Applying novel imaging and transcriptomics to mechanisms of cirrhosis- related kidney dysfunction

About This Grant

PROJECT SUMMARY/ABSTRACT Cirrhosis, the late-stage complication of liver disease, stands as a leading cause of death globally and frequently causes kidney dysfunction. Yet, the mechanisms leading to kidney function loss in cirrhosis remain incompletely understood, which in turn limits the development of effective therapeutic options. I have generated data showing subclinical injury to the proximal kidney tubules (PTs) in stable outpatients with cirrhosis irrespective of glomerular filtration rate (GFR), the prevailing clinical assessment of kidney function, suggesting PTs are an early target in cirrhosis that may not be captured by glomerular markers. Contrasting with passive filtration, the tubules depend on kidney cellular energy production for solute secretion and reabsorption. Various pathways have linked cirrhosis to impaired tubular metabolism including mismatched demands for sodium/water reabsorption, exposure to retained bile acids and toxins, and pro-inflammatory gut bacterial products, however further investigation of these early mechanisms is challenged by a lack of measures aligned with the target of injury or studies in patients with cirrhosis already experiencing overt kidney disease. I hypothesize that the collective ischemic and toxic-metabolic environment causes attenuation in kidney cellular metabolism, affecting downstream energy-dependent functions of tubular secretory clearance (TSC) and reabsorption, that is not captured by glomerular markers alone. I propose a prospective nested cohort study of patients with cirrhosis characterized with longitudinal data and biosample collections, multi- modal imaging, and gene expression profiling, to reveal novel pathways of kidney dysfunction and potential therapeutic targets, as well as more holistic assessments of kidney function beyond GFR. I will recruit 140 patients with cirrhosis and preserved eGFR to participate in 3 study visits to determine the association of baseline measures of PT function and injury with kidney-related outcomes (eGFR slope, acute kidney injury [AKI], and ascites severity). I will apply novel methods developed in our lab to estimate TSC by measuring plasma and urine levels of highly secreted endogenous solutes, which I have used in studies of AKI, drug clearance models, and CKD development. In a sub-cohort (N=20) compared to age-matched controls (N=20), I will delineate the effect of cirrhosis on tubular oxidative metabolism using state-of-the-art imaging with 11C- acetate as well as measuring TSC using an exogenous tracer, 99mTc-MAG3. Finally, I will obtain kidney biopsies in a sub-cohort (N=9) of patients with cirrhosis to characterize tubular pathways of injury, metabolism, and fibrosis using a novel spatial transcriptomics platform. As part of this career development award, this work will allow me to develop new expertise in study design, systems biology, and biostatistics, yield a novel cohort and data in patients with cirrhosis to uncover new insights into mechanisms of kidney dysfunction, and provides a basis for future discovery to develop monitoring and treatment strategies as an independent translational researcher of kidney dysfunction in cirrhosis.