Research

Molecular phenotyping AKI

Acute kidney injury (AKI) is the most common form of organ failure in sepsis and sepsis-induced AKI is associated with prolonged hospitalization, acute dialysis, and death. Despite the substantial clinical impact of AKI, no treatment can alter the course of the condition. One reason may be that AKI consists of heterogeneous pathophysiologic processes but is defined as a single clinical entity, thereby diluting the mean impact of therapies and concealing potentially responsive sub-populations. Identifying AKI sub-phenotypes that either have higher risk of disease-related outcomes (prognostic enrichment) or differential response to therapy (predictive enrichment) could enable a ‘precision medicine’ approach in sepsis-induced AKI.

In a Discovery and Replication ICU cohort, we identify two distinct AKI sub-phenotypes (AKI-SP1 and AKI-SP2).
These AKI sub-phenotypes can be differentiated by biomarker concentrations of Angiopoietin-2:1 ratio (Ang-2/1) and soluble Tumor Necrosis Factor Receptor-1 (sTNFR-1).

Our work on AKI sub-phenotypes identified characteristics that suggest severity of illness and outcomes in patients with AKI.These AKI sub-phenotypes respond differently to treatment, such as with the early addition of vasopressin therapy for shock. This work is supported by the NIH and Roche Molecular Diagnostics.
AKI sub-phenotypes respond differently to the early addition of vasopressin therapy for shock.

COVID-19

In the first weeks of the COVID-19 pandemic in the U.S., our team studied the factors that contributed to patients becoming severely ill. We also published on the pathogenesis and outcomes of COVID-19 in critically ill populations. The COVID-19 Host Response and Outcomes (CHROME) study is collecting biological samples of blood, urine, respiratory specimens from COVID-19 patients in order to identify biomarkers that predict disease and to identify novel targets for treatment development. The CHROME cohort aligned with the multi-center Severe Acute Respiratory Infection and Preparedness (SARI-PREP) Cohort and University of Washington is the central biorepository for SARI-PREP. This work is supported by the Centers for Disease Control Foundation, NIH and the Bill and Melinda Gates Foundation.

 

Initial Seattle region experience with COVID-19.

covid biomarkers
Biomarkers of host endothelial, epithelial and inflammatory response in ICU patients with and without COVID-19.

 

Antibiotic associated nephrotoxicity in Cystic Fibrosis

Individuals with cystic fibrosis (CF) often are chronically infected with gram negative organisms in their lungs, and have intermittent flares of these infections, requiring antibiotic treatment. Aminoglycosides and polymyxins are commonly used antibiotics to treat these infections but are limited due to side effects, such as acute kidney injury (AKI) as described by our group and others. Repeated nephrotoxic antibiotic exposures are associated with  an increased prevalence of chronic renal dysfunction in CF(2).  Despite the burden of kidney disease in CF, we still lack effective methods for early identification of antibiotic associated AKI.

Our lab is utilizing a an ex-vivo 3D renal epithelial cell proximal tubule microphysiological system (MPS) developed at the University of Washington and enrolling a prospective cohort of CF patients who receive nephrotoxic antibiotics to discover novel biomarkers associated with kidney injury. This work is supported by the Cystic Fibrosis Foundation and the NIDDK.

kidney on a chip
Kidney-on-a-chip system that can model nephrotoxic injury, developed through a collaboration between UW School of Pharmacy, UW Medicine, Kidney Research Institute, and Nortis.

 

Tubular Secretion in AKI

We are exploring better methods of assessing and treating patients in the ICU with kidney dysfunction. In critical illness, kidney proximal tubular secretion is poorly correlated with serum creatinine. Estimates of tubular secretory clearance could improve assessment of kidney function and dosing of essential ICU medications.

In critical illness, kidney proximal tubular secretion is poorly correlated with serum creatinine. Estimates of tubular secretory clearance could improve assessment of kidney function and dosing of essential ICU medications.

Genetics of AKI

Acute kidney injury (AKI) is common in hospitalized patients, and improved understanding into the pathophysiology of AKI could lead to the development of novel diagnostics and therapeutics. While common genetic risks for chronic kidney disease are well established, genetic factors influencing risk for acute kidney injury (AKI) are poorly understood.

Our lab is leveraging partnerships with the Kidney Precision Medicine Project (KPMP) to determine whether identification of AKI sub-phenotypes supports discovery of novel genetic risk.

NIRVANA clinical trial

Pilot, double-blind, placebo-controlled, multicenter, interventional clinical trial with oral nicotinamide riboside (NR) 500 mg (versus placebo) twice daily for a total of 10 days in hospitalized patients with COVID-19. Biospecimens will be collected in participants. This work is funded by NIDDK.