Matrix Metalloproteinases and Their Regulators as Urinary Markers for Obstructive Hydronephrosis in Ureteropelvic Junction Obstruction
Patricia S. Cho, M.D., Stephen A. Kostel, M.S., Adelle M. Dagher, B.S., David Zurakowski, Ph.D., John W. Froehlich, Ph.D., Lily D. Cabour, B.S., Marsha A. Moses, Ph.D., Richard S. Lee, M.D..
Boston Children's Hospital, Boston, MA, USA.
Introduction and Objective
Ureteropelvic junction obstruction (UPJO) is a common etiology for antenatal hydronephrosis and renal obstruction that can result in abnormal kidney maturation and loss of function. Early surgical intervention may prevent damage, but determining whether and when surgery is needed is challenging. The decision usually relies on clinical judgment from repeated invasive testing with ionizing radiation. A non-invasive test to determine if and when to intervene would be beneficial. We aimed to determine whether urinary levels of proteins associated with tissue fibrosis or renal damage could be used for patient stratification in UPJO.
Pre-operative bladder urine samples were obtained from patients undergoing pyeloplasty for clinically defined UPJO and healthy controls. MMPs (-2, -7, -9), NGAL, KIM-1, VEGF, and ADAM12 were assayed and quantified by mono-specific ELISAs in an initial cohort of 20 UPJO patients and 20 age-matched controls. From this data, a focused panel of markers was studied in 79 UPJO and 79 age-matched control patients. All marker protein levels were normalized to total protein. Age, gender, hydronephrosis grade on pre-operative ultrasound, differential renal function and t1/2 by MAG3 scan, and etiology of UPJO were examined in univariate and multivariate statistical analyses.
In the initial screening cohort, MMP-2 and MMP-7 were significantly elevated in UPJO patients versus controls. For the remaining cohort, the focused panel consisted of MMP-2, MMP-7, and NGAL, with TIMP-1 and TIMP-2 (regulators of MMPs). Univariate analysis (medians) revealed significant differences in UPJO vs. control in MMP-2 (4.4 vs. 3.0 pg/ug, p = 0.023), MMP-7 (84.4 vs. 36.0 pg/ug, p = 0.001), and TIMP-2 (120.4 vs. 134.0 pg/ug, p = 0.049) but no differences in NGAL or TIMP-1. Multivariable conditional logistic regression confirmed MMP-7 and TIMP-2 as significant independent predictors of UPJO with ROC analysis with the Youden J-index indicating optimal cut-off values of >58 pg/ug for MMP-7 and 58 pg/ug (odds ratio: 3.5, 95% CI: 1.8-6.8, p < 0.001) and TIMP-2 <162 pg/ug (odds ratio: 2.7, 95% CI: 1.3-5.7, p = 0.009).
These results suggest that urinary MMP-7 and TIMP-2 levels could be a useful biomarker for patients with hydronephrosis from UPJO and indicate dysregulated renal tissue remodeling in this condition. Serial MMP-7 and TIMP-2 may potentially serve as a prognostic and diagnostic marker for patients with hydronephrosis undergoing observation. Changes in baseline levels, when followed longitudinally, may identify the need for additional imaging or surgical intervention. Analysis of urine obtained directly from the kidneys of severely obstructed patients and sampling post-repair are in progress to assess the durability of these findings. Additional multivariate analysis including clinical parameters is under way. These markers may serve as an alternative to current diagnostics for improved patient stratification.
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