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Urinary TIMP-2 Predicts the Presence and Duration of Delayed Graft Function in Donation After Circulatory Death Kidney Transplant Recipients

Bank, Jonna R., MD1; Ruhaak, Renée, PhD2; Soonawala, Darius, MD, PhD1; Mayboroda, Oleg, DM3; Romijn, Fred P.2; van Kooten, Cees1; Cobbaert, Christa M., PhD2; de Fijter, Johan W., MD, PhD1

doi: 10.1097/TP.0000000000002472
Original Clinical Science—General
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Background. Urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP7) have been validated as biomarkers for acute kidney injury. We investigated the performance of both markers in predicting the occurrence and duration of functionally defined delayed graft function (fDGF) in donation after circulatory death (DCD) kidney transplant recipients.

Methods. Urine samples of 74 DCD recipients were analyzed. TIMP-2 and IGFBP7 were measured with ELISA on postoperative days 1 to 7, day 10, week 6, and month 6, and values were corrected for osmolality (mOsm). Immunosuppression consisted of anti-CD25 antibody induction and triple maintenance therapy (steroids, mycophenolate mofetil, and calcineurin inhibitor). Statistical analysis included receiver operating characteristic curves and multivariate logistic regression.

Results. Fifty-one (69%) renal transplant recipients had fDGF, of which 14 experienced prolonged fDGF (≥21 days). TIMP-2/mOsm on day-1 and day-10 adequately identified patients with fDGF (area under the curve [AUC], 0.91) and prolonged fDGF (AUC, 0.80), respectively, whereas IGFBP7/mOsm did not (AUC, 0.63 and 0.60). Multivariate analysis on day 1 identified 24-hour urinary creatinine excretion and TIMP-2/mOsm as significant predictors of fDGF (AUC, 0.90, 95% confidence interval, 0.80-0.98). The best predictors of prolonged fDGF on day 10 were 24-hour urinary creatinine excretion, TIMP-2/mOsm, and total warm ischemia time with an AUC of 0.85 (95% confidence interval, 0.72-0.95). Consecutive TIMP-2/mOsm values showed a decrease in TIMP-2/mOsm before an increase in estimated glomerular filtration rate, enabling us to monitor fDGF and predict resolution of fDGF.

Conclusions. Urinary TIMP-2, but not IGFBP7, is a promising biomarker to predict the occurrence and duration of fDGF in DCD kidney transplant recipients.

1 Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

2 Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

3 Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.

Received 3 February 2018. Revision received 3 August 2016.

Accepted 16 August 2018.

The authors declare no funding or conflicts of interest.

J.R.B. participated in the study design, data collection and interpretation, analysis, and writing of the article. R.H. participated in study design and data collection and interpretation (ELISAs). D.S. participated in study design and writing of the article. O.M. participated in data analysis (clinical data). F.P.R. participated in data interpretation and conducting ELISAs. C.vK participated in study design, data interpretation, and writing of the article. C.M.C. participated in the study design and data interpretation. J.W.dF. participated in study design, data interpretation, and writing of the article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: J.W. de Fijter, MD, PhD, Department of Nephrology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands. (jwdefijter@lumc.nl).

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