Salivary proline-rich proteins are non-canonical serum biomarkers of chronic kidney disease

Salivary proline-rich proteins (sPRPs) are major proteins in saliva. However, their physiological function and dysregulation in disease, particularly beyond the local oral environment, remain largely unknown. We investigated the potential functions of sPRPs and their potential as biomarkers in chronic kidney disease (CKD) using mouse and human models. In mice, we used a unilateral nephrectomy model combined with a high-phosphate diet and FGF23-deficient mice. Single-cell RNA sequencing was used to identify sPRP-expressing cell-types in mouse and human salivary glands. The potential of sPRPs as CKD biomarkers was evaluated using saliva and serum from 1,023 human subjects. Association of serum sPRPs, eGFR, and ePTFp with the serum proteome were examined using Olink and SomaScan proteomic platforms. We found that sPRP expression is upregulated by a high-phosphate diet in a mouse CKD model and is positively regulated by FGF23. Human studies revealed that sPRPs are present not only in saliva but also in serum. Furthermore, serum, but not salivary, sPRP levels correlated with canonical CKD biomarkers, eGFR and ePTFp. Importantly, analysis of the human serum proteome revealed common and distinct CKD-related molecular signatures captured by eGFR and ePTFp, with serum sPRPs representing predominantly common features. Comparison of these serum sPRP-associated proteomic signatures with a comprehensive panel of serum biomarkers across 59 non-CKD human diseases found that 65.64% (1,106 of 1,685) of these signatures showed no association with any of the 59 non-CKD diseases. Together, these results uncover potentially CKD-specific systemic mechanisms reflected by serum sPRPs and their associated serum proteomic landscape. Our results show that serum sPRP levels reflect systemic mechanisms commonly captured by eGFR and ePTFp and exhibit specificity for CKD. Together, our findings demonstrate the complementary utility of eGFR, ePTFp, and serum sPRPs as biomarkers for mechanistic studies of CKD and may contribute to improved diagnosis and treatment.