*2.5. Summary of the Results*

Tables 4–6 provide a detailed summary of each study results. When DTA analysis was available (29 studies), the results are summarized in Table 4 for diagnostic studies (24/38) and Table 5 for prediction studies (5/38). Descriptive results from the remaining nine studies are briefly reported in Table 6. For each DTA study, the particular outcome of interest and characteristics of the control population are reported with sample size for each group included in the final DTA analysis. The urinary biomarker of interest, thresholds (when available) and test design (training, validation, or particular comparisons between groups) are also detailed. For prediction studies, time from transplantation to urinary biomarker analysis is also reported (between 1 day to 6 months post-transplantation). Sensitivity, specificity, positive and negative predictive values (PPV, NPV), and area under the receiver operating characteristic curve (AUC) are reported as measures of diagnostic test accuracy when available (Tables 4 and 5) and results are in bold text when arising from validation cohorts. Results confirmation in at least one validation cohort was available in less than one third of studies (7/29, 24%). Of these, two were case-control studies [25,33], while the others were the previously mentioned five cross-sectional studies with the lowest risk of bias score [16,17,21,41,45]. Sensitivity and specificity values were highly variable between studies, ranging from 9% to 100% and from 34% and 100%, respectively. PPV and NPV were also variable, ranging from 15% to 98% and from 32% to 100%, respectively.





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dysfunctional

 graft patients (-B, biopsied); STA, stable graft patients (-B, biopsied).

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**Table 5.** Summary of the study results—Predictive studies with DTA. This table shows the outcome of prediction studies. Outcome and control group for the DTA analysis are reported (sample size when available), followed by the studied urinary biomarker(s), thresholds and time from transplant to test.

ALL, all patients irrespectively of allograft function (-B, biopsied); STA, stable graft patients (-B, biopsied).

## 2.5.1. Acute Rejection Diagnosis

Among studies with the lowest risk of bias, only three studies [16,17,45] yielded a very good (0.8–0.9) or excellent (> 0.9) performance as diagnostic AUC (Table 4). All of these studies provided diagnostic accuracy measure for the diagnosis of AR, considering both TCMR and ABMR as outcome of interest. Tinel et al. found that the combination of urinary CXCL9 and CXCL10 could distinguish AR patients among almost three-hundred heterogeneous patients with an AUC of 0.70 [16]. These results strengthened the good performance previously described, among dysfunctional allografts, separately for CXCL9 (AUC 0.71) and CXCL10 (AUC 0.74) by Rabant and colleagues [51]. Yang et al. separately validated the so-called *Q score* in two validation cohorts for the diagnosis of AR. A *Q score* ≥ 32 maintained an excellent diagnostic performance (AUC 0.96) also when validated in the entire study population (*n* = 364), with high PPV and NPV (87–98%) [17]. Banas et al., after identifying a urinary metabolite signature with good diagnostic performance for TCMR [27], validated it in a cohort of 109 patients for the diagnosis of AR with and AUC of 0.71 [21]. Through unbiased metabolomics, Sigdel et al. identified a signature of eleven urinary peptides able to segregate AR patients from normal histology, chronic allograft nephropathy and BK virus nephropathy patients with an excellent AUC of 0.94 in validation cohort [45]. The same authors proved a urine cell sediment gene expression-based score (*uCRM score*) able to diagnose AR with 96.6% accuracy and potentially quantify the degree of injury [24].


**Table 6.** Summary of the study results—Studies with no DTA. This table describes the main results from studies with no DTA. Sample size is reported for the outcome and control group when available.

Statistically significant (*p* < 0.05) results are shown in **bold**. \* Prediction study. ALL, all patients irrespectively of allograft function (-B, biopsied); DYS, dysfunctional graft patients (-B, biopsied); STA, stable graft patients (-B, biopsied).
