Testican-2 Is Associated with Reduced Risk of Incident ESKD

Abstract

Significance Statement 

Standard blood markers of kidney function undergo renal clearance and are thus inversely correlated with estimated glomerular filtration rate (eGFR). Recent work has shown that blood levels of the podocyte-derived protein testican-2 are positively correlated with eGFR among individuals with relatively normal kidney function. The current study considers blood testican-2 levels among three cohorts of >8,000 individuals in total, including many with established kidney disease. Testican-2 levels are positively correlated with eGFR across the full range of kidney health, with higher levels associated with lower risk of incident end stage kidney disease (ESKD), even after adjusting for baseline eGFR, proteinuria, and other kidney disease risk factors. This study highlights a positive association between testican-2 and kidney health and prognosis.

Background 

Testican-2 was recently identified as a podocyte-derived protein that is released into circulation by the kidneys and is positively correlated with eGFR and eGFR slope. However, whether higher testican-2 levels are associated with lower risk of ESKD is unknown.

Methods 

Aptamer-based proteomics assessed blood testican-2 levels among participants in the African American Study of Kidney Disease and Hypertension (AASK, n=703), the Chronic Renal Insufficiency Cohort (CRIC) study (n=3196), and the Atherosclerosis Risk in Communities (ARIC) study (n=4378). We compared baseline characteristics by testican-2 tertile and used Cox proportional hazards models to study the association of testican-2 with incident ESKD.

Results 

Higher testican-2 levels were associated with higher measured GFR (mGFR) in AASK, higher eGFR in the CRIC and ARIC studies, and lower albuminuria in all cohorts. Baseline testican-2 levels were significantly associated with incident ESKD in Cox proportional hazards models adjusted for age, sex, and race (model 1) and model 1+mGFR or eGFR+comorbidities (model 2). In model 3 (model 2+proteinuria), the associations between testican-2 (per SD increase) and incident ESKD were AASK (hazard ratio [HR]=0.84 [0.72 to 0.98], P=0.023), CRIC (HR=0.95 [0.89 to 1.02], P=0.14), ARIC (HR=0.54 [0.36 to 0.83], P=0.0044), and meta-analysis (HR=0.92 [0.86 to 0.98], P=0.0073).

Conclusions 

Across three cohorts spanning >8000 individuals, testican-2 is associated with kidney health and prognosis, with higher levels associated with reduced risk of ESKD.