Dataset Information

Proteomic analysis of urinary exosomes in cystinuria patients

ABSTRACT: Cystinuria is a rare renal genetic disease caused by mutations in cystine transporter genes and characterized by defective cystine reabsorption leading to kidney stones. In 14% of cases patients undergo nephrectomy, but given the difficulty to predict the evolution of the disease, the identification of markers of kidney damage would improve the follow up of patients with a higher risk. The aim of the present study is to develop a robust, reproducible and non-invasive methodology for proteomic analysis of urinary exosomes using high resolution mass spectrometry. A clinical pilot study, conducted on 8 cystinuria patients vs. 10 controls, highlighted 165 proteins, of which 38 were up-regulated, that separate cystinuria patients from controls, and further discriminate between severe and moderate forms of the disease. These proteins include markers of kidney injury, circulating proteins and a neutrophil signature. Analysis of selected proteins by immunobloting, performed on six additional cystinuria patients, validated the mass spectrometry data. To our knowledge, this is the first successful proteomic study in cystinuria unmasking potential role of inflammation in this disease. The workflow we have developed is applicable to investigate urinanry exosomes in different renal diseases and to search for diagnostic/prognostic markers.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Urine

DISEASE(S): Cystinuria

SUBMITTER: Chiara guerrera

LAB HEAD: Ida Chiara Guerrera

PROVIDER: PXD001430 | Pride | 2014-11-17

REPOSITORIES: Pride

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A new workflow for proteomic analysis of urinary exosomes and assessment in cystinuria patients.

Bourderioux Matthieu M Nguyen-Khoa Thao T Chhuon Cerina C Jeanson Ludovic L Tondelier Danielle D Walczak Marta M Ollero Mario M Bekri Soumeya S Knebelmann Bertrand B Escudier Estelle E Escudier Bernard B Edelman Aleksander A Guerrera Ida Chiara IC

Journal of proteome research 20141112 1

Cystinuria is a purely renal, rare genetic disease caused by mutations in cystine transporter genes and characterized by defective cystine reabsorption leading to kidney stones. In 14% of cases, patients undergo nephrectomy, but given the difficulty to predict the evolution of the disease, the identification of markers of kidney damage would improve the follow-up of patients with a higher risk. The aim of the present study is to develop a robust, reproducible, and noninvasive methodology for pro ...[more]

PMID: 25365230

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Project description:Cystinuria is the most frequent monogenic cause of renal calculi. We previously described a urinary inflammatory signature in 8 cystinuric patients through quantitative proteomic analysis. Our data suggested an association of abnormal renal function and an inflammatory protein profile. The objectives of the present study were to investigate: i) the urinary proteomic profile in cystinuric patients without chronic kidney disease (CKD), and in a control group of healthy volunteers; ii) the potential effect of urine alkalinization on the urinary proteomic profile in cystinuric patients as this is the cornerstone of the preventive medical treatment. Urinary inflammatory profile was evaluated at baseline in the control group and in cystinuric patients not yet treated or for whom the alkalizing treatment or the cysteine- binding thiols have been discontinuated for at least 3 months and with an eGFR (using the CKD-EPI formula) greater than 60 ml/min/1.73m2 (so without CKD G3-G5). In cystinuric patients, change from baseline urinary inflammatory profile was evaluated after 3 months of alkalizing treatment. Urine proteome was analyzed by Nano- liquid chromatography coupled to high resolution mass spectrometry. Twenty-one cystinuric patients (12 men, median age [IQR] 30.0 years [25.0 – 44.0]), and 7 healthy volunteers (2 men, median age 43.1 years [31.0 – 53.9]) were included. Median eGFR in these two groups was 95 ml/min/1.73m2 [87.5 – 111.5] and 116 ml/min/1.73m2 [91.0 – 120.0] respectively (p=0.38). Healthy volunteers had no inflammatory signature. The inflammatory signature was present in the cystinuric patients at different degrees. A hierarchical clustering of the cystinuric patients according to the intensity of the profile of core inflammation signature (11 proteins) was performed. The signature could clearly separate 5 cystinuric patients with a high inflammation from other cystinuric patients and healthy volunteers. The alkalizing treatment was associated with a decrease in the intensity of the urinary inflammatory profile in all 5 cystinuric patients compared to the initial high level of urinary inflammation. A panel of 11 proteins was found as elevated in some cystinuric patients without CKD G3- G5 and could work as an early inflammatory signature. The alkalizing treatment was associated with a reduction of this urinary inflammation signature, suggesting that this panel of proteins could also be a new tool to monitor the treatment of cystinuric patient.

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