Sjögren's Disease-Associated Renal Tubular Acidosis: An Integrated Immuno-Tubular Model of Tubular Dysfunction

Sjögren's disease (SjD) is traditionally viewed as an autoimmune exocrinopathy; however, renal involvement-particularly renal tubular acidosis (RTA)-is an underrecognized extraglandular manifestation that often precedes classical sicca symptoms and contributes to diagnostic delay. Distal RTA (dRTA) represents the dominant phenotype and arises from immune-mediated injury to α-intercalated cells, leading to disruption of key acidification components, including vacuolar H⁺-ATPase (V-ATPase), carbonic anhydrase II (CAII), and anion exchanger 1 (AE1). Beyond impaired distal proton secretion, systemic acidosis is proposed to induce adaptive responses in the proximal tubule, based largely on general renal physiology rather than SjD-specific data. Intracellular acidification may enhance sodium-dependent dicarboxylate cotransporter 1 (NaDC-1)-mediated citrate reabsorption and mitochondrial citrate metabolism. These processes may reduce urinary citrate excretion (hypocitraturia) and promote a lithogenic milieu characterized by calcium phosphate supersaturation. This integrated distal-proximal axis provides a plausible mechanistic link between tubular dysfunction and clinical manifestations such as nephrolithiasis, nephrocalcinosis, and hypokalemic paralysis. Incomplete dRTA further expands the disease spectrum and is frequently overlooked despite its clinical relevance. Current management is centered on alkali and potassium replacement, which correct metabolic abnormalities but do not address underlying immune-mediated injury. Treatment response is stage-dependent and often limited once fibrosis is established. This review proposes an integrated immuno-tubular framework that links clinical phenotype, pathogenesis, and therapeutic strategy, and highlights the need for early detection, biomarker-driven risk stratification-particularly using hypocitraturia-and incorporation of renal-specific endpoints to enable mechanism-based and precision-guided care.