Nature Reviews Nephrology

Complex multicellular life in mammals relies on functional cooperation of different organs for the survival of the whole organism. The kidneys play a critical part in this process through the maintenance of fluid volume and composition homeostasis, which enables other organs to fulfil their tasks. The renal endothelium exhibits phenotypic and molecular traits that distinguish it from endothelia of other organs. Moreover, the adult kidney vasculature comprises diverse populations of mostly quiescent, but not metabolically inactive, endothelial cells (ECs) that reside within the kidney glomeruli, cortex and medulla. Each of these populations supports specific functions, for example, in the filtration of blood plasma, the reabsorption and secretion of water and solutes, and the concentration of urine. Transcriptional profiling of these diverse EC populations suggests they have adapted to local microenvironmental conditions (hypoxia, shear stress, hyperosmolarity), enabling them to support kidney functions. Exposure of ECs to microenvironment-derived angiogenic factors affects their metabolism, and sustains kidney development and homeostasis, whereas EC-derived angiocrine factors preserve distinct microenvironment niches. In the context of kidney disease, renal ECs show alteration in their metabolism and phenotype in response to pathological changes in the local microenvironment, further promoting kidney dysfunction. Understanding the diversity and specialization of kidney ECs could provide new avenues for the treatment of kidney diseases and kidney regeneration.

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Targeting immune cell metabolism in kidney diseases

Paulo José Basso,Vinicius Andrade-Oliveira,Niels Olsen Saraiva Câmara

doi : 10.1038/s41581-021-00413-7

Nature Reviews Nephrology volume 17, pages465–480 (2021)

Insights into the relationship between immunometabolism and inflammation have enabled the targeting of several immunity-mediated inflammatory processes that underlie infectious diseases and cancer or drive transplant rejection, but this field remains largely unexplored in kidney diseases. The kidneys comprise heterogeneous cell populations, contain distinct microenvironments such as areas of hypoxia and hypersalinity, and are responsible for a functional triad of filtration, reabsorption and secretion. These distinctive features create myriad potential metabolic therapeutic targets in the kidney. Immune cells have crucial roles in the maintenance of kidney homeostasis and in the response to kidney injury, and their function is intricately connected to their metabolic properties. Changes in nutrient availability and biomolecules, such as cytokines, growth factors and hormones, initiate cellular signalling events that involve energy-sensing molecules and other metabolism-related proteins to coordinate immune cell differentiation, activation and function. Disruption of homeostasis promptly triggers the metabolic reorganization of kidney immune and non-immune cells, which can promote inflammation and tissue damage. The metabolic differences between kidney and immune cells offer an opportunity to specifically target immunometabolism in the kidney.

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The evolving complexity of the collecting duct renin–angiotensin system in hypertension

Minolfa C. Prieto,Alexis A. GonzalezL, Gabriel Navar

doi : 10.1038/s41581-021-00414-6

Nature Reviews Nephrology volume 17, pages481–492 (2021)

The intrarenal renin–angiotensin system is critical for the regulation of tubule sodium reabsorption, renal haemodynamics and blood pressure. The excretion of renin in urine can result from its increased filtration, the inhibition of renin reabsorption by megalin in the proximal tubule, or its secretion by the principal cells of the collecting duct. Modest increases in circulating or intrarenal angiotensin II (ANGII) stimulate the synthesis and secretion of angiotensinogen in the proximal tubule, which provides sufficient substrate for collecting duct-derived renin to form angiotensin I (ANGI). In models of ANGII-dependent hypertension, ANGII suppresses plasma renin, suggesting that urinary renin is not likely to be the result of increased filtered load. In the collecting duct, ANGII stimulates the synthesis and secretion of prorenin and renin through the activation of ANGII type 1 receptor (AT1R) expressed primarily by principal cells. The stimulation of collecting duct-derived renin is enhanced by paracrine factors including vasopressin, prostaglandin E2 and bradykinin. Furthermore, binding of prorenin and renin to the prorenin receptor in the collecting duct evokes a number of responses, including the non-proteolytic enzymatic activation of prorenin to produce ANGI from proximal tubule-derived angiotensinogen, which is then converted into ANGII by luminal angiotensin-converting enzyme; stimulation of the epithelial sodium channel (ENaC) in principal cells; and activation of intracellular pathways linked to the upregulation of cyclooxygenase 2 and profibrotic genes. These findings suggest that dysregulation of the renin–angiotensin system in the collecting duct contributes to the development of hypertension by enhancing sodium reabsorption and the progression of kidney injury.

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Conceptual advances and evolving terminology in acute kidney disease

John A. Kellum,Claudio Ronco,Rinaldo Bellomo

doi : 10.1038/s41581-021-00410-w

Nature Reviews Nephrology volume 17, pages493–502 (2021)

Over the past decade, new insights into epidemiology, pathophysiology and biomarkers have modified our understanding of acute kidney dysfunction and damage, and their association with subsequent chronic kidney disease. The concept of acute kidney injury (AKI), which has relied on established but nonetheless flawed biomarkers of solute clearance (serum creatinine levels and urinary output), has been challenged by the identification of novel biomarkers of tubular stress and/or damage. The expression of some of these novel biomarkers precedes changes in conventional biomarkers or can increase their predictive power, and might therefore enhance the clinical accuracy of the definition of AKI. In addition, the need to consider AKI recurrence, duration and progression to chronic kidney disease within the clinical and epidemiological framework of AKI led to the emergence of the concept of acute kidney disease. New definitions of acute syndromes of kidney impairment and injury are needed.

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Author Correction: Conceptual advances and evolving terminology in acute kidney disease

John A. Kellum,Claudio Ronco,Rinaldo Bellomo

doi : 10.1038/s41581-021-00426-2

Nature Reviews Nephrology volume 17, page503 (2021)

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