Respiratory side effects that sometimes occur during treatment with anti-CD3 MAb OKT3 might result from pulmonary sequestration of activated neutrophils. Therefore, we studied complement activation in relation to activation and pulmonary sequestration of neutrophils during antirejection treatment with OKT3. In each of nine patients studied, plasma C3a-desarg and C4b/c levels increased compared with pretreatment values already in the first sample taken 15 minutes after the first dose of OKT3 (P < 0.05), with peak values at 15 and 30 minutes, respectively. Levels of neutrophil degranulation product elastase (complexed to alpha 1-antitrypsin) also increased already at 15 minutes after the first dose of OKT3 (P < 0.05), which is before elevated levels of the cytokines TNF alpha, IL-6 or IL-8 were detectable. In contrast, upon subsequent OKT3 administrations or in the control group treated with methylprednisolone, neither complement activation, cytokine release nor neutrophil degranulation occurred. In five studied patients treated with OKT3, pulmonary sequestration of radiolabeled granulocytes was observed from 3 until 15 minutes after the first dose of OKT3, together with peripheral blood granulocytopenia, which lasted at least 30 minutes. In conclusion, we demonstrate a simultaneous activation of complement and pulmonary sequestration of activated granulocytes immediately following the first dose of OKT3. These phenomena may be involved in the development of respiratory side effects complicating this therapy.

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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.

Serum and urine interleukin-6 (IL-6) levels and serum neopterin/creatinine ratios were longitudinally studied in 86 renal transplant recipients until 4 months after transplantation. During acute rejection and acute tubular necrosis (ATN), serum and urine IL-6 levels were elevated compared to during stable transplant function (P < 0.001). During acute rejection, serum IL-6 levels increased at least 2 days before plasma creatinine started to rise (P < 0.05), indicating its early involvement in the rejection process. During cytomegalovirus (CMV) disease, serum, but not urine, IL-6 levels were higher (P < 0.01), and serum neopterin/creatinine values were higher than during stable transplant function, ATN, or acute rejection (P < 0.01). No significant differences with stable transplant function occurred during cyclosporin A toxicity. Measurement of serum IL-6 provided a sensitivity of 84% and a specificity of 85% for the diagnosis of acute rejection episodes not coinciding with ATN. All cases of CMV disease could be diagnosed by measurement of serum neopterin/creatinine, which provided a specificity of 73%.