SLC9A4 encodes NHE4, a basolateral electroneutral antiporter that exchanges sodium for protons or ammonium ions, regulating intracellular pH and cell volume in epithelial tissues 1. In renal medullary thick ascending limb cells, SLC9A4 mediates basolateral ammonium extrusion and is critical for establishing the corticopapillary ammonia gradient required for renal acid excretion 1. Disruption of murine NHE4 causes metabolic acidosis with impaired ammonia absorption, though additional transporters contribute to this process 1. Beyond renal function, SLC9A4 functions as a sodium sensor in osmotic regulation and regulates gastric acid secretion in parietal cells. Genetically, SLC9A4 variants associate with multiple inflammatory and metabolic conditions. Rare exonic variants linked to eczema susceptibility are found in conserved functional domains 2. SLC9A4 shows pleiotropy with antihypertensive-induced new-onset diabetes, Crohn's disease, and inflammatory bowel disease 3. Variants associate with obstructive sleep apnea independent of BMI effects 4, and differential associations with non-obese versus obese asthma in African Americans 5. SLC9A4 expression is significantly reduced in type 2 diabetic neutrophils 6, suggesting involvement in diabetic inflammatory complications. These findings identify SLC9A4 as a pleiotropic locus relevant to multiple disease pathways.