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Elevated Urinary Matrix Metalloproteinase-7 Detects Underlying Renal Allograft Inflammation and Injury
Julie Ho1, David N Rush, Oleg Krokhin
11 Section of Nephrology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.2 Manitoba Centre for Proteomics and Systems Biology, University of Manitoba and Health Sciences Centre, Winnipeg, Manitoba, Canada.3 Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.4 Institute for Technical Biochemistry, University of Stuttgart, Stuttgart, Germany.5 University of Manitoba, Winnipeg, Manitoba, Canada.6 Cardiac Sciences Program, Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada.7 Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.
Insights
Matrix metalloproteinase-7 (MMP7) in urine improves noninvasive detection of kidney transplant inflammation when combined with CXCL10. This biomarker combination enhances diagnosis of rejection and injury, aiding patient care.
Area of Science:
- Nephrology
- Transplant Immunology
- Biomarker Discovery
Background:
- Urinary CXC chemokine ligand (CXCL)10 is a noninvasive marker for renal transplant inflammation but lacks sensitivity and specificity.
- Novel urinary biomarkers are needed to improve the diagnosis of alloimmune inflammation in kidney transplant recipients.
Purpose of the Study:
- To identify novel urinary biomarkers for improved diagnosis of renal allograft inflammation.
- To evaluate the diagnostic performance of urinary matrix metalloproteinase-7 (MMP7) alone and in combination with CXCL10.
Main Methods:
- Urine proteomic analysis (LC-MS/MS) identified MMP7 as a candidate biomarker.
- Prospective study of 148 urines from 133 adult renal transplant patients with matched biopsies.
- Diagnostic performance evaluated using C-statistics, net reclassification improvement, and integrated discrimination improvement.
Main Results:
- Urinary MMP7:creatinine (Cr) levels were lower in normal transplants than in inflamed allografts.
- Both MMP7:Cr and CXCL10:Cr distinguished noninflamed from inflamed biopsies (AUC 0.74 and 0.70).
- Adding MMP7:Cr to CXCL10:Cr significantly improved diagnostic performance for subclinical and clinical inflammation/injury.
Conclusions:
- Urinary MMP7:Cr enhances the diagnostic accuracy of CXCL10:Cr for differentiating normal histology from inflammation/injury in kidney transplants.
- The combination is effective for detecting subclinical and clinical inflammation/injury, but not subclinical inflammation alone.
Background:
The urinary CXC chemokine ligand (CXCL)10 detects renal transplant inflammation noninvasively, but has limited sensitivity and specificity. In this study, we performed urinary proteomic analysis to identify novel biomarkers that may improve the diagnostic performance of urinary CXCL10 for detecting alloimmune inflammation in renal transplant patients.
Methods:
In preliminary studies, adult renal transplant patients with normal histology (n = 5), interstitial fibrosis and tubular atrophy (n = 6), subclinical (n = 6) and clinical rejection (n = 6), underwent in-depth urine protein compositional analysis with LC-MS/MS, and matrix metalloproteinase-7 (MMP7) were identified as a potential candidate for the diagnosis of renal allograft inflammation. Urine MMP7 performance was then studied in a larger, prospective adult renal transplant population (n = 148 urines from n = 133 patients) with matched surveillance/indication biopsies. The diagnostic performance of urinary MMP7 and CXCL10 in combination was next evaluated using concordance (C-) statistics, net reclassification improvement and integrated discrimination improvement indices, to determine whether it was better than CXCL10 alone.
Results:
Urinary MMP7:creatinine (Cr) was lower in normal transplants compared to those with inflammation: glomerulonephritis (P = 0.009), viral nephropathies (P = 0.002), interstitial fibrosis and tubular atrophy and inflammation (P = 0.04), borderline (P = 0.08), subclinical (P = 0.01) and clinical rejection (P = 0.0006), and acute tubular necrosis (P < 0.0001). Urinary MMP7:Cr and CXCL10:Cr significantly distinguished noninflamed from inflamed biopsies (area under the curve, 0.74 and 0.70, respectively). The addition of urinary MMP7:Cr to CXCL10:Cr improved the diagnostic performance for subclinical and clinical inflammation/injury by integrated discrimination improvement (P = 0.002) and net reclassification improvement (P = 0.006) analyses.
Conclusions:
Urinary MMP7:Cr improves the overall diagnostic performance of urinary CXCL10:Cr for distinguishing normal histology from subclinical and clinical inflammation/injury, but not subclinical inflammation alone.
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