Interorgan Signaling in Kidney Health and Disease

Organ crosstalk plays a vital role in maintaining physiological homeostasis and adapting to environmental cues. The kidney is increasingly recognized as an integrative organ that participates in bidirectional communication with distant tissues through hemodynamic, endocrine, metabolic, immune, and neural pathways. Dysfunction of the kidney is now viewed as a systemic disease rather than organ injury. Yet, kidney-organ crosstalk is usually described broadly and associatively. This review examines recent mechanistic advances in kidney-organ signaling, with an emphasis on experimentally supported molecular mediators and causal models. We highlight emerging circulating mediators, neuroimmune circuits, microbial pathways, and tissue-specific signaling mechanisms, placing the kidney as both recipient and active sender of mediators in systemic health and diseases. We also highlight the limitations of the current approaches in studying kidney-organ signaling, including reliance on global genetic manipulation, indirect measures of signal transfer, and isolated organ-pair frameworks. In addition, we discuss how advancements in technology may help us recognize new mediators and help identify cellular origins, routes, and consequences of interorgan communication with greater resolution. A better integrated understanding of the interorgan signaling in kidney health and disease is mandatory to identify biomarkers and develop new therapies to treat kidney diseases with fewer adverse effects on other organs.