Harmonizing the diagnosis of citrate accumulation - a call for standardized criteria

Abstract Regional citrate anticoagulation (RCA) has emerged as the gold-standard strategy for continuous renal replacement therapy (CRRT), yet its widespread adoption remains hindered by perceived complexity, heterogeneous protocols, unclear contraindications, and inconsistent terminology. A central challenge lies in the recognition and management of citrate accumulation, for which no single, reliable biomarker exists. The total-to-ionized calcium ( t Ca/ i Ca) ratio is widely utilized as a sensitive surrogate, but its specificity is limited by multiple confounding factors, including serum albumin concentration, acid-base status, and exogenous calcium administration. Current evidence supports a paradigm shift from reliance on static thresholds toward a dynamic, physiology-based assessment to define citrate accumulation. The kinetics of the t Ca/ i Ca ratio, when interpreted alongside evolving metabolic parameters, particularly lactate trends, systemic ionized calcium, and acid-base status, provide a more robust framework for identifying citrate accumulation. Crucially, an elevated t Ca/ i Ca ratio should not indiscriminately prompt the discontinuation of RCA. Targeted adjustments to the CRRT prescription can often safely mitigate citrate burden while preserving circuit patency. In the absence of a validated and widely available method for the direct measurement of plasma citrate levels, we propose a stepwise approach incorporating routinely measured screening tools and confirmatory parameters. Studies incorporating direct plasma citrate concentration measurements should be conducted to validate these criteria alongside readily available bedside surrogate markers. Refining this framework is essential to enhance the safe implementation of RCA and ultimately improve outcomes in critically ill patients.