In both animal models and patients, the development of extra-capillary glomerular crescents represents a pathological hallmark feature of rapidly progressive glomerulonephritis (RPGN). Experimentally, the progression of these lesions has been defined in two phases: first an acute proliferative phase, which is followed by a chronic pro-fibrotic phase. Clinically, patient biopsies can contain features of each individual phase or a mixture of both. Now, the current therapeutic management of RPGN is centered around significant untargeted immunosuppression, aiming to disarm the hyperactive immune response that represents the trigger for the formation of crescents. In some cases, we observe that patients show a significant recovery of renal function and in some cases, the frequency of crescents is reduced in a second biopsy after treatment has started. Together, these pathological and clinical observations may suggest that to a certain degree crescents have the potential to resolve. However, in the literature, little is known about the mechanism involved in crescent progression and regression.
Several different signaling pathways (ie. CD44, CD9 and PDGF-B) have been described by our team and others in association with an activated cellular state of parietal epithelial cells (PECs), which has a causative link to crescent formation. Genetic and/or pharmacological inhibition of these pathways, prevented the development of experimental disease. However, these approaches might be difficult to establish in a clinical setting due to late presentation of patients with already fully evolved, and sometimes fibrotic crescents, which are likely to result in nephron loss. Therefore, deciphering whether crescentic lesions have a potential capacity for healing is paramount to predict and influence glomerular loss during the disease course.
In the second funding period, we have identified a key signaling pathway involved in both prevention and treatment of crescent formation, which will allow us to study the potential for crescent recovery and loss. Our team has also developed new technologies to systematically integrate morphological and molecular changes with high spatial resolution, which is essential to characterize the evolution, and potential for regression of cellular crescents.
In this third funding period, we aim to characterize the potential for cellular crescent resolution and define glomerular subsets that are most likely to recover and those that are unlikely to respond to therapy based on an integrative multiscale mapping of the key signaling pathways involved in crescent resolution and loss in experimental and human RPGN. Overall, this project will shed light on a central aspect in the management of RPGN, which has the potential to directly impact patient stratification (ie. risk status), establish “molecular windows” for current medication, and broaden the spectrum of therapeutic options, paving the way to an individualized medicine in patients affected by RPGN.