Background and Aims Although IgA nephropathy (IgAN) is the most common primary glomerulonephritis in many parts of the world, risk of progressive kidney function decline is significant. Furthermore, the effect of immunosuppressive treatment in IgAN currently remains uncertain. There is no validated tool to predict disease progression or response to treatment. To serve this unmet need, we aimed at developing a urinary biomarker-based algorithm that predicts fast disease progression in patients with IgAN, thus enabling a personalized risk stratification and potentially improving patient management. Method In this multicenter study in 7 centers in Europe and in Canada urine samples were collected as part of clinical routine at time of biopsy in n= 300 patients (63% male, age 42±14 years) with biopsy proven IgAN. The follow-up data were collected for at least one year. Progressive disease was defined as an annual loss of kidney function (estimated glomerular filtration rate, eGFR) of more than -5ml/min/1.73m2 per year or when end-stage kidney disease (ESKD) was reached. The institutional review boards of each of the participating centers approved this study. Urine samples were analyzed using capillary electrophoresis coupled mass spectrometry (CE-MS). Whole proteome/peptidome profile was obtained for each sample. This study received funding from the European Union´s ERA PerMed program. Results Urine proteome/peptidome profiles were obtained from n=294 patients. On average, 2383 peptides were detected per sample. The data were subsequently divided into a discovery (n=154) and validation cohort (n=140). The comparison of the progressors (n=35) and non-progressors (n=119) in the discovery cohort resulted in the definition of more than 100 significant peptides. These included mainly fragments from collagen, mostly type 1 (decreased in progressors) and from different blood derived proteins like alpha-1-antitrypsin, alpha-2-HS-glycoprotein and apolipoproteins (increased in progressors). The distribution of the 100 most significant peptides in the progressor and non-progressor group is shown in the figure. The peptides were combined into a classifier using support vector machine. After optimizing the classifier employing a take-one-out procedure combined with n-1 cross-validation, the urine-peptide based algorithm enabled separation of progressors versus no progressors with an accuracy of 90% in take-one-out cross-validation. This classifier was subsequently applied to the validation cohort and resulted in highly significant separation of progressive from non-progressive IgAN patients. Furthermore, this classifier will be further applied blinded in an independent well characterized multicenter cohort of 267 IgAN patients. Conclusion We identified a urinary proteome profile which was associated with progressive loss of GFR in patients with IgAN. Further validation of this profile in an independent cohort is ongoing. The data indicate that CE-MS-based urinary proteomics enables identifying IgAN patients at high risk of disease progression. These patients may benefit from aggressive immunosuppressive treatment. Upon validation of the classifier in an independent cohort, its value in predicting response to immunosuppression will be assessed, aiming at establishing an innovative strategy that could improve patient management and personalize treatment of IgAN patients.

Background Trimethylamine N-oxide (TMAO), a metabolite from red meat and fish consumption, plays a role in promoting cardiovascular events. However, data regarding TMAO and its impact on clinical outcomes are inconclusive, possibly due to its undetermined dietary source. Objective We hypothesized circulating TMAO derived from fish intake might cause less harm compared to red meat source by examining the concomitant level of 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), a known biomarker of fish intake, and investigated the association between TMAO, CMPF and outcomes. Design Patients were recruited from the European QUALity study on treatment in advanced CKD (EQUAL) among individuals ≥65 years whose eGFR had dropped for the first time to ≤20mL/min/1.73m2 during last 6 months. The association between TMAO, CMPF and outcomes including all-cause mortality and kidney replacement therapy (KRT) was assessed among 737 patients. Patients were further stratified by median cut-offs of TMAO and CMPF, suggesting high/low red meat and fish intake. Results During a median of 39 months’ follow-up, 232 patients died. Higher TMAO was independently associated with an increased risk of all-cause mortality (multivariable-hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.17, 1.83). Higher CMPF was associated with a reduced risk of both all-cause mortality (HR 0.79, 95%CI 0.71, 0.89) and KRT (HR 0.80, 95%CI 0.71, 0.90), independent of TMAO and other clinically relevant confounders. In comparison to patients with low TMAO and CMPF, patients with low TMAO and high CMPF had reduced risk of all-cause mortality (adjusted HR 0.49, 95% CI 0.31, 0.73), whereas those with high TMAO and high CMPF showed no association across adjusted models. Conclusions High CMPF conferred an independent role in health benefits and might even counteract the unfavorable association between TMAO and outcomes. Whether higher circulating CMPF are due to fish consumption, and/or CMPF is a protective factor remains to be verified.

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Background Patients with stage 4/5 chronic kidney disease (CKD) suffer from various symptoms. The retention of uremic solutes is thought to be associated with those symptoms. However, there are relatively few rigorous studies on the potential links between uremic toxins and symptoms in patients with CKD. Methods The EQUAL study is an ongoing observational cohort study of non-dialyzed patients with stage 4/5 CKD. EQUAL patients from Germany, Poland, Sweden, and the United Kingdom were included in the present study (n = 795). Data and symptoms self-report questionnaires were collected between April 2012 and September 2020. Baseline uric acid and parathyroid hormone and ten uremic toxins were quantified. We tested the association between uremic toxins and symptoms, and adjusted p-values for multiple testing. Results Symptoms were more frequent in women than in men with stage 4/5 CKD, while levels of various uremic toxins were higher in men. Only trimethylamine-N-oxide (positive association with fatigue), p-cresylsulfate with constipation, and 3 carboxy-4-methyl-5-propyl-2-furanpropionic acid (negative association with shortness of breath) demonstrated moderately strong associations with symptoms in adjusted analysis. The association of phenylacetylglutamine with shortness of breath was consistent in both sexes, although only reached statistical significance in the full population. By contrast, trimethylamine-N-oxide (fatigue) and p-cresyl sulfate and phenylacetylglutamine (constipation) were only associated with symptoms in men, who presented higher serum levels than women. Conclusion Only a limited number of toxins were associated with symptoms in persons with stage 4/5 CKD. Other uremic toxins, uremia related factors or psychosocial factors not yet explored might contribute to symptom burden.