months post-enrolment.

Kaplan–Meier curve for the association of chronic renal allograft fibrosis with uNGAL (A) and ROC curve for the association between uNGAL at enrolment and chronic renal allograft fibrosis (B) were demonstrated.