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Specific Populations of Urinary Extracellular Vesicles and Proteins Jayachandran et al. Orphanet J Rare Dis (2020) 15:319 https://doi.org/10.1186/s13023-020-01607-1 RESEARCH Open Access Specifc populations of urinary extracellular vesicles and proteins diferentiate type 1 primary hyperoxaluria patients without and with nephrocalcinosis or kidney stones Muthuvel Jayachandran1,2,3* , Stanislav V. Yuzhakov2,3, Sanjay Kumar1, Nicholas B. Larson4, Felicity T. Enders4, Dawn S. Milliner1, Andrew D. Rule1 and John C. Lieske1,5 Abstract Background: Primary hyperoxaluria type 1 (PH1) is associated with nephrocalcinosis (NC) and calcium oxalate (CaOx) kidney stones (KS). Populations of urinary extracellular vesicles (EVs) can refect kidney pathology. The aim of this study was to determine whether urinary EVs carrying specifc biomarkers and proteins difer among PH1 patients with NC, KS or with neither disease process. Methods: Mayo Clinic Rare Kidney Stone Consortium bio-banked cell-free urine from male and female PH1 patients without (n 10) and with NC (n 6) or KS (n 9) and an eGFR > 40 mL/min/1.73 m2 were studied. Urinary EVs were quantifed =by digital fow cytometer= and results= expressed as EVs/ mg creatinine. Expressions of urinary proteins were measured by customized antibody array and results expressed as relative intensity. Data were analyzed by ANCOVA adjusting for sex, and biomarkers diferences were considered statistically signifcant among groups at a false discov- ery rate threshold of Q < 0.20. Results: Total EVs and EVs from diferent types of glomerular and renal tubular cells (11/13 markers) were signifcantly (Q < 0.20) altered among PH1 patients without NC and KS, patients with NC or patients with KS alone. Three cellular adhesion/infammatory (ICAM-1, MCP-1, and tissue factor) markers carrying EVs were statistically (Q < 0.20) diferent between PH1 patients groups. Three renal injury (β2-microglobulin, laminin α5, and NGAL) marker-positive urinary EVs out of 5 marker assayed were statistically (Q < 0.20) diferent among PH1 patients without and with NC or KS. The number of immune/infammatory cell-derived (8 diferent cell markers positive) EVs were statistically (Q < 0.20) difer- ent between PH1 patients groups. EV generation markers (ANO4 and HIP1) and renal calcium/phosphate regulation or calcifying matrixvesicles markers (klotho, PiT1/2) were also statistically (Q < 0.20) diferent between PH1 patients groups. Only 13 (CD14, CD40, CFVII, CRP, E-cadherin, EGFR, endoglin, fetuin A, MCP-1, neprilysin, OPN, OPGN, and PDGFRβ) out of 40 proteins were signifcantly (Q < 0.20) diferent between PH1 patients without and with NC or KS. *Correspondence: [email protected] 1 Division of Nephrology and Hypertension, College of Medicine and Science, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Full list of author information is available at the end of the article © The Author(s) 2020 corrected publication 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jayachandran et al. Orphanet J Rare Dis (2020) 15:319 Page 2 of 14 Conclusions: These results imply activation of distinct renal tubular and interstitial cell populations and processes associated with KS and NC, and suggest specifc populations of urinary EVs and proteins are potential biomarkers to assess the pathogenic mechanisms between KS versus NC among PH1 patients. Keywords: Microvesicles, Exosomes, Urinary vesicles, Urinary proteins, Oxalate, Renal calcifcation, Urinary stone disease Background (40–1000 nm) from the plasma membrane and exosomes Primary hyperoxaluria type 1 (PH1) is a rare metabolic (30–150 nm) from mature endosome) that can refect disorder with signifcant morbidity and mortality. PH1 and/or mediate early and late disease process [15–17]. is caused by mutations of glyoxylate alanine aminotrans- Indeed, our previous studies demonstrated a relation- ferase (AGT), a hepatocyte peroxisomal enzyme respon- ship between specifc populations of urinary EVs and KS sible for conversion of glyoxylate to glycine, resulting in disease, revealing a diferent urinary EV pattern between overproduction of oxalate [1, 2]. Age of clinical presenta- frst time (incident) stone formers, prevalent calcium tion varies from infancy to adulthood (median 5.5 years stone formers undergoing surgical procedures, and age- [3]) with 20 to 50% of patients having advanced chronic and sex-matched non-stone formers [17, 18]. kidney disease (CKD) at the time of diagnosis, and end A detailed urinary biomarker profle including EV stage kidney disease (ESKD) occurring at a median age characterization that could possibly elucidate poten- of 24–34 years [4–6]. Both nephrocalcinosis (NC) and tial mechanisms of KS and NC in PH1 has not yet been kidney stones (KS) are common features of PH1, but are reported. Specifc renal tubular and interstitial infamma- pathophysiologically distinct entities [7]. In PH1 patients, tory cellular biomarkers that refect early as well as late NC describes calcium oxalate (CaOx) crystal deposi- disease processes in PH1 patients are needed to identify tion within in renal tubular cells, interstitium or tubular specifc targets or biomarkers for therapeutic interven- lumen, either at the corticomedullary juncture or within tional trials. We hypothesized that PH1 patients with the medulla. NC does not always lead to KS formation ongoing intrarenal pathological calcifcation (NC or KS) and KS can occur in the apparent absence of NC, but excrete distinct populations of EVs containing specifc these two also often occur together in the same patient. renal and interstitial cellular, infammatory and injury Tus although these 2 pathologies are distinct they are markers into their urine due to localized renal cellular also intimately related, and have many common risk fac- events. Furthermore, those EVs that are present in the tors [7, 8]. An experimental animal studies suggest that urine of PH1 patients may contain unique renal tubular NC involved NLRP3 (nucleotide-binding oligomeriza- and interstitial cell injury and infammatory biomarkers tion domain (NOD)-leucine rich repeats (LLR)-and that could be used to diferentiate NC and KS patholo- pyrin domain-containing protein 3) mediated-activation gies, and to monitor these disease activities. To test this of pro-infammatory and pro-fbrotic macrophages and hypothesis, urinary EV populations and candidate solu- suppression of anti-infammatory macrophages [9]. KS ble proteins involved in soft tissue calcifcations were on the other hand form in the renal calyx attached to the measured in PH1 patients with and without NC or KS. papillae via tubular plugs or interstial Randall’s plaque. Te vast majority (> 95%) of KS in PH patients are com- Results posed of CaOx monohydrate [10]. Although KS cause Clinical characteristics much morbidity and expense, NC is perhaps more omi- In general, the age, body mass index, systolic and diastolic nous since it is associated with CKD risk [7]. Tus a key blood pressures, serum creatinine, eGFR, and 24 h urine gap in knowledge is the precise basic renal cellular mech- volume, urine pH, and excretions of calcium, creatinine, anisms involved in NC and KS formation, and the specifc and total protein were comparable in PH1 patients with- renal cellular and protein biomarkers of key pathophysi- out and with NC or KS (Table 1). Urine citrate excre- ological processes that occur during renal calcifcation. tion trended lower in PH1 patients with KS compared to Kidney cells can be injured by increased local concen- other groups. Urine osmolality tended lower whereas uri- trations of oxalate or by CaOx crystals [11, 12]. Some nary oxalate trended higher in PH1 patients with NC and studies support a role for renal tubular cell injury in the KS relative to patients without NC or KS (Table 1). pathophysiology of nephrolithiasis, especially that asso- ciated with hyperoxaluria [11, 13, 14]. Such activated Urinary extracellular vesicles (EVs) or injured cells could release biologically active mem- Te total number of EVs and EVs from diferent types of brane-bound extracellular vesicles (EVs; microvesicles glomerular and renal tubular cells (11/13 markers) were Jayachandran et al. Orphanet J Rare Dis (2020) 15:319 Page 3 of 14 Table 1 Baseline clinical characteristics of study patients Clinical characteristics Primary hyperoxaluria type 1 (PH1) PH1 without NC or KS PH1 with NC PH1 with KS Total p value (n 10) (n 6) (n 9) (n 25) = = = = Age (years) 21 (18, 25) 16 (16, 17) 20 (17, 24) 18 (16, 22) 0.13 Sex Female (%) 7 (70%) 3 (50%) 2 (22%) 12 (48%) 0.14 Male (%) 3 (30%) 3 (50%)
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