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.

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.

Our findings suggest for the first time that in AKI patients, application of HTEMS is associated with a faster normalization of lowered NOx and elevated ADMA and ET-1 plasma levels. We hypothesize that the more rapid amelioration of these parameters in the HTEMS group contributed to the accelerated recovery of AKI. With regard to the small study groups with different causes of AKI, investigations in a greater number of AKI patients is required.

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Treatment-resistant depression (TRD) and treatment-resistant bipolar depression (TRBD) poses a significant clinical and societal burden, relying on different operational definitions and treatment approaches. The detection of clinical predictors of resistance is elusive, soliciting clinical subtyping of the depressive episodes, which represents the goal of the present study. Methods: A hundred and thirty-one depressed outpatients underwent psychopathological evaluation using major rating tools, including the Hamilton Rating Scale for Depression, which served for subsequent principal component analysis, followed-up by cluster analysis, with the ultimate goal to fetch different clinical subtypes of depression. Results: The cluster analysis identified two clinically interpretable, yet distinctive, groups among 53 bipolar (resistant cases = 15, or 28.3%) and 78 unipolar (resistant cases = 20, or 25.6%) patients. Among the MDD patients, cluster "1" included the following components: "Psychic symptoms, depressed mood, suicide, guilty, insomnia" and "genitourinary, gastrointestinal, weight loss, insight". Altogether, with broadly defined "mixed features," this latter cluster correctly predicted treatment outcome in 80.8% cases of MDD. The same "broadly-defined" mixed features of depression (namely, the standard Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition-DSM-5-specifier plus increased energy, psychomotor activity, irritability) correctly classified 71.7% of BD cases, either as TRBD or not. Limitations: Small sample size and high rate of comorbidity. Conclusions: Although relying on different operational criteria and treatment history, TRD and TRBD seem to be consistently predicted by broadly defined mixed features among different clinical subtypes of depression, either unipolar or bipolar cases. If replicated by upcoming studies to encompass also biological and neuropsychological measures, the present study may aid in precision medicine and informed pharmacotherapy.