Assessment of Urine Proteomics in Type 1 Primary Hyperoxaluria

Abstract

Background: Primary hyperoxaluria type 1 (PH1) and idiopathic hypercalciuria (IHC) are stone-forming diseases that may result in the formation of calcium (Ca) oxalate (Ox) stones, nephrocalcinosis, and progressive chronic kidney disease (CKD). Poorer clinical outcome in PH1 is segregated by the highest urine (Ur)-Ox (UrOx), while IHC outcomes are not predictable by UrCa. We hypothesized that differences would be found in selected Ur-protein (PRO) patterns in PH1 and IHC, compared to healthy intra-familial sibling controls (C) of PH1 patients. We also hypothesized that the PRO patterns associated with higher UrOx levels would reflect injury, inflammation, biomineralization, and abnormal tissue repair processes in PH1. Methods: Twenty four-hour Ur samples were obtained from 3 cohorts: PH1 (n = 47); IHC (n = 35) and C (n = 13) and were analyzed using targeted platform-based multi-analyte profile immunoassays and for UrOx and UrCa by biochemical measurements. Results: Known stone matrix constituents, osteopontin, calbindin, and vitronectin were lowest in PH1 (C > IHC > PH1; p < 0.05). Ur-interleukin-10; chromogranin A; epidermal growth factor (EGF); insulin-like growth factor-1 (IGF-1), and macrophage inflammatory PRO-1α (MIP-1α) were higher in PH1 > C (p = 0.03 to p < 0.05). Fetuin A; IGF-1, MIP-1α, and vascular cell adhesion molecule-1 were highest in PH1 > IHC (p < 0.001 to p = 0.005). Conclusion: PH1 Ur-PROs reflected overt inflammation, chemotaxis, oxidative stress, growth factors (including EGF), and pro-angiogenic and calcification regulation/inhibition compared to the C and IHC cohorts. Many of the up- and downregulated PH1-PROs found in this study are also found in CKD, acute kidney injury, stone formers, and/or stone matrices. Further data analyses may provide evidence for PH1 unique PROs or demonstrate a poorer clinical outcome.

Urine proteomic profiling in patients with nephrolithiasis and cystinuria

“…In a similar fashion, CaOx and CaP crystals have been shown to dissolve within lysosomes following binding and internalization of cultured renal cells [13], but the involvement of CHMP was not described. Indeed, none of the endosomal proteins we found in CYS were part of the urinary proteomes of our patients with nephrolithiasis and hypercalciuria [14], nor were described by others in patients with hyperoxaluria [15], indicating their unique significance in CYS.…”

“…Of those, 18/38 were circulating inflammatory proteins (e.g., complement C3 and C8; fibrinogen alpha, beta, and gamma chain; and serum paraoxonase 1), and 14/38 were derived from neutrophils. Additionally, significant inflammation was found in the urine proteome of patients with nephrolithiasis and hypercalciuria [14], and type 1 primary hyperoxaluria [15]. Altogether, these findings indicate that inflammation plays an important role in the pathogenesis of kidney stone disease irrespective of its metabolic cause.…”

A blood-based multi-omic landscape for the molecular characterization of kidney stone disease

“…Interleukin-10 (IL-10) is an anti-inflammatory cytokine that participates in KSD incidence by tempering the body's inflammatory response. There is a report that the IL-10 level in kidney stone patients was increased, 55 supporting the result that the IL-10 pathway was up-regulated in the case of disease. The MAPK6 (also known as ERK3)–MAPK4 (also known as ERK4) signaling pathway is part of the larger family of mitogen-activated protein kinases (MAPKs), which are involved in various cellular processes such as proliferation, differentiation, and stress responses.…”

Effect of urine alkalization on urinary inflammatory markers in cystinuric patients

“…However, in this study, some patients were treated and eGFR was sometimes lacking [ 21 ], which could have affected the urine proteome profile [ 10 ]. Urinary proteomics in other rare kidney stone diseases [ 22 ] has identified specific proteins, for example, to discriminate medullary sponge kidney disease from idiopathic calcium nephrolithiasis or autosomal dominant polycystic kidney disease [ 23–25 ] or type 1 primary hyperoxaluria from idiopathic hypercalciuria [ 26 ]. Interestingly, although some similar urinary proteins are found in rare kidney stone disease and in idiopathic calcium nephrolithiasis, differences are reported.…”