Chronic kidney disease (CKD) is common, affecting 14% of the U.S. population. Cardiovascular disease is the leading cause of morbidity and mortality among CKD patients, with heart failure (HF) having the highest incidence and prevalence. Patients with CKD have a 3-fold increased risk of HF compared to those without CKD and have higher rates of HF complications such as hospitalizations and death. Decline of kidney function is one of the most common HF complications, perhaps from cardiorenal physiology or parallel biological processes affecting both the heart and kidney, and is the most powerful predictor of death in HF. Despite the high burden of HF in CKD, early identification of CKD patients at high-risk for HF and HF complications, specifically loss of kidney function, remains challenging. Novel, promising cardiac biomarkers may provide insight into biological pathways linking CKD with cardiovascular disease as well as improve identification of CKD patients at risk for HF and HF complications. Galectin-3 is a beta-galactoside-binding lectin expressed by activated macrophages that induces cardiac fibroblasts to proliferate and deposit type I collagen, possibly promoting myocardial fibrosis and adverse remodeling. Soluble ST2 (sST2) is a member of the IL-1 receptor family is thought to function as a decoy receptor, which neutralizes IL -33. IL-33 exerts antihypertrophic effects in cardiomyoctyes, reduces myocardial fibrosis and reduces cardiomyoctye hypertrophy. Growth differentiation factor (GDF)-15 is member of the TGF-beta cytokine superfamily whose expression from cardiac myocytes is increased in response to ischemia, mechanical stretch and proinflammatory cytokines. Given the shared physiological pathways between CKD and HF, it is plausible that subclinical cardiovascular disease (as indicated by elevations in cardiac biomarkers), would be associated with clinical HF and decline of kidney function. Galectin-3, sST2 and GDF- 15 have been shown to be associated with HF and incident CKD in the general population. It is unknown whether these biomarkers are also relevant in a prevalent CKD population, due to competing CKD-specific risk factors (e.g. albuminuria) or differing pathophysiology. In the proposed study, we will merge the Seattle Kidney Study with C-PROBE, a NIDDK George O'Brien Kidney Translational Core Center, to form a larger multicenter, racially/ethnically diverse cohort of CKD patients to study associations of galectin-3, sST2 and GDF-15 with incident HF (Aim 1) and progression of kidney disease (Aim 2). This project aims to provide data on whether promising cardiac biomarkers can identify a subset of CKD patients at high-risk for HF and important HF complications, such as progression of kidney disease. The data generated from this study may be used to develop a clinical trial to test whether targeted interventions can modify levels of these biomarkers in the short-term and whether these biomarkers can be used to guide clinical therapies with the ultimate goal of improving clinical outcomes in CKD.
Chronic kidney disease is common and patients with chronic kidney disease are at highest risk for heart failure and progression to end-stage renal disease. This study will examine the use of biomarkers measured in the blood to identify patients with kidney disease at highest risk for heart failure and worsening kidney disease.
| Tuegel, Courtney; Katz, Ronit; Alam, Mariam et al. (2018) GDF-15, Galectin 3, Soluble ST2, and Risk of Mortality and Cardiovascular Events in CKD. Am J Kidney Dis 72:519-528 |
| Nair, Viji; Robinson-Cohen, Cassianne; Smith, Michelle R et al. (2017) Growth Differentiation Factor-15 and Risk of CKD Progression. J Am Soc Nephrol 28:2233-2240 |
