Association of Urinary Biomarkers of Inflammation, Injury, and Fibrosis with Renal Function Decline: The ACCORD Trial

Abstract

Background and objectives Current measures for predicting renal functional decline in patients with type 2 diabetes with preserved renal function are unsatisfactory, and multiple markers assessing various biologic axes may improve prediction. We examined the association of four biomarker-to-creatinine ratio levels (monocyte chemotactic protein-1, IL-18, kidney injury molecule-1, and YKL-40) with renal outcome.Design, setting, participants, & measurements We used a nested case-control design in the Action to Control Cardiovascular Disease Trial by matching 190 participants with $40% sustained eGFR decline over the 5-year follow-up period to 190 participants with #10% eGFR decline in a 1:1 fashion on key characteristics (age within 5 years, sex, race, baseline albumin-to-creatinine ratio within 20 mg/mg, and baseline eGFR within 10 ml/min per 1.73 m 2 ), with #10% decline. We used a Mesoscale Multiplex Platform and measured biomarkers in baseline and 24-month specimens, and we examined biomarker associations with outcome using conditional logistic regression.Results Baseline and 24-month levels of monocyte chemotactic protein-1-to-creatinine ratio levels were higher for cases versus controls. The highest quartile of baseline monocyte chemotactic protein-1-to-creatinine ratio had fivefold greater odds, and each log increment had 2.27-fold higher odds for outcome (odds ratio, 5.27; 95% confidence interval, 2.19 to 12.71 and odds ratio, 2.27; 95% confidence interval, 1.44 to 3.58, respectively). IL-18-tocreatinine ratio, kidney injury molecule-1-to-creatinine ratio, and YKL-40-to-creatinine ratio were not consistently associated with outcome. C statistic for traditional predictors of eGFR decline was 0.70, which improved significantly to 0.74 with monocyte chemotactic protein-1-to-creatinine ratio.Conclusions Urinary monocyte chemotactic protein-1-to-creatinine ratio concentrations were strongly associated with sustained renal decline in patients with type 2 diabetes with preserved renal function.

Urinary Biomarkers of Tubular Damage Are Associated with Mortality but Not Cardiovascular Risk among Systolic Blood Pressure Intervention Trial Participants with Chronic Kidney Disease

“…This study found that higher donor urinary YKL-40 concentrations were associated with reduced risk of delayed graft function, suggesting that YKL-40 may positively impact the response to acute tubular injury [39]. In the ambulatory setting, a nested case-control study within the Action to Control Cardiovascular Risk in Diabetes trial found no association between urinary YKL-40 and kidney function decline during follow-up [40]. Our study builds upon the relatively sparse literature on urinary YKL-40 by demonstrating novel associations with mortality risk among persons with CKD.…”

Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy

“…5 With regard to the kidney, it has been shown that serum and urinary TFF3 significantly increase in patients with chronic kidney disease (CKD). [6][7][8] However, it is unclear whether the renal TFF3 expression is localized in the tubular epithelial cells, and whether it increases in the association with the tubulointerstitial injury in patients with CKD. No previous study has analyzed the mRNA expression in patients with CKD such as glomerulonephritis.…”

“…The TFF3 expression increases in various organs as the consequence of tissue damage such as inflammation or fibrosis . With regard to the kidney, it has been shown that serum and urinary TFF3 significantly increase in patients with chronic kidney disease (CKD) . However, it is unclear whether the renal TFF3 expression is localized in the tubular epithelial cells, and whether it increases in the association with the tubulointerstitial injury in patients with CKD.…”

Urinary Markers of Fibrosis and Risk of Cardiovascular Events and Death in Kidney Transplant Recipients: The FAVORIT Trial

“…(12) Higher urine concentrations have been associated with greater fibrosis in diabetic nephropathy and with disease progression. (13) PINP and PIIINP are cleaved from type 1 and type 3 collagen fibrils during collagen deposition, which is an important step in fibrogenesis. (14) Urine PIIINP is the N-terminal fragment of type III collagen and is released during newly deposited collagen type III and is correlated with interstitial fibrosis (11) and kidney function decline(15) in patients with CKD of different etiologies (16) and in KTRs.…”