Do we adequately monitor for severe anion gap metabolic acidosis during sodium thiosulfate therapy for calciphylaxis?

Calciphylaxis is a rare but devastating disorder of vascular calcification predominantly affecting patients with end-stage renal disease (ESRD) and is associated with extremely high morbidity and mortality. In the absence of approved disease specific therapies, sodium thiosulfate (STS) has become one of the most frequently used off-label treatments due to its calcium chelating, antioxidant, and vasodilatory properties. Contemporary reviews and expert consensus documents continue to describe STS as a central adjunctive therapy in calciphylaxis management, despite the lack of randomized controlled trial data1. Despite its widespread clinical use, the safety profile of STS remains incompletely defined. Metabolic acidosis, particularly high anion gap metabolic acidosis (AGMA), has been reported as an adverse effect of STS; however, severe AGMA is insufficiently emphasized and likely under-recognized in routine clinical practice. For clinical clarity, severe AGMA may be defined as arterial pH <7.20, serum bicarbonate <10 mmol/L, or acidosis necessitating treatment interruption, bicarbonate therapy, or renal replacement intervention. Observational cohorts evaluating STS therapy have reported metabolic acidosis in approximately 20–40% of treated patients, with clinically significant acidosis requiring dose modification or discontinuation occurring in nearly 5–10% of cases, highlighting a potentially underappreciated treatment related risk2,3. Recent systematic reviews evaluating therapeutic strategies for calciphylaxis highlight substantial heterogeneity in safety reporting related to STS. Although acid base disturbances are acknowledged, they are rarely quantified or analyzed in detail, limiting accurate risk assessment. A contemporary systematic review underscores that while STS remains widely administered, robust safety data including the incidence of clinically significant AGMA are lacking, emphasizing the need for structured pharmacovigilance4. Importantly, existing calciphylaxis management recommendations endorse STS use but provide limited practical guidance regarding metabolic monitoring strategies or thresholds for therapy modification, representing a critical gap between therapeutic adoption and safety oversight1,3. In patients with ESRD, baseline acid base homeostasis is already fragile, and the additional acid burden generated through STS metabolism to sulfate may precipitate severe metabolic derangements. STS undergoes hepatic and mitochondrial metabolism resulting in the formation of sulfate and other sulfur containing anions, contributing to accumulation of unmeasured acids and elevation of the anion gap. Impaired renal clearance in advanced kidney disease may further potentiate this acid load, predisposing patients to progressive AGMA5. Importantly, recent clinical guidance documents and institutional protocols caution against continued STS administration in the setting of worsening metabolic acidosis and recommend close biochemical monitoring during therapy3. Failure to recognize STS associated AGMA may lead to hemodynamic instability, diagnostic confusion with sepsis or uremic acidosis, and adverse clinical outcomes. In light of these observations, we propose that severe AGMA should be recognized as a clinically important and under-appreciated complication of STS therapy in calciphylaxis. Structured monitoring should be considered, including baseline assessment of serum bicarbonate and anion gap prior to therapy initiation, followed by periodic electrolyte and acid base evaluation during treatment, particularly among dialysis-dependent patients. Therapy reassessment or dose adjustment should be considered in patients demonstrating progressive anion gap elevation or declining serum bicarbonate levels. Routine monitoring of acid–base parameters and heightened clinical awareness are essential. Future prospective studies are urgently required to define the true incidence, risk factors, and clinical consequences of STS-induced metabolic acidosis, thereby optimizing patient safety while preserving potential therapeutic benefit. TITAN Guidelines: This manuscript complies with the 2025 TITAN Guidelines, stating that no artificial intelligence was used6.