Early Low Urinary CXCL9 and CXCL10 Might Predict Immunological Quiescence in Clinically and Histologically Stable Kidney Recipients

Abstract

We monitored the urinary C-X-C motif chemokine (CXCL)9 and CXCL10 levels in 1722 urine samples from 300 consecutive kidney recipients collected during the first posttransplantation year and assessed their predictive value for subsequent acute rejection (AR). The trajectories of urinary CXCL10 showed an early increase at 1 month (p = 0.0005) and 3 months (p = 0.0009) in patients who subsequently developed AR. At 1 year, the AR-free allograft survival rates were 90% and 54% in patients with CXCL10:creatinine (CXCL10:Cr) levels <2.79 ng/mmoL and >2.79 ng/mmoL at 1 month, respectively (p < 0.0001), and 88% and 56% in patients with CXCL10:Cr levels <5.32 ng/mmoL and >5.32 ng/mmoL at 3 months (p < 0.0001), respectively. CXCL9:Cr levels also associate, albeit less robustly, with AR-free allograft survival. Early CXCL10:Cr levels predicted clinical and subclinical rejection and both T cell-and antibody-mediated rejection. In 222 stable patients, CXCL10:Cr at 3 months predicted AR independent of concomitant protocol biopsy results (p = 0.009). Although its positive predictive value was low, a high negative predictive value suggests that early CXCL10:Cr might predict immunological quiescence on a triple-drug calcineurin inhibitor-based immunosuppressive regimen in the first posttransplantation year, even in clinically and histologically stable patients. The clinical utility of this test will need to be addressed by dedicated prospective clinical trials.Abbreviations: ABMR, antibody-mediated rejection; AR, acute rejection; AUC, area under the curve; CI, confidence interval; CXCL10, urinary C-X-C motif chemokine 10; CXCL9, urinary C-X-C motif chemokine 9; CXCL9:Cr, urinary C-X-C motif chemokine 9:creatine ratio; CXCL10:Cr, urinary C-X-C motif chemokine 10: creatine ratio; DSA, donor-specific antibody; MFI, mean fluorescence intensity; NPV, negative predictive value; PPV, positive predictive value; ROC, receiver operating characteristic; TCMR, T cell-mediated rejection

Urinary miR‐155‐5p and CXCL10 as prognostic and predictive biomarkers of rejection, graft outcome and treatment response in kidney transplantation

“…It induces, maintains and amplifies both inflammatory and immune responses and plays a critical role in AR . Our results are also in line with recent findings that early urinary CXCL10 levels and the CXCL10:Cr ratio in kidney recipients can be prognostic biomarkers of subsequent rejection .…”

“…Several studies have found a robust association between CXCL10 levels and renal allograft outcome participates in the recruitment of alloantigen primed T cells to the site of inflammation and during the induction of proinflammatory cytokines . It induces, maintains and amplifies both inflammatory and immune responses and plays a critical role in AR .…”

“…In another study, urinary CXCL10 levels were linked to risk of AR, and moreover, CXCL10 levels during the first 4 weeks post‐transplantation were associated with graft function at 6 months . High urinary CXCL10 levels were also associated with AR from 1 month to 1 year post‐transplantation, and the CXCL10:Cr ratio correlated with AR risk .…”

Longitudinal assessment of the CXCL10 blood and urine concentration in kidney transplant recipients with BK polyomavirus replication—a retrospective study

“…Since increased CXCL10 levels have been associated with long‐term allograft dysfunction in KTRs, an increased CXCL10 concentration due to low level but sustained BKPyV replication could also possibly adversely influence allograft survival . Correspondingly, a constantly low CXCL10 urinary concentration was recently correlated with histologically stable allografts and freedom of rejection . Thus, it is indeed possible that CXCL10 might serve as inflammatory marker to individualize immunosuppressive treatment, this, however, requires further studies.…”

Urine biomarkers in renal allograft

“…Levels of circulating MMPs and TIMPs fluctuate in SLE, and increased MMP-2, MMP-3, MMP-7, TIMP-1 and TIMP-2 probably reflect an aggravated Effective for the early detection and prognosis of several acute kidney diseases [27] Yao Xu [28] ; Michael R. Bennett [13] CXCL9/CXCL10 Urinary CXCL9 promising for clinical decision-making following kidney transplantation Noninvasive biomarkers to screen for subclinical tubulitis [29] Hricik DE [14] ; Rabant M [30] ; Paola Romagnani [31] [TIMP-2 ]* [IGFBP7]…”