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The kidney medulla is characterized by extreme electrolyte concentrations. We here address how its main osmolytes, NaCl and urea, regulate tubular cell cytokine expression and monocyte chemotaxis.<\/jats:p><jats:p>In the healthy human kidney, more monocytes were detected in medulla than cortex. The monocyte gradient was attenuated in patients with medullary NaCl depletion by loop diuretic therapy and in the nephrotic syndrome. Renal tubular epithelial cell gene expression responded similarly to NaCl and tonicity control mannitol, but not urea. NaCl significantly upregulated chemotactic cytokines, most markedly <jats:italic>CCL26<\/jats:italic>, <jats:italic>CCL2<\/jats:italic>, and <jats:italic>CSF1<\/jats:italic>. This induction was inhibited by the ROS scavenger <jats:italic>n<\/jats:italic>\u2010acetylcysteine. In contrast, urea, the main medullary osmolyte in catabolism, dampened tubular epithelial <jats:italic>CCL26<\/jats:italic> and <jats:italic>CSF1<\/jats:italic> expression. Renal medullary chemokine and monocyte marker expression decreased in catabolic mice. NaCl\u2010, but not urea\u2010stimulated tubular epithelium or CCL2 and CCL26, promoted human classical monocyte migration. CCL26 improved bactericidal function. In the human kidney medulla, monocyte densities correlated with tubular CCL26 protein abundance.<\/jats:p><jats:p>In summary, medullary\u2010range NaCl, but not urea, promotes tubular cytokine expression and monocyte recruitment. This may contribute to the pyelonephritis vulnerability in catabolism but can possibly be harnessed against pathologic inflammation.<\/jats:p>","DOI":"10.1002\/eji.202149723","type":"journal-article","created":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T05:19:32Z","timestamp":1652073572000},"page":"1258-1272","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Renal medullary osmolytes NaCl and urea differentially modulate human tubular cell cytokine expression and monocyte recruitment"],"prefix":"10.1002","volume":"52","author":[{"given":"Jessica","family":"Schmitz","sequence":"first","affiliation":[{"name":"Nephropathology Unit Institute for Pathology Hannover Medical School Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Brauns","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Division of Nephrology and Hypertension Hannover 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