(From the August 2015 Issue of Research Now)
Thrombosis is a deadly and often underappreciated complication of nephrotic syndrome, a group of symptoms that include protein in the urine (proteinuria), low blood protein levels, high cholesterol levels, high triglyceride levels and swelling. While rare, thrombosis incidence is increasing in both pediatric and adult populations. Hypercoagulopathy, or excessive blood clotting, is highly correlated with nephrotic disease severity. However, identifying which patients should be treated with prophylactic anticoagulants that prevent excessive clotting from occurring is a question that nephrologists are still struggling to answer.
A study published in the Journal of the American Society of Nephrologists suggests that proteinuria and/or hypoalbuminemia – which is a medical condition where blood levels of albumin, a major protein in the human body, are abnormally low – could be developed as clinically meaningful surrogate biomarkers of hypercoagulopathy. This would aid physicians in identifying patients with the greatest risk of thrombotic disease and targeting prophylactic treatments to prevent blood clots in those patients.
“Nephrotic syndrome carries a very high risk of thrombosis compared to other kidney diseases,” says William E. Smoyer, MD, an author on the publication who is also a nephrologist and director of the Center for Clinical and Translational Research at The Research Institute at Nationwide Children’s Hospital. “Prompt and accurate identification of those patients most at risk could greatly improve our ability to prevent these life-threatening thrombotic episodes.”
According to the report, nephrotic-range proteinuria is well known to be associated with acquired complex hypercoagulopathy. This state is the result of derangements of proteins in the hemostatic regulatory cascade, which is integral to the process for blood clot formation, leading to an enhanced capacity for generating thrombin, which is an enzyme that promotes blood clotting.
“Our findings strongly suggest that the enhanced thrombin-generating capacity of nephrotic hypercoagulopathy is responsible for the predisposition to forming blood clots,” says Bryce Kerlin, MD, lead author on the study and a hematologist specializing in blood clotting disorders at Nationwide Children’s. “The thrombotic capacity of blood progressively increases proportionately to disease severity.”
Despite knowing that thrombin generating assay is a predictor of thrombosis risk, testing a patient’s thrombin levels in the clinic setting is not so easy. Poor inter-laboratory standardization of thrombin generating assay techniques and low accessibility of the assay are partly to blame. The potential ability to use comparatively easy to measure non-invasive biomarkers to assess thrombosis risk is thus highly appealing.
Kerlin and his team used animal models of nephrotic syndrome to investigate the relationship between levels of proteinuria and albumin and thrombotic tendency (derangement of thrombin levels). Thrombin levels were shown to be highly correlated with both increased proteinuria and hypoalbuminemia in the models.
“We are working on validating these phenomena in humans,” says Dr. Kerlin, who is also director of The Joan Fellowship in Pediatric Hemostasis-Thrombosis and a principal investigator in the Center for Clinical and Translational Research. “Once we understand if these results are true for humans with nephrotic syndrome, we can work toward identifying the actual mechanisms behind these phenomena and ultimately the best therapeutic targets.”
He adds that the effects of proteinuria and hypoalbuminemia on thrombin generation should be further studied in the context of glomerular biology and in prospective clinical cohorts in order to determine their predictive abilities. If confirmed, they could become readily available surrogate biomarkers for identifying patients most at risk for thrombosis.
Kerlin BA, Waller AP, Sharma R, Chanley MA, Nieman MT, Smoyer WE. Disease severity correlates with thrombotic capacity in experimental nephrotic syndrome.Journal of the American Society of Nephrologists. 2015 Apr 8. [Epub ahead of print]