01.14 Plasma Heparan Sulfate is a Biomarker of Acute Kidney Allograft Rejection

Posted on January 25, 2017

L. Lin1, M. McRae1, A. MacDonald1, T. V. Brennan1  1Duke University Medical Center,Surgery,Durham, NC, USA

Introduction:
Non­invasive biomarkers of acute allograft rejection (AR) are needed to allow for early diagnosis. Serum creatinine (Cr) is an imperfect monitor of allograft dysfunction because it rises late in the process of immune injury, can be elevated for non-immunological reasons, and the magnitude of change above baseline in the setting of AR can be subtle. During AR lymphocytic invasion of allograft tissues requires the degradation of extracellular matrix. Activated CD4+ T cells express heparanase that degrade ECM and releases cleaved heparan sulfate (HS). We propose the use of plasma HS measurements to overcome the limitations of the serum Cr assay for the detection of AR.

Methods:
Serum and plasma samples from Duke University from consented kidney transplant recipients were collected and stored with approval of the Duke University IRB committee. HS concentrations in the plasma were determined by enzyme-linked immunosorbent assay. Patient groups were compared by two-tailed Student's t-test.

Results:
Patients with biopsy demonstrated AR had significantly higher plasma HS levels within 2 weeks of biopsy than patients with stable function (20.86+/-18.12 ug/mL, 95% CI=12.38-28.34 vs. 2.71+/-1.90 ug/mL, 95% CI=2.35-3.07; p<0.0001). Similarly, patients with biopsy demonstrated AR had significantly higher plasma HS levels than patients undergoing biopsy for cause, but without AR (20.86+/-18.12 ug/mL, 95% CI=12.38-28.34 vs. 3.23+/-1.61 ug/mL, 95% CI=2.26-4.20; p=0.0015) within 2 weeks of biopsy (Fig. 1A). No elevations of HS levels were found in patients with BK viremia (n=13, viral titer range 374 – 1.26×10^7 copies/mL). In comparison, elevations in serum Cr levels in patients with biopsy demonstrated AR versus patients undergoing biopsy for cause, but without AR were lesser in magnitude (5.35+/-3.18 mg/dL, 95% CI=4.09-6.60 vs. 2.64+/-1.15 mg/dL, 95% CI=1.95-3.33; p=0.0052) (Fig. 1B).

Conclusion:
Plasma HS is a sensitive biomarker of AR of kidney allografts because it is detectable prior to AR and has a greater magnitude of elevation compared with serum Cr.