Is It Time to Abandon the Kidney-Centered View on the Origin of Primary Hypertension?

Traditionally, the kidney has been thought to play a key role in the development of hypertension. Disturbed sodium regulatory pathways can lead to primary hypertension, with abnormalities in the pressure-natriuresis mechanism contributing to its onset. An adverse intrauterine environment and postnatal stressors can affect nephron number, further linking renal development to hypertension risk. The development of hypertension may, however, also be influenced by alternative factors beyond the kidney. Monogenic diseases and polygenic risk scores are associated with hypertension development. Epigenetic mechanisms can influence the phenotype of the vascular endothelium in response to environmental stimuli, potentially leading to changes in blood pressure. Regulation of vascular tone, microvascular rarefaction, and interactions with the immune system are other nonrenal factors contributing to hypertension. The exposome, including air pollution and noise, has its impact already before conception via maternal and paternal influences, as well as later in life. In addition, lifestyle factors such as sodium and alcohol intake and tobacco use have been linked to hypertension through mechanisms such as increased sympathetic activity and vasoconstriction, highlighting the importance of behavioral factors in hypertension development. Age-related stiffening becomes important in later life, influences blood pressure phenotype, and may even precede hypertension development. Considering these multiple contributors, relevant for pathophysiology, prevention, and management of hypertension, the question arises whether the kidney-centered view on hypertension is sufficient or whether a more integrative, multifactorial perspective is needed. Full understanding of renal and nonrenal factors and their interactions driving hypertension is crucial to curb the global burden of this disease.