Urea as a passive transport marker for arthritis biomarker studies

Objective. To develop a method to correct for the unknown dilution of synovial fluid that occurs during lavage of a joint, we evaluated the utility of urea, a molecule that is neither synthesized nor metabolized by joint tissues, as a means of correcting for the dilutional effects of lavage procedures and effusions. Methods. Joint fluids were obtained from normal canine joints by direct aspiration (n = 41) and lavage (n = 10). Acute joint injury was induced in 4 joints by intraarticular injection of chymopapain. Serum and joint fluid levels of urea and joint fluid concentrations of glucose, lactate, cartilage oligomeric matrix protein (COMP), and keratan sulfate (KS) were measured in these 55 joints. Results. Urea concentrations in joint fluid were directly proportional to those in serum throughout a wide range of concentrations in normal joints. From this relationship, the dilution factor introduced by joint lavage was determined. This method was applied to quantify biomarker concentrations in synovial lavage fluid and was found to successfully correct for lavage-induced dilution of glucose, lactate, COMP, and KS to levels equivalent to those in samples aspirated directly. In the context of chymopapain-induced joint effusion, urea concentrations continued to be proportional to serum concentrations, but were much lower, enabling an estimation of the change in the volume of distribution (V-d) of a marker due to a change in joint water content in the setting of inflammation characterized by effusion. Lactate and KS levels rose markedly in response to chymopapain. After adjustment for the V-d, the glucose concentration in the chymopapain-injected joints did not change. Conclusion. Urea provides a robust method of quantifying and correcting for the dilution of synovial fluid due to joint lavage or inflammation. This method is potentially applicable to surrogate marker studies in human arthritis.