Screening for Urinary Chemokines in Long Term Renal Transplant Patients Associates with Cellular Rejection, Microvascular Damage and Falls in GFR Over Time

Non-invasive biomarkers are required to evaluate risk of rejection following kidney transplantation as an alternative to biopsy. Urinary CXCL-9 and CXCL-10 have been to shown to be associated with and predict the development of T cell and antibody mediated rejection when measured in the early transplant period. We assessed the clinical utility of urinary CXCL-9 and CXCL-10 evaluation in long-term transplant patients. From November 2015 to November 2016, 185 urine samples from renal transplant patients (n=120) were screened over a median of 47 (2-400) months after transplant. Patients were followed until November 2017 to determine rates of fall in GFR, and whether biopsies confirmed rejection. Over this period, 15 biopsies were performed and scored according to Banff (8 acute cellular rejection, 2 mixed cellular/microvascular damage, 3 isolated microvascular damage and 3 transplant glomerulopathy(TG)). Seven of these patients were biopsied as a result of elevated CXCL-10 results. CXCL-9/urinary creatinine ratio did not differentiate between stable graft function or any type of rejection in this cohort. CXCL-10/urinary creatinine ratio values were higher in acute cellular rejection as compared to stable patients (p<0.001). Values were also higher in those who were diagnosed with TG or microvascular damage compared to stable graft function (p=0.005). The ROC curves were significant p=0.005 with AUC=0.66. Sensitivity- specificity analysis revealed a cut-off point of 3.7 ng/mmoL to differentiate between microvascular damage and stable graft function, with a specificity of 94% and sensitivity of 30%. Excluding those with rejection on biopsy; Elevated CXCL-10/urinary creatinine associated with clinically significant falls in GFR over the time of follow-up. No patients in the lowest quartile CXCL-10/urinary creatinine (<2.7ng/mmoL) developed significant worsening of GFR (>10 ml/min/1.73m2) over 12-24 months. In the remaining 3 quartiles of CXCL-10/urinary creatinine, 12% of patients developed >10 ml/min/1.73m2 per year loss of GFR per year or graft failure. Elevated CXCL-10/urinary creatinine ratio associates with microvascular damage in long-term renal transplant patients. A very low level of urinary CXCL-10 predicts stable graft function over time. In long-term transplant patients, screening for higher CXCL-10 levels in urine may uncover microvasular damage and low levels of urinary CXCL-10 are reassuring for stable graft function. Additional studies are needed to further clarify the clinical utility of CXCL-10 to stratify rejection risk in transplant patients.