Previous research underscores the significance of CXCL10 as a biomarker in the prognosis of kidney graft injuries (acute rejection (AR), TCMR, ABMR), examining its presence in both serum and urinary assays. Investigations have not only focused on CXCL10 as an isolated marker but have also encompassed its correlative studies with serum creatinine levels.

These studies propose that CXCL10 may serve as an integral biomarker, offering predictive insights into the functional status of renal transplants [5, 6, 15,16,17, 20]. Rabant et al. suggested that low levels of urinary CXCL10 could predict immunological quiescence, or a low risk of acute rejection, as early as one month into stable graft conditions [31]. The study by Mühlbacher J et al. highlighted that the association of urinary CXCL10/Cr ratio with donor-specific antibodies (DSA) significantly improved the identification of ABMR and the prediction of graft loss. Their finding emphasizes the potential of CXCL10 as a biomarker in transplant medicine [19]. Earlier research, demonstrated that measuring the serum level of CXCL10 before kidney transplantation could be a predictor of acute rejection which suggest that CXCL10 levels could serve as an important indicator for preemptive measures in transplant recipients [32]. Finally, Jackson et al. concluded that CXCL10 levels don’t seem to distinguish between AR and BK virus infection. They both show elevated levels of this chemokine, although diagnostic certainty is still possible when combined with other tests like a creatinine assay [33].This study presents a comprehensive systematic review and meta-analysis that focuses on the clinical validation and comparison of CXCL10 and CXCL10/Cr urinary levels in the detection of post-kidney transplantation injuries. The analysis encompasses data from 10 studies (9 articles) involving a total of 3035 kidney transplant recipients. The findings indicate that CXCL10 protein level demonstrated a sensitivity of 0.78 (0.69–0.89) and a specificity of 0.82 (0.72–0.94), while CXCL10/Cr level exhibited a sensitivity of 0.77 (0.72–0.81) and a specificity of 0.73 (0.60–0.90). These results indicate that assessing the sensitivity and specificity of CXCL10, as opposed to CXCL10/Cr, may offer greater efficacy in predicting injuries in kidney transplant recipients. It may be related to notable variations in urinary creatinine excretion rates (uCER) among kidney transplant recipients. For instance, those with delayed graft function may have values below 300 mg/day, while patients showing prompt graft function can exceed 2,100 mg/day [34]. These differences can be influenced by several factors, including age, sex, race [35], daily changes in creatinine production, levels of physical activity, dietary habits, emotional stress, muscle mass, and overall health condition [36]. Research indicates that urinary creatinine can fluctuate significantly even within an individual, with intraindividual coefficients of variation (CVs) reported to be between 10.5% and 14.4%. Additionally, creatinine excretion may vary throughout the day and across different days [37]. Some studies have found that normalizing urinary biomarker values to creatinine, such as in the case of neutrophil gelatinase-associated lipocalin (NGAL), can help lower these intraindividual CVs [38, 39]. Waikar et al. noted that kidney injury molecule-1(KIM-1) excretion and uCER have different responses during acute disease states [34], suggesting that normalizing to creatinine is not always appropriate. Therefore, the appropriateness of normalizing urinary creatinine depends significantly on the specific research objectives, the biomarker involved, and the clinical context of the patients being studied [40].

This review encompassed nine articles [18, 24,25,26,27,28,29,30,31], five of which examined urinary CXCL10 protein levels, [25,26,27, 29, 30] while one included two groups [27]. The first group exclusively evaluated urinary CXCL10 protein levels, while the second group measured urinary CXCL10 to serum Cr ratio. The other four articles in the review explored urinary CXCL10 to urinary Cr ratio as a biomarker under study [18, 24, 28, 31].

Moreover, Matz et al. conducted a study involving two groups, acute cellular rejection and borderline rejection (BR), which were assessed at three different time points (2/3, 4/5, and 6/7 days) prior to rejection. The study reported varying sensitivities of 0.47, 0.62, and 0.71, with a consistent specificity of 0.95 for all time points, focusing on early post-transplant urinary CXCL10 protein levels after kidney transplantation. These data were subsequently aggregated for inclusion in the final evaluation, yielding a combined sensitivity and specificity of 0.63 and 0.95, respectively [29].

The other study that was pooled is Rabant et al. that examined urinary samples collected at three time points post-kidney transplantation 10 days, 1 month, and 3 months. The study focused on measuring the CXCL10/Cr ratio in recipients with ABMR, TCMR, and mixed rejection. The reported sensitivities for these time points were 0.57, 0.83, and 0.53, with specificities of 0.52, 0.51, and 0.76, respectively. Upon combining the data from these time points, the resulting sensitivity and specificity were 0.74 and 0.66, respectively [31].

The last study that was pooled for including in meta-analysis is Van loon et al. [24] who assessed the CXCL10/Cr protein level through an automated immunoassay method at three distinct thresholds (5%, 16%, and 25%) derived from a 5-parametere model for the non-invasive detection of acute rejection. The sensitivities reported at theses thresholds were 0.882, 0.392, and 0.248, with corresponding specificities of 0.314, 0.9, and 0.96. When the data of these threshold were combined the resulting sensitivity and specificity were 0.8 and 0.93, respectively.

The detection methods used for urinary CXCL10 in the included studies were based on assessing protein expression levels. All studies detected this urinary protein using ELISA, except for Hu [30] and Van loon [24] who used luminex assay and automated immunoassay, respectively. Across all included studies, an increased level of urinary CXCL10 was associated with a type of kidney graft injury. All urinary samples were collected post-transplantation and almost always before biopsy procedures (Table S1). Finally, it is worth noting that measuring urinary protein levels based on antibody-using tests such as ELISA is currently one of the most reliable and accurate existing methods.

The injuries related to the included studies in this review encompassed 14 different types of dysfunctions of kidney grafts. These included AR, TCMR, ABMR, mixed rejection (MR), BR, subclinical rejection (SR), clinical rejection (CLR), acute vascular rejection (AVR), BK virus nephropathy (BKVN), acute tubular necrosis (ATN), chronic rejection (CHR), late clinical rejection, graft functional decline, and graft loss. This review discusses the potential role of urinary CXCL10 assessment before performing an invasive biopsy procedure in identifying high-risk kidney transplant recipients who were developing at least one of the 14 different types of dysfunctions. Therefore, serial urinary CXCL10 monitoring in the weeks and months following transplantation may help accelerate clinical diagnosis of recipients at risk for rejection or graft loss which might help in reducing the number of biopsies. Accordingly, CXCL10 shows promise as a marker for identifying post-kidney transplant injuries, particularly rejection, further comprehensive studies are essential. These studies should focus on standardizing factors such as study design, sample type, evaluation methods, types of post-transplant injuries, and patient monitoring for a minimum of 6 months before and after transplantation. Moreover, combining the clinical data of CXCL10 with indicators like serum urea, creatinine, and proteinuria could lead to more precise models for predicting various potential injuries following kidney transplantation.

This manuscript is subject to several limitations. Firstly, numerous articles were excluded from the analysis due to insufficient information for calculating effect size. Additionally, a standardized method for grouping patients was not available, resulting in the comparison of studies with vastly different study groups, making it impossible to merge their results. Moreover, the articles employed two distinct approaches - studying CXCL10 levels and CXCL10/Cr ratios - which are not compatible for combination. These factors led to a significant decrease in the number of studies included in the meta-analysis.