Correlation between Saliva Levels and Serum Levels of Free Uremic Toxins in Healthy Volunteers

International audienceThe objective of the present study was to investigate the putative correlation between the saliva concentration and free serum concentration for 10 uremic toxins (UTs; eight protein-bound solutes: 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), hippuric acid (HA), indole-3-acetic acid (3-IAA), indoxyl sulfate (I3S), kynurenic acid (KA), kynurenine (KYN), p-cresyl glucuronide (pCG), and p-cresyl sulfate (pCS); two free, water-soluble, low-molecular weight solutes: phenylacetylglutamine (PAGN) and trimethylamine N-oxide (TMAO); and three precursors: tyrosine (Tyr), phenylalanine, and tryptophan). Saliva samples and blood samples were collected simultaneously from 18 healthy volunteers. After the addition of internal standards, 50 µL of saliva or serum were precipitated with methanol. UTs and precursors were quantified using a validated LC-MS/MS method. The saliva–serum correlation was statistically significant (according to Spearman’s coefficient) for six UTs (TMAO, HA, I3S, pCS, 3-IAA, and CMPF). Tyr presented a weak saliva-serum correlation (p = 0.08), whereas the other two precursors did not show a saliva–serum correlation. For three UTs (KYN, KA and pCG), we were unable to test the correlation since the saliva or serum levels were too low in many of the volunteers. The present study is the first to report on the saliva concentrations of TMAO, KYN, HA, PAGN, pCG, and 3-IAA

The Role of Uremic Retention Solutes in the MIA Syndrome in Hemodialysis Subjects

International audienceIntroduction: In chronic kidney disease (CKD), the high morbidity and mortality risk for cardiovascular disease (CVD) are not easily explained only on the basis of traditional factors. Among nontraditional ones involved in CKD, malnutrition, inflammation, and atherosclerosis/calcification have been described as the "MIA syndrome."Methods: In this pilot study, we evaluated the association between the variation in serum levels of 27 uremic retention solutes plus 6 indexes related to the MIA syndrome processes in a population of dialysis patients. Results: As expected, we found a direct correlation between serum albumin and both phosphate and total cholesterol (r = 0.54 and 0.37, respectively; p < 0.05). Moreover, total cholesterol and phosphate directly correlate (r = 0.40, p < 0.05). The relationship between malnutrition and inflammation is highlighted by the correlation of serum cholesterol levels with serum alpha-1 acid glycoprotein and IL-6 levels (r = -0.56, r = -0.39, respectively; p < 0.05). Moreover, the relation between inflammation and atherosclerosis/calcification is supported by the correlation of IL-6 with VEGF levels and vascular smooth muscle cell high-Pi in vitro calcification (r = 0.81, r = 0.66, respectively; p < 0.01). Conclusion: We found significant correlations between several uremic retention solutes and malnutrition, inflammation, and atherosclerosis/calcification. Our findings support the hypothesis of a central role of the uremic milieu in the MIA syndrome and ultimately in the pathogenesis of CKD-specific CVD risk factors

Effect of Sevelamer and Nicotinamide on Albumin Carbamylation in Patients with End-Stage Kidney Disease

International audienceBackground and Objective: In end-stage kidney disease, high urea levels promote the carbamylation of lysine side chains on a variety of proteins, including albumin. Albumin carbamylation has been identified as a risk factor for mortality and sevelamer led to a decrease in urea levels in dialysis patients. In the present secondary analysis of the NICOREN trial, we investigated the putative impacts of sevelamer and nicotinamide on albumin carbamylation, and the potential correlation between carbamylation and vascular calcifications. Methods: All possible carbamylation of circulating albumin were screened for with high-resolution liquid chromatography-tandem mass spectrometry. Levels of three carbamylated peptides were then measured as a guide to the extent of albumin carbamylation. Carbamylation was measured at baseline in 55 patients included in the NICOREN trial and 29 patients at 24 weeks of treatment. Calcifications on plain radiographs were quantified as the Kauppila score and the Adragao score. Results: Baseline albumin carbamylation was present at three different sites in subjects with end-stage kidney disease. At baseline, we observed only a correlation between urea and the KQTA carbamylation site in these patients. Albumin carbamylation levels did not decrease after 24 weeks of treatment with either sevelamer or nicotinamide. Furthermore, the proportion of carbamylated serum albumin was not correlated with vascular calcification scores in this population. Conclusions: Our results confirmed the presence of carbamylated albumin in patients with end-stage kidney disease and demonstrated the presence of carbamylation beyond the LRVP residues. The results also demonstrated the lack of impact of sevelamer or nicotinamide on albumin carbamylation levels. Therapeutic strategies to lower carbamylation load should probably be focused on direct anti-carbamylation processes and/or potentially anti-inflammatory therapies

Association of Serum Phosphate with Efficacy of Statin Therapy in Hemodialysis Patients

International audienceBACKGROUND AND OBJECTIVES: Statins are less efficacious in reducing cardiovascular disease risk in patients on dialysis than in the general population. Recent experimental data showed that phosphate excess promotes cellular de novo cholesterol synthesis through 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activation. Whether this mechanism might account for the resistance of patients on dialysis to statins has not yet been explored. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this post hoc analysis, we examined the efficacy of statin treatment according to serum phosphate levels in the patients on dialysis who were participants of the A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) trial using serum phosphate levels at baseline and during the trial course. We first classified the patients by groups of similar phosphate trajectories over time and tested whether phosphate as a longitudinal exposure (summarized by the identified trajectory groups) modulated the occurrence of major adverse cardiovascular events and all-cause death. We replicate the analysis in the Deutsche Diabetes Dialyze Studie (4D) trial. RESULTS: In the AURORA trial, using multivariable analysis, we found that the treatment effect of statin on major adverse cardiovascular events and all-cause death was significant and protective effects in patients with low values of serum phosphate gradually faded for higher phosphate levels >5 mg/dl. A similar lack of statin treatment efficacy for both outcomes was observed with high baseline phosphate levels (>5 mg/dl). In the 4D trial, we found a comparable but not significant trend toward losing treatment efficacy in the presence of high serum phosphate levels for both outcomes. CONCLUSIONS: Our results demonstrated the limited treatment efficacy of statins in patients on dialysis in the presence of hyperphosphatemia. Copyrigh

Patient-reported factors influencing the choice of their kidney replacement treatment modality

International audienceBACKGROUND: Access to various kidney replacement therapy (KRT) modalities for patients with end-stage kidney disease differs substantially within Europe. METHODS: European adults on KRT filled out an online or paper-based survey about factors influencing and experiences with modality choice (e.g. information provision, decision-making and reasons for choice) between November 2017 and January 2019. We compared countries with low, middle and high gross domestic product (GDP). RESULTS: In total, 7820 patients [mean age 59 years, 56% male, 63% on centre haemodialysis (CHD)] from 38 countries participated. Twenty-five percent had received no information on the different modalities, and only 23% received information >12 months before KRT initiation. Patients were not informed about home haemodialysis (HHD) (42%) and comprehensive conservative management (33%). Besides nephrologists, nurses more frequently provided information in high-GDP countries, whereas physicians other than nephrologists did so in low-GDP countries. Patients from low-GDP countries reported later information provision, less information about other modalities than CHD and lower satisfaction with information. The majority of modality decisions were made involving both patient and nephrologist. Patients reported subjective (e.g. quality of life and fears) and objective reasons (e.g. costs and availability of treatments) for modality choice. Patients had good experiences with all modalities, but experiences were better for HHD and kidney transplantation and in middle- and high-GDP countries. CONCLUSION: Our results suggest European differences in patient-reported factors influencing KRT modality choice, possibly caused by disparities in availability of KRT modalities, different healthcare systems and varying patient preferences. Availability of home dialysis and kidney transplantation should be optimized

Work status and work ability of patients receiving kidney replacement therapy: results from a European survey

International audienceBACKGROUND: Employment is important for the quality of life and financial security of patients of working age receiving kidney replacement therapy (KRT). We aimed to examine self-reported work status and general, physical and mental work ability and to determine associations between demographic, disease-related, work-related and macroeconomic factors and employment. . METHODS: Europeans from 37 countries, ages 19-65 years, treated with dialysis or kidney transplantation, filled out the web-based or paper-based cross-sectional EDITH kidney patient survey between November 2017 and January 2019. We performed descriptive analyses and multivariable generalized logistic mixed models. RESULTS: Of the 3544 patients, 36.5% were employed and working [25.8% of dialysis patients, 53.9% of kidney transplant recipients (KTRs)]. The mean general work ability was 5.5 out of 10 (dialysis: 4.8, KTRs: 6.5). Non-working patients (all: 4.1, dialysis: 3.9, KTRs: 4.7) scored lower than working patients (all: 7.7, dialysis 7.3, KTRs: 8.0). Working dialysis patients scored lower on physical and mental work ability (7.1 and 8.1) than working KTRs (8.0 and 8.4; P < 0.001). Impaired physical work ability (42.7%) was more prevalent than impaired mental work ability (26.7%). Male sex, age 40-49 years, higher education, home dialysis or kidney transplantation as current treatment, treatment history including kidney transplantation, absence of diabetes mellitus, better general work ability and higher country gross domestic product were positively associated with employment (P < 0.05). CONCLUSIONS: Low employment rates and impaired work ability were prevalent among European patients receiving KRT. Demographic, disease-related, work-related and macro-economic factors were associated with employment

Extracorporeal Techniques in End-Stage Kidney Disease

International audienceDuring the last decades, various strategies have been optimized to enhance clearance of a variable spectrum of retained molecules to ensure hemodynamic tolerance to fluid removal and improve long-term survival in patients affected by end-stage kidney disease. Treatment effects are the result of the interaction of individual patient characteristics with device characteristics and treatment prescription. Historically, the nephrology community aimed to provide adequate treatment, along with the best possible quality of life and outcomes. In this article, we analyzed blood purification techniques that have been developed with their different characteristics

Decreased monocyte calcium sensing receptor expression in patients with chronic kidney disease is associated with impaired monocyte ability to reduce vascular calcification

International audienceIn chronic kidney disease (CKD), calcium-sensing receptor (CaSR) expression and function have been extensively studied in parathyroid tissue and vascular tissues. To examine whether similar changes occurred in other tissues, we measured total and surface CaSR expression in monocytes of patients with various stages of CKD and healthy volunteers respectively in cross-sectional studies. We further explored in vitro the impact of uremic serum on CaSR expression in monocytes (U937 and THP-1 cell lines), and whether human peripheral blood mononuclear cells or U937 and THP-1 monocytes might modify vascular calcium deposition in rat carotid arteries in vitro. CKD was associated with a decrease in peripheral blood mononuclear cell CaSR expression both in total and at the monocyte surface alone (43% and 34%, respectively in CKD stages 4-5). This decrease was associated with a reduction in the ability of monocytes to inhibit vascular calcification in vitro. Pretreatment with the calcimimetic NPSR568 of peripheral blood mononuclear cells isolated from patients with CKD significantly improved monocyte capacity to reduce carotid calcification in vitro. The fewer peripheral blood mononuclear cells expressing cell surface CaSR, the more calcimimetic treatment enhanced the decrease of carotid calcium content. Thus, we demonstrate that monocyte CaSR expression is decreased in patients with CKD and provide in vitro evidence for a potential role of this decrease in the promotion of vascular calcification. Hence, targeting this alteration or following monocyte CaSR expression as an accessible marker might represent a promising therapeutic strategy in CKD-associated arterial calcification

Nephrology: achieving sustainability

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EDTAKI: A Nephrology and Public Policy Committee platform call for more European involvement in acute kidney injury

International audienceBackground: Acute kidney injury (AKI) is an often neglected but crucial element of clinical nephrology. The aim of the Nephrology and Public Policy Committee (NPPC) of the European Renal Association-European Dialysis and Transplant Association is to promote several key aspects of European nephrology. One of the targets proposed by the NPPC was to advance European nephrology involvement in AKI. Methods: We undertook a literature analysis to define the current position of European nephrology in the field of AKI compared with other regions and to determine how different European countries compare with each other. Results: It appeared that vis-à-vis countries with a comparable socio-economic status (the USA, Australia, New Zealand and Canada), the European contribution was almost 50% less. Within Europe, Central and Eastern Europe and countries with a lower gross domestic product showed lower scientific output. Nephrologists contributed to less than half of the output. There was no trend of a change over the last decade. Conclusions: There is room to improve the contribution of European nephrology in the field of AKI. We propose a model on how to promote clinical collaboration on AKI across Europe and the creation of a pan-European nephrology network of interested units to improve clinical outcomes, increase nephrologist involvement and awareness outside nephrology and stimulate research on AKI in Europe. Accordingly, we also propose a list of research priorities and stress the need for more European funding of AKI research