What is the Role of Soluble Urokinase-Type Plasminogen Activator in Renal Disease?

CONTEXT: Soluble urokinase-type plasminogen activator -(suPAR) is an inflammatory signal with pleiotropic biological effects depending on context and post-translational modifications. Recently, [Hayek, et al: Nat Med 2017; 23: 945-953] it has been found that there is a link between suPAR and renal disease in several guises, and a key question is whether it is a driver or a marker of renal disease, and if so of which types of kidney damage. Subject of Review: Circulating suPAR has been postulated to cause acute proteinuric kidney disease, specifically focal segmental glomerulosclerosis (FSGS), though both the animal models and clinical data in the original reports have been challenged. More recently, suPAR levels are linked to the risk of progression of chronic kidney disease (CKD) by directly activating signaling pathways in the podocyte or as a sensitive early biomarker. Second Opinion: The evidence for suPAR as a driver of FSGS proteinuria is not yet established, and more needs to be done, particularly by measuring different circulating suPAR fragments and identifying "second hits," to clarify if any role exists. The evidence for suPAR as a sensitive biomarker for CKD progression is currently stronger, and needs further independent validation as well as prospective serial suPAR measurements in CKD cohorts. Whether it is a surrogate marker for ongoing inflammatory drivers of kidney disease, or has direct mechanistic effects in podocytes will depend on further studies, as well as trials of suPAR removal or direct blockade of downstream pathways.