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Profibrotic circulating proteins and risk of early progressive renal decline in Type 2 Diabetes patients with and without albuminuria

OBJECTIVE: The role of
fibrosis in early progressive renal decline in type 2 diabetes is unknown. Circulating
WFDC2 (WAP four-disulfide core domain protein 2) and MMP-7 (Matrilysin) are
postulated to be biomarkers of renal fibrosis. This study examined an
association of circulating levels of these proteins with early progressive
renal decline.

RESEARCH DESIGN AND METHODS: Individuals with
type 2 diabetes enrolled in the Joslin Kidney Study with eGFR ≥60 ml/min/1.73m2
were followed for 6-12 years to ascertain fast early progressive renal decline
defined as eGFR loss ≥5 ml/min/1.73m2/year. 

RESULTS: A total of 1,181 individuals were
studied: 681 without and 500 with albuminuria. Median eGFR and ACR at baseline
were 97 ml/min/1.73m2 and 24 mg/g, respectively. During follow-up,
152 individuals experienced fast early progressive renal decline: 6.9% in those
with normoalbuminuria and 21% with albuminuria. In both subgroups risk of renal
decline increased with increasing baseline levels of WFDC2 (p <0.0001) and MMP-7
(p <0.0001). After adjustment for relevant clinical characteristics and known
biomarkers, an increase by one quartile in the Fibrosis Index (combination of
levels of WFDC2 and MMP-7) was associated with higher risk of renal decline (OR
1.63; 95% CI 1.30-2.04). The association was similar and statistically
significant among patients with and without albuminuria. 

CONCLUSIONS: Elevation of
circulating profibrotic proteins is associated with the development of early
progressive renal decline in type 2 diabetes. This association is independent
from albuminuria status and points to the importance of the fibrotic process in
development of early renal decline.