Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune–derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic relevance of varying suPAR levels in SI-AKI was explored in a polymicrobial sepsis model in WT, (s)uPAR-knockout, and transgenic suPAR-overexpressing mice. At all time points studied, suPAR provided a robust classification of SI-AKI disease severity, with improved prediction of renal replacement therapy (RRT) and mortality compared with established kidney biomarkers. Patients with suPAR levels of greater than 12.7 ng/mL were at highest risk for RRT or death, with an adjusted odds ratio of 7.48 (95% CI, 3.00–18.63). suPAR deficiency protected mice against SI-AKI. suPAR-overexpressing mice exhibited greater kidney damage and poorer survival through inflamed kidneys, accompanied by local upregulation of potent chemoattractants and pronounced kidney T cell infiltration. Hence, suPAR allows for an innate immune–derived and kidney function–independent staging of SI-AKI and offers improved longitudinal risk stratification. suPAR promotes T cell–based kidney inflammation, while suPAR deficiency improves SI-AKI.

Focal segmental glomerulosclerosis (FSGS) represents the most common primary glomerular disease responsible for the development of end-stage renal disease (ESRD) in the United States (US). The disease progresses from podocyte injury to chronic kidney disease (CKD), ultimately leading to total nephron degeneration. Extensive basic science research has been conducted to unwind the mechanisms of FSGS and, with those insights, understand major contributors of CKD in general. As a result, several putative molecules and pathways have been studied, all implicated in the disease; some serve, in addition, as early biomarkers. The ongoing research is currently focusing on understanding how these molecules and pathways can interplay and be utilized as potential diagnostic and therapeutic targets. Among these molecules, the soluble urokinase plasminogen activating receptor (suPAR) has been studied in detail, both clinically and from a basic science perspective. By now, it has emerged as the earliest and most robust marker of future CKD. Other circulating factors harming podocytes include anti-CD40 auto-antibody and possibly cardiotrophin-like cytokine factor-1. Understanding these factors will aid our efforts to ultimately cure FSGS and possibly treat a larger portion of CKD patients much more effectively.

Prostate cancer (CaP) is the most diagnosed cancer in males and the second leading cause of cancer deaths. Patients with localized tumors are generally curable. However, no curative treatment exists for patients with advanced and metastatic disease. Therefore, identifying critical proteins involved in the metastatic process would help to develop new therapeutic options for patients with advanced and aggressive CaP. We provide strong evidence that Myeloid differentiation factor-2 (MD2) plays a critical role in metastasis and CaP progression. Analysis of tumor genomic data showed that amplifications of MD2 and increased expression are associated with poor outcomes in patients. Immunohistochemistry analysis of tumor tissues showed a correlation between the expression of MD2 and cancer progression. The Decipher-genomic test validated the potential of MD2 in predicting metastasis. In vitro studies demonstrated that MD2 confers invasiveness by activating MAPK and NF-kB signaling pathways and inducing epithelial–mesenchymal transition. Furthermore, we show that metastatic cells release MD2 (sMD2). We measured serum-sMD2 in patients and found that the level is correlated to disease extent. We determined the significance of MD2 in metastasis in vivo and as a therapeutic target, showing that the molecular and pharmacological targeting of MD2 significantly inhibited metastasis in murine models. We conclude that MD2 predicts metastatic behavior, and serum-MD2 could be studied as a potential non-invasive biomarker for metastasis, whereas MD2 presence on prostate biopsy predicts adverse disease outcome. We suggest MD2-targeted therapies could be developed as potential treatments for aggressive metastatic disease.

The field of nephrology has recently directed a considerable amount of attention towards the stimulator of interferon genes (STING) molecule since it appears to be a potent driver of chronic kidney disease (CKD). STING and its activator, the cyclic GMP-AMP synthase (cGAS), along with intracellular RIG-like receptors (RLRs) and toll-like receptors (TLRs), are potent inducers of type I interferon (IFN-I) expression. These cytokines have been long recognized as part of the mechanism used by the innate immune system to battle viral infections; however, their involvement in sterile inflammation remains unclear. Mounting evidence pointing to the involvement of the IFN-I pathway in sterile kidney inflammation provides potential insights into the complex interplay between the innate immune system and damage to the most sensitive segment of the nephron, the glomerulus. The STING pathway is often cited as one cause of renal disease not attributed to viral infections. Instead, this pathway can recognize and signal in response to host-derived nucleic acids, which are also recognized by RLRs and TLRs. It is still unclear, however, whether the development of renal diseases depends on subsequent IFN-I induction or other processes involved. This review aims to explore the main endogenous inducers of IFN-I in glomerular cells, to discuss what effects autocrine and paracrine signaling have on IFN-I induction, and to identify the pathways that are implicated in the development of glomerular damage.