The identification of reliable metrics to assess renal fibrosis, the final common pathway for progressive renal disease, is of paramount importance. Currently the gold standard method for determining renal fibrosis is obtaining tissue by biopsy. Unfortunately, renal biopsy is by definition invasive, associated with complications such as pain, bruising, infection and even death. As a result of the risk profile, cost and complexity, renal biopsy is not a practical tool for routine use in research or clinical care. Therefore, there is great interest in the development of non-invasive surrogates, such as biomarkers, to query fibrosis at the tissue level. Elevated levels of plasma fibrosis biomarkers rarely provide organ specific information but rather report on global burden of systemic disease. However, urine biomarkers report much more directly on renal specific pathology as urine is in direct contact with the renal parenchyma. We recently presented data on the utility of urine galectin-3 to predict risk of adverse events in high risk heart failure patients with renal dysfunction. Notably, urine galectin-3 was independently associated with an increased risk of death, but more importantly, urine galectin-3 levels were able to risk stratify patients with renal dysfunction into high vs. low risk groups. The overarching goal of the current proposal is to leverage biospecimens available from The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study to further evaluate urine galectin-3 as a new cardio-renal biomarker. Additionally, data from several mechanistic animal studies have demonstrated that aldosterone antagonism can substantially attenuate renal interstitial fibrosis leading to reduced collagen deposition. As a result of the urine biospecimen availability and the randomized anti-fibrotic intervention, the TOPCAT trial dataset and biorepository represents an ideal resource for an Exploratory/Developmental Research Grant to explore urine galectin-3 as a biomarker of cardio- renal dysfunction.
Our aims are to 1) Determine if urine galectin-3 levels can provide independent information regarding the risk of adverse clinical outcomes and differentiate high vs. low risk forms of renal dysfunction in patients with heart failure. 2) To determine if urine galectin-3 levels correlate with a validated marker of renal tissue fibrosis, urinary amino-terminal propeptide of type III procollagen. 3) To assess whether treatment with spironolactone is associated with reductions (or attenuation in rise) of urine galectin-3 levels compared with placebo.
The role of galectin-3 in fibrosis (the placement of excessive connective tissue) of major organs is well established. However, the current data available from studies performed in patient populations ranging from those without heart failure to those with a heart transplant, suggests that elevations in blood levels of galectin-3 may not specifically reflect fibrosis of the heart or kidney. The purpose of this research is to determine if urine galectin-3 can better help us understand the severity and risk of kidney problems in patients with heart failure.
