Prediction of Long-term Renal Allograft Outcome By Early Urinary CXCL10 Chemokine Levels

Patricia Hirt-Minkowski, Julie Ho, Ang Gao, Patrizia Amico, Michael T Koller, Helmut Hopfer, David N Rush, Peter W Nickerson, Stefan Schaub, Patricia Hirt-Minkowski, Julie Ho, Ang Gao, Patrizia Amico, Michael T Koller, Helmut Hopfer, David N Rush, Peter W Nickerson, Stefan Schaub

Abstract

Predictive biomarkers for long-term renal allograft outcome could help to individualize follow-up strategies and therapeutic interventions.

Methods: We investigated the predictive value of urinary CXC chemokine ligand 10 (CXCL10) measured at different timepoints (ie, at 3 and 6 months, and mean of 3 and 6 months coined CXCL10-burden) for long-term allograft outcomes in 154 patients. The primary outcome was a composite graft endpoint of death-censored allograft loss and/or biopsy-proven rejection and/or decline of estimated glomerular filtration rate greater than 20% occurring beyond 6 months after transplantation.

Results: After a median follow-up of 6.6 years (interquartile range, 5.7-7.5 years) the endpoint was reached in 43/154 patients (28%). In a multivariable Cox-regression model independent predictors were 6-month CXCL10 levels, the CXCL10-burden, HLA-mismatches, donor age and delayed graft function while previous (sub)clinical rejection, estimated glomerular filtration rate and proteinuria at 6 months, as well as 3-month CXCL10 levels were not. Time-dependent receiver operating characteristic analysis revealed an area under the curve of 0.68 (6-month CXCL10) and 0.67 (CXCL10-burden). Grouped by optimal cutoff, low 6-month CXCL10 (<0.70 ng/mmol) was associated with a 95% endpoint-free 5-year survival compared to 78% with high 6-month CXCL10 (P = 0.0007). Only 2 of 62 patients (3%) with low 6-month CXCL10 levels (<0.70 ng/mmol) experienced late rejection or graft loss due to rejection compared to 15 of 92 patients (16%) with high 6-month CXCL10 levels (P = 0.008). Similar results were obtained when patients were grouped according to CXCL10-burden (cutoff, 1.06 ng/mmol).

Conclusions: Six-month urinary CXCL10 is an independent predictor for long-term graft outcome and thus might be a supplementary tool to tailor surveillance strategies and therapy.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Patient flow diagram demonstrating exclusions, follow-up time and outcomes. Patients were stratified by the number of surveillance biopsy/urine pairs (ie, 1 pair obtained at 3 or 6 months posttransplant vs 2 pairs obtained at 3 and 6 months after transplantation).
FIGURE 2
FIGURE 2
Outcomes of 154 patients stratified by early urinary CXCL10 levels. A, Freedom from graft outcome endpoint (ie, death-censored graft loss, clinical rejection beyond 6 months posttransplant, >20% decline of eGFR). B, Freedom from clinical composite endpoint (ie, death, graft loss, clinical rejection beyond 6 months posttransplant, >20% decline of eGFR).
FIGURE 3
FIGURE 3
Individual longitudinal urinary CXCL10 levels and graft outcome. Urinary CXCL10 chemokine levels measured at 3 and 6 months after transplantation of the 154 patients with 2 pairs of surveillance biopsies/urines were ordered by the 6-month CXCL10 values and correlated with graft outcomes (coloured arrows). The cause of graft failures are indicated above the corresponding arrow. GN, glomerulonephritis.

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