Kidney Stone Disease: Epigenetic Dysregulation in Homocystinuria and Mitochondrial Sulfur Trans-Sulfuration Ablation Driven by COVID-19 Pathophysiology.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought to light unexpected complications beyond respiratory illness, including effects on kidney function and a potential link to kidney stone disease (KSD). This review proposes a novel framework connecting COVID-19-induced epigenetic reprogramming to disruptions in mitochondrial sulfur metabolism and the pathogenesis of kidney stones. We examine how SARS-CoV-2 interferes with host methylation processes, leading to elevated homocysteine (Hcy) levels and impairment of the trans-sulfuration pathway mechanisms particularly relevant in metabolic disorders such as homocystinuria. These epigenetic and metabolic alterations may promote specific kidney stone subtypes through disrupted sulfur and oxalate handling. Additionally, we explore the role of COVID-19-associated gut dysbiosis in increasing oxalate production and driving calcium oxalate stone formation. Together, these pathways may accelerate the transition from acute kidney injury (AKI) to chronic KSD, linking viral methylation interference, sulfur amino acid imbalance, mitochondrial dysfunction, and microbiota changes. Unlike earlier reviews that address these mechanisms separately, this work offers an integrated hypothesis to explain post-viral renal lithogenesis and highlights the potential of targeting sulfur metabolism and redox pathways as therapeutic strategies for KSD triggered or aggravated by viral infections such as COVID-19.