LAUSR

Since the first association between HLA and diseases of native kidneys was described almost 50 years ago, technological and conceptual advances in HLA biology and typing, together with better case ascertainment, have led to an improved understanding of HLA associations with a variety of renal diseases. A substantial body of evidence now supports the existence of HLA genetic associations in the field of renal disease beyond the role of HLA in allogeneic responses in transplant recipients. Allomorphs of HLA have emerged as important risk factors in most immune-mediated renal diseases, which, together with other genetic and environmental factors, lead to loss of tolerance and autoimmune-mediated renal inflammation. HLA associations have also been described for renal diseases that are less traditionally seen as autoimmune or immune-mediated. Here, we review essential concepts in HLA biology and the association of HLA with diseases of the native kidneys, and describe the current understanding of the epistatic and mechanistic bases of HLA-associated kidney disease. Greater understanding of the relationship between HLA and kidney function has the potential not only to further the understanding of immune renal disease at a fundamental level but also to lead to the development and application of more effective, specific and less toxic therapies for kidney diseases.This Review explores the mechanistic links underlying the associations between HLA and kidney diseases. The authors discuss how these links might provide insights into disease pathogenesis and describe the clinical implications of these insights.Key pointsThe HLA, which is the most polymorphic region of the human genome, is associated with various kidney diseases; some of these diseases are immune-mediated whereas in others the pathogenesis is uncertain or the relevance of HLA is less clear.Advances in molecular techniques and the use of model systems have helped define the mechanistic basis of HLA associations and in some instances have epistatically linked HLA to other genes.The characteristics of some renal diseases potentially enable them to serve as archetypes for the study of HLA associations in other conditions.Exactly how HLA facilitates the development of immune kidney diseases at the level of HLA–peptide–T cell receptor interactions is a fundamental research question; mechanistic insights will have clear translational implications for the development of more targeted therapies.