Abstract Citrate, a tricarboxylic acid cycle intermediate, plays a central role in renal physiology by acting as both a urinary base equivalent and a potent inhibitor of calcium stone formation. Hypocitraturia, a common metabolic abnormality in calcium nephrolithiasis, is not a binary disorder but a continuum shaped by acid-base status, diet, potassium balance, proximal tubular handling, and systemic citrate status. We provide an update on the biology of citrate, renal regulation of its excretion, clinical pathophysiology and treatment of hypocitraturia. Identical urinary citrate levels may have different implications depending on systemic acid-base status and urinary calcium excretion. Hypocitraturia prevalence is increasing, paralleling rises in metabolic syndrome, obesity, and dietary habit changes. Experimental models confirm that systemic or intracellular acidosis, potassium deficiency, and upregulation of renal transport and metabolism of citrate reduce urinary citrate, enhancing stone risk. Potassium citrate remains the cornerstone of therapy, increasing both urinary citrate and pH. However, its use requires caution in calcium phosphate stone formers and patients with chronic kidney disease. Citrate resistance, defined as inadequate urinary citrate response despite good potassium delivery, is a therapeutic challenge. Novel interventions including sodium-dicarboxylate cotransporter-1 (NaDC-1) inhibitors and citrate analogues like hydroxycitrate may offer future alternatives. In conclusion, urinary citrate must be interpreted within physiological and clinical contexts. Recognizing hypocitraturia as a modifiable, non-binary risk factor allows for more precise risk stratification and individualized therapy in stone prevention, particularly when lithogenicity overlaps with acid-base and renal abnormalities.
Zomorodian et al. (2025) studied this question.