Immune mediated mechanisms of tubulointerstitial injury in childhood nephrotic syndrome

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Ann & Robert H Lurie Children's Hospital of Chicago $164,580 on September 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847, Project Grant K08DK147611) to investigate immune-mediated mechanisms of tubulointerstitial injury in childhood nephrotic syndrome.

The award funds basic research characterizing how dendritic cells and related inflammatory pathways contribute to tubulointerstitial injury and fibrosis progression in steroid-resistant nephrotic syndrome (SRNS), a leading cause of pediatric end-stage kidney disease. The research employs a mouse model of congenital nephrotic syndrome to isolate secondary effects of proteinuria and primary glomerular dysfunction, with focus on identifying targetable injury pathways that could enable development of treatments to slow renal fibrosis progression in affected children.

Performance occurs in Chicago, Illinois through May 31, 2031. The program supports extramural basic and clinical biomedical research improving understanding of disease mechanisms and leading to improved prevention, diagnosis, and treatment of diabetes, digestive, and kidney diseases across NIDDK's programmatic areas.

Abstract

Primary steroid resistant nephrotic syndrome (srns) is one of the leading causes of pediatric end stage kidney disease (eskd). 50% of children with srns progress to eskd, and this rate increases to 60% in children with multi-drug-resistant nephrotic syndrome (NS). While srns is caused by damage to podocytes, cells that help form the filtration barrier in the renal glomerulus, injury from persistent glomerular dysfunction and massive urinary protein loss is ultimately communicated to the renal tubulointerstitium. Progression of this tubulointerstitial injury to tubulointerstitial fibrosis eventually heralds the onset of eskd. Therefore, defining the mechanisms responsible for tubulointerstitial injury in NS will enable the development of treatments to ameliorate the progression of renal fibrosis in these patients. My long-term goal is to promote the advent of such treatments by characterizing targetable injury pathways in NS. Maladaptive inflammation is one of the broader mechanisms that contributes to tubulointerstitial injury in NS, but the exact pathways and cell types that constitute this inflammatory response are not fully understood. Recently, dendritic cells (DCS) have been shown to mediate tubulointerstitial injury in proteinuric kidney diseases, but the animal models used to investigate DCS in this context employ widespread forms of renal injury that indiscriminately injure both the glomerulus and the tubulointerstitium, making IT difficult to isolate the secondary effects of proteinuria and primary glomerular dysfunction. Therefore, i used a mouse model of congenital nephrotic syndrome (CNS) to replicate primary childhood srns and showed a significant expansion of activated, mature conventional type 1 dendritic cells (CDC1S) in the renal tubulointerstitium of these mice. Given that mature CDC1S are known to activate TH1-cells and CD8+ t-cells (ctls) and that CNS kidneys also demonstrate an increase in activation of both t-cell subsets, i hypothesize that the expanded population of active, mature CDC1S in NS kidneys orchestrates a t-cell-mediated inflammatory response that damages the tubulointerstitium. I will address this hypothesis by the following 3 aims. In specific aims 1 and 2, i will determine the contribution of CDC1S, CD4+ t-cells, and ctls to tubulointerstitial inflammation and injury in CNS kidneys. In specific aim 3, i will use spatial transcriptomics (ST) of pediatric srns kidneys to validate the relevance of the immune findings from our murine model of CNS to human srns - this is a critical step that will justify further investigation of these mechanisms in animal models. Completion of these aims will advance our understanding of the roles CDC1S and t-cells play in primary NS, create a ST dataset of pediatric srns kidneys that will be made publicly available for the global research community, and will generate new mouse models to study the role of CDC1S and t-cells in primary NS. Execution of the proposed scientific and career development activities under the guidance of my distinguished mentorship team will also equip me with the technical and practical skills required for my transition to an independent research career as a pediatric nephrologist and scientist.