Non-invasive ²³Na MRI Identifies Functionally Distinct Cyst Phenotypes in Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cysts from different nephron segments, yet their origin remains inaccessible to in vivo imaging. Building on ex vivo studies that cyst sodium concentration ([Na⁺]) may reflect tubular origin, we developed a non-invasive ²³ Na magnetic resonance imaging (MRI) approach at 7 Tesla to phenotype ADPKD cysts in vivo based on cyst sodium. In nephrectomized ADPKD kidneys, cyst fluid [Na ⁺ ] closely matched ²³ Na MRI signal intensities, revealing two distinct cyst phenotypes: serum-like high-[Na ⁺ ] cysts and low-[Na ⁺ ] cysts. High-[Na ⁺ ] cysts expressed the proximal tubular marker sodium-glucose cotransporter-2, whereas low-[Na ⁺ ] cysts expressed markers of distal tubules and collecting ducts. The vasopressin V2 receptor (V2R), the therapeutic target of tolvaptan, was detected exclusively in low-[Na ⁺ ] cysts, linking sodium phenotype to therapeutic target expression. In vivo, ²³Na MRI enabled classification of 2,299 cysts in 20 ADPKD patients. High-[Na ⁺ ] cysts were 1.8-fold more frequent overall. Anatomical cyst localization did not predict sodium phenotype, underscoring the need for functional imaging rather than structural inference. Patients exhibited marked interindividual variation in cyst composition, with low-[Na ⁺ ] cysts comprising 4.6% to 83.9% of all cysts. Given the exclusive expression of V2R in low-[Na ⁺ ] cysts, this heterogeneity may influence disease progression and therapeutic responsiveness. These findings establish ²³Na MRI as a non-invasive method to phenotype ADPKD cysts in vivo and provide a functional imaging approach with potential relevance for stratifying patients and guiding future therapeutic interventions.