The systemic nature of CKD

Key Points CKD is an inherently systemic disease Energy balance, innate immunity and neuroendocrine control of organ function are highly integrated biological processes; such integration is disrupted by loss of kidney function, which generates a high risk clinical phenotype The clinical profile of chronic kidney disease (CKD) includes inflammation, malnutrition, altered activity of the autonomic and central nervous systems, and cardiopulmonary, vascular and bone disease The gut and the lung are emerging as critical mediators of the interaction between the kidney and the environment, and are involved in cardiovascular disease and other systemic complications of CKD Alterations in macrovascular and microvascular function induced by sleep apnoea, inflammation and oxidative stress increase the risk of brain disease in CKD The application of omics sciences will enable in-depth studies of the pathophysiology and treatment of CKD Chronic kidney disease (CKD) affects numerous organs and systems, which in turn have effects on kidney function. This Review provides an overview of CKD as a systemic disease and discusses the multidirectional links between the kidney, bone, nervous and immune systems, and metabolism. The accurate definition and staging of chronic kidney disease (CKD) is one of the major achievements of modern nephrology. Intensive research is now being undertaken to unravel the risk factors and pathophysiologic underpinnings of this disease. In particular, the relationships between the kidney and other organs have been comprehensively investigated in experimental and clinical studies in the last two decades. Owing to technological and analytical limitations, these links have been studied with a reductionist approach focusing on two organs at a time, such as the heart and the kidney or the bone and the kidney. Here, we discuss studies that highlight the complex and systemic nature of CKD. Energy balance, innate immunity and neuroendocrine signalling are highly integrated biological phenomena. The diseased kidney disrupts such integration and generates a high-risk phenotype with a clinical profile encompassing inflammation, protein–energy wasting, altered function of the autonomic and central nervous systems and cardiopulmonary, vascular and bone diseases. A systems biology approach to CKD using omics techniques will hopefully enable in-depth study of the pathophysiology of this systemic disease, and has the potential to unravel critical pathways that can