Korean J Transplant.  2023 Dec;37(4):250-259. 10.4285/kjt.23.0048.

Cell cycle arrest biomarkers for the early detection of acute allograft dysfunction and acute rejection in living donor kidney transplantation: a cross-sectional study from Egypt

• Elnokeety MM
• Hussein WM
• Abdelrazek SA
• Momtaz M

• KMID: 2550236
• DOI: http://doi.org/10.4285/kjt.23.0048

Abstract

Background
Urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) are G1 cell arrest biomarkers that have demonstrated accuracy and validity in predicting and diagnosing acute kidney injury (AKI). This study aimed to evaluate the validity of [TIMP-2]×[IGFBP7] in diagnosing acute allograft dysfunction and its utility in distinguishing acute rejection (AR) from nonrejection causes in kidney transplantation.
Methods
This study included 48 adult living donor kidney transplant recipients (KTRs; 18 with AR, 15 with nonrejection causes of AKI, and 15 with stable grafts). Urinary TIMP- 2 and IGFBP7 were measured, and [TIMP-2]×[IGFBP7] was calculated in all subjects.
Results
IGFBP7, TIMP-2, and [TIMP-2]×[IGFBP7] were statistically significantly higher in KTRs with acute allograft dysfunction than in those with stable grafts. [TIMP-2]×[IGFBP7] was statistically significantly higher in KTRs with AR than in those with nonrejection AKI. [TIMP-2]×[IGFBP7] at a cutoff level of 0.278 (ng/mL)² /1,000 had an area under the curve (AUC) of 0.99 with a sensitivity of 100% and a specificity of 93.3% in diagnos-ing acute allograft dysfunction, while at a cutoff level of 0.803 (ng/mL)² /1,000 had an AUC of 0.939 with a sensitivity of 94.4% and a specificity of 83.3% in diagnosing AR.
Conclusions
Besides its role in the early detection of acute allograft dysfunction, [TIMP-2]×[IGFBP7] may help to differentiate between AR and nonrejection causes in KTRs. However, whether and how urinary [TIMP-2]×[IGFBP7] can be used in clinical diagnosis still requires further research.

Keyword

Kidney transplantation; Urinary TIMP-2; Urinary IGFBP7; Acute allograft dysfunction; Acute rejection

Figure

• 

  Fig. 1 Urinary insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in acute graft dysfunction and acute graft rejection in kidney transplant recipients (KTRs). (A) Urinary IGFBP7 level was higher in KTRs with acute allograft dysfunction than those with stable grafts, with mean±standard error (SE) 1.65±0.16 pg/mg creatinine, and 0.44±0.05 pg/mg creatinine, respectively (P<0.001). (B) Urinary TIMP-2 level was higher in KTRs with acute allograft dysfunction than those with stable grafts, with mean±SE 681.60±32.18 ng/mg creatinine, and 407.65±20.61 ng/mg creatinine, respectively (P<0.001). (C) [TIMP-2]×[IGFBP7] was higher in KTRs with acute allograft dysfunction than those with stable grafts, with mean±SE 1.08±0.10 (ng/mL)2/1,000, and 0.18±0.03 (ng/mL)2/1,000, respectively (P<0.001). (D) Urinary IGFBP7 level was significantly higher in KTRs with acute rejection (AR) than those with nonrejection acute kidney injury (AKI), with mean±SE 2.06±0.23 pg/mg creatinine, and 1.16±0.12 pg/mg creatinine, respectively (P<0.001). (E) Urinary TIMP-2 level was higher in KTRs with AR than those with nonrejection AKI, with mean±SE 722.33±39.53 ng/mg creatinine, and 632.81±51.18 ng/mg creatinine, respectively (P=0.169). (F) [TIMP-2]×[IGFBP7] was significantly higher in KTRs with AR than those with nonrejection AKI, with mean±SE 1.38±0.14 (ng/mL)2/1,000, and 0.70±0.07 (ng/mL)2/1,000, respectively (P<0.001).

• 

  Fig. 2 Receiver operating characteristic (ROC) curve analysis of insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloprotease-2 (TIMP-2), and [TIMP-2]×[IGFBP7] as markers of acute graft dysfunction. (A) IGFBP7 was able to diagnose acute allograft dysfunction with a sensitivity of 97.0%, specificity of 93.3%, and area under the curve (AUC) of 0.97 at a cutoff level of 0.65 pg/mg creatinine. (B) TIMP-2 was able to diagnose acute allograft dysfunction with a sensitivity of 69.7%, specificity of 100%, and AUC 0.91 at cutoff level 519.3 ng/mg creatinine. (C) The [TIMP-2]×[IGFBP7] at its cutoff level 0.278 (ng/mL)2/1,000 had a sensitivity of 100%, specificity of 93.3%, and AUC 0.99 in diagnosing acute graft dysfunction. (D) ROC curves analysis of IGFBP7, TIMP-2, and the [TIMP-2]×[IGFBP7] as markers of acute rejection. IGFBP7 was able to diagnose acute rejection with a sensitivity of 77.8%, specificity of 86.7%, and AUC 0.881 at a cutoff level of 1.3 pg/mg creatinine. (E) TIMP-2 was able to diagnose acute rejection with a sensitivity of 94.4%, specificity of 56.7%, and AUC 0.800 at a cutoff level of 439.1 ng/mg creatinine. (F) The [TIMP-2]×[IGFBP7] at its cutoff level 0.803 (ng/mL)2/1,000 had a sensitivity of 94.4%, specificity of 83.3%, and AUC 0.939 in diagnosing acute rejection. Red stars correspond to optimum criterion cut-off points.

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