Cystatin C-Based Equation to Estimate GFR without the Inclusion of Race and Sex.

BACKGROUND: The accuracy of estimation of kidney function with the use of routine metabolic tests, such as measurement of the serum creatinine level, has been controversial. The European Kidney Function Consortium (EKFC) developed a creatinine-based equation (EKFC eGFRcr) to estimate the glomerular filtration rate (GFR) with a rescaled serum creatinine level (i.e., the serum creatinine level is divided by the median serum creatinine level among healthy persons to control for variation related to differences in age, sex, or race). Whether a cystatin C-based EKFC equation would increase the accuracy of estimated GFR is unknown. METHODS: We used data from patients in Sweden to estimate the rescaling factor for the cystatin C level in adults. We then replaced rescaled serum creatinine in the EKFC eGFRcr equation with rescaled cystatin C, and we validated the resulting EKFC eGFRcys equation in cohorts of White patients and Black patients in Europe, the United States, and Africa, according to measured GFR, levels of serum creatinine and cystatin C, age, and sex. RESULTS: On the basis of data from 227,643 patients in Sweden, the rescaling factor for cystatin C was estimated at 0.83 for men and women younger than 50 years of age and 0.83 + 0.005 × (age - 50) for those 50 years of age or older. The EKFC eGFRcys equation was unbiased, had accuracy that was similar to that of the EKFC eGFRcr equation in both White patients and Black patients (11,231 patients from Europe, 1093 from the United States, and 508 from Africa), and was more accurate than the Chronic Kidney Disease Epidemiology Collaboration eGFRcys equation recommended by Kidney Disease: Improving Global Outcomes. The arithmetic mean of EKFC eGFRcr and EKFC eGFRcys further improved the accuracy of estimated GFR over estimates from either biomarker equation alone. CONCLUSIONS: The EKFC eGFRcys equation had the same mathematical form as the EKFC eGFRcr equation, but it had a scaling factor for cystatin C that did not differ according to race or sex. In cohorts from Europe, the United States, and Africa, this equation improved the accuracy of GFR assessment over that of commonly used equations. (Funded by the Swedish Research Council.).

Supplementation with selenium and coenzyme Q10 in an elderly Swedish population low in selenium - positive effects on thyroid hormones, cardiovascular mortality, and quality of life.

BACKGROUND: Selenium-dependent deiodinases play a central role in thyroid hormone regulation and metabolism. In many European countries, insufficient selenium intake may consequently lead to adverse effects on thyroid function. In this randomised placebo-controlled double-blind study, we examined the effect of supplementation with selenium and coenzyme Q10 on thyroid hormonal status, cardiovascular (CV) mortality and health-related quality of life (Hr-QoL). METHODS: Free T3, free T4, reverse T3, and TSH were determined in 414 individuals at baseline, and the effect of selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) supplementation on hormone concentrations, CV mortality and Hr-QoL was evaluated after 48 months using Short Form 36 (SF-36). Pre-intervention plasma selenium was low, mean 67 µg/L, corresponding to an estimated intake of 35 µg/day. Changes in concentrations of thyroid hormones following the intervention were assessed using T-tests, repeated measures of variance, and ANCOVA analyses. RESULTS: In the total population, the group with the lowest selenium concentration at baseline presented with significantly higher levels of TSH and lower levels of fT3 as compared to subjects with the highest selenium concentration. Supplementation with selenium and coenzyme Q10 for 4 years significantly increased fT3 and rT3, decreased fT4, and diminished the increase in TSH levels compared with placebo treatment (p = 0.03, all). In the placebo group, TSH and fT4 values above the median were associated with an increase in 10-year CV mortality, as compared with the mortality rate among those with TSH and fT4 below the median (p < 0.04, both), with no difference in mortality rate according to TSH and fT4 levels in the active intervention group. Similarly, TSH > median and fT3 < median were associated with a decline in mental Hr-QoL measures vs. TSH < and fT3 > median in the placebo group during 4 years of follow-up, but this was wiped out in the active group. CONCLUSIONS: Supplementation with selenium and coenzyme Q10 had a beneficial effect on thyroid hormones with respect to CV mortality and Hr-QoL outcomes. The initial deficient selenium status was associated with an impaired thyroid function and the changes in thyroid hormone levels can be explained by increased activity of deiodinases. We conclude that a substantial part of the elderly study population might suffer from suboptimal thyroidal function with adverse clinical implications due to selenium deficiency. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov and has the identifier NCT01443780. Since it was not mandatory to register at the time the study began, the study has been registered retrospectively.

Anti-histone and anti-nucleosome rather than anti-dsDNA antibodies associate with IFN-induced biomarkers in Sudanese and Swedish Systemic Lupus Erythematosus patients.

OBJECTIVES: In SLE, anti-dsDNA can co-occur with autoantibodies against other chromatin components, like histones and nucleosomes. These antibodies induce type-1 interferon production, a hallmark of SLE. We measured antinuclear antibody (ANA) sub-specificities and investigated their associations to inflammatory biomarkers including interferon-regulated chemokines. METHODS: We included 93 Sudanese and 480 Swedish SLE patients and matched controls (N = 104 + 192). Autoantibodies targeting ANA-subspecificites: dsDNA, Sm, Sm/U1RNPcomplex, U1RNP, SSA/Ro52, SSA/Ro60, SSB/La, ribosomal P, PCNA and histones were quantified in all subjects, anti-nucleosome only in the Swedish patients, with a bead-based multiplex immunoassay. Levels of 72 plasma biomarkers were determined with Proximity Extension Assay technique or ELISA. RESULTS: Among Sudanese patients, the investigated antibodies significantly associated with 9/72 biomarkers. Anti-histone antibodies showed the strongest positive correlations with MCP-3 and S100A12 as well as with interferon I-inducible factors MCP-1 and CXCL10. Anti-dsDNA antibodies associated with CXCL10 and S100A12, but in multivariate analyses, unlike anti-histone, associations lost significance.Among Swedish patients, MCP-1, CXCL10, SA100A12 also demonstrated stronger associations to anti-histone and anti-nucleosome antibodies, compared with anti-dsDNA and other ANA sub-specificities. In multiple regression models, anti-histone/nucleosome retained the strongest associations. When excluding anti-histone or anti-nucleosome positive patients, the associations between MCP-1/CXCL10 and anti-dsDNA were lost. In contrast, when excluding anti-dsDNA positive patients, associations with anti-histone and anti-nucleosome remained significant. CONCLUSION: In two cohorts of different ethnical origin, autoantibodies targeting chromatin correlate stronger with IFN-induced inflammatory biomarkers than anti-dsDNA or other ANA sub-specificities. Our results suggest that anti-histone/nucleosome autoantibodies may be main drivers of type-1 interferon activity in SLE.

Patient result monitoring of HbA1c shows small seasonal variations and steady decrease over more than 10 years.

OBJECTIVES: Internal and external quality assurance materials often use highly processed matrixes. This can render the materials non-commutable. Monitoring laboratory methods with patient medians helps in identifying and correcting systematic errors that may affect diagnostic accuracy. The aim of the present study was to use HbA1c patient results for monitoring of method performance over time. METHODS: Test HbA1c results from 2010 to 2022 was analyzed (n=722,553) regarding changes over time and seasonal variation. The HbA1c testing was initially performed on a Cobas 501 instrument using immunological detection but in May 2017 the method was replaced by capillary electrophoresis on Capillarys 3 Tera. RESULTS: There was a steady decrease in HbA1c values. From 2011 to 2021 the decrease was for 0.10 percentile 6.6 %, lower quartile 7.9 %, median 10.2 %, mean values 9 %, upper quartile 11.2 %, and 0.90 percentile 9.3 %. No clear shift in HbA1c levels was observed due to the shift in methods. The median HbA1c values per month was approximately 44 mmol/mol (6.2 %, DCCT/NGSP). The only month with a median HbA1c that differed by more than 1 mmol/mol was July with a median value of 42 mmol/mol (6.0 %). CONCLUSIONS: The patient data showed a similar decrease as in the National Diabetes Register which indicates that the method is stable over time without any sudden changes and that the seasonal variation is low. The continuous decrease in HbA1c values over time is most likely to a shift towards earlier detection of patient with diabetes and improved treatment.

The predictive value of cardiovascular outcomes and mortality assessed by the C-reactive protein to albumin ratio in the UK Biobank.

BACKGROUND: The C-reactive protein/albumin ratio (CAR) seems to mirror disease severity and prognosis in several acute disorders particularly in elderly patients, yet less is known about if CAR is superior to C-reactive protein (CRP) in the general population. METHODS: Prospective study design on the UK Biobank, where serum samples of CRP and Albumin were used. Cox regression analyses were conducted to assess all-cause and cardiovascular mortality, myocardial infarction, ischemic stroke, and heart failure over a follow-up period of approximately 12.5 years. The Cox model was adjusted for established cardiovascular disease (CVD) risk factors, including age, sex, smoking habits, physical activity level, BMI level, systolic blood pressure, LDL-cholesterol, statin treatment, diabetes, and previous CVD, with hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Analyses were also stratified by sex, CRP level (< 10 and ≥ 10 mg/ml) and age (< 60 and ≥ 60 years). RESULTS: In total, 411,506 individuals (186,043 men and 225,463 women) were included. In comparisons between HRs for all adverse outcomes, the results were similar or identical for CAR and CRP. For example, both CAR and CRP, adjusted HRs for all-cause mortality were 1.13 (95% CI 1.12-1.14). Regarding CVD mortality, the adjusted HR for CAR was 1.14 (95% CI 1.12-1.15), while for CRP, it was 1.13 (95% CI 1.11-1.15). CONCLUSIONS: Within this study CAR was not superior to CRP in predictive ability of mortality or CVD disorders. CLINICAL TRIAL REGISTRATION NUMBER: Not applicable (cohort study).

Extending the cystatin C based EKFC-equation to children - validation results from Europe.

BACKGROUND: A new cystatin C based European Kidney Function Consortium (EKFCCysC) equation was recently developed for adults, using the same mathematical form as the previously published full age spectrum creatinine based EKFC-equation (EKFCCrea). In the present study the cystatin C based EKFC-equation is extended to children, by defining the appropriate cystatin C rescaling factor QCysC. METHODS: Rescaling factor QCysC for cystatin C was defined as: a) 0.83 mg/L, exactly as it was defined for young adults in the adult equation, and b) a more complex QCysC-age relationship based on 4th degree cystatin C-age polynomials after evaluation of data from Uppsala, Stockholm and Canada and aggregated data from Germany. The EKFCCysC equation was then validated in an independent dataset in European children (n = 2,293) with measured GFR, creatinine, cystatin C, age, height and sex available. RESULTS: The EKFCCysC with the simple QCysC-value of 0.83 had a bias of -7.6 [95%CI -8.4;-6.5] mL/min/1.73 m2 and a P30-value of 85.8% [95%CI 84.4;87.3] equal to the EKFCCysC with the more complex 4th degree QCysC-value. The arithmetic mean of the EKFCCrea and EKFCCysC with the simple QCysC of 0.83 had a bias of -4.0 [95%CI -4.5;-3.1] mL/min/1.73 m2 and P30 of 90.4% [95%CI 89.2;91.6] similar to using the more complex 4th degree QCysC-polynomial. CONCLUSION: Using exactly the same QCysC of 0.83 mg/L, the adult EKFCCysC can easily be extended to children, with some bias but acceptable P30-values. The arithmetic mean of EKFCCrea and EKFCCysC results in bias closer to zero and P30 slightly over 90%.

Biomarkers associated with cardiovascular disease in women with spontaneous preterm birth: A case-control study.

INTRODUCTION: Women with spontaneous preterm birth have an increased risk of cardiovascular disease later in life. Studies suggest potential pathophysiological mechanisms in common, but whether these could be identified by measurement of soluble circulating protein biomarkers in women with spontaneous preterm birth is unknown. The aim of this study was to determine if protein biomarkers associated with cardiovascular disease distinguish women with spontaneous preterm birth from healthy controls, both at pregnancy and at follow up. MATERIAL AND METHODS: Study participants were identified in the population-based Uppsala biobank of pregnant women in Sweden, where plasma samples were collected in mid-pregnancy. In a first screening phase, we identified participants who subsequently experienced spontaneous preterm birth (<37 weeks) in the index pregnancy (N = 13) and controls (N = 6). In these samples, differences in protein expression were examined by comparative mass spectrometry. In a second validation phase, we invited 100 cases with previous spontaneous preterm birth in the index pregnancy and 100 controls (matched for age, body mass index, and year of delivery) from the same source population, to a follow-up visit 4-15 years after pregnancy. At follow up, we collected plasma samples and data on cardiovascular risk factors. We measured concentrations of selected biomarkers identified in the screening phase, as well as lipid profiles in samples both from pregnancy (biobank) and follow up. CLINICALTRIALS: gov registration NCT05693285. RESULTS: In the screening phase, fibrinogen, cadherin-5, complement C5, factor XII, plasma kallikrein, apolipoprotein M, and vitamin D-binding protein differed significantly at pregnancy. In the validation phase, 65 women agreed to participate (35 cases and 30 controls), with a median follow-up time of 11.8 years since pregnancy. The concentration of fibrinogen (p = 0.02) and triglycerides (p = 0.03) were slightly higher in cases compared with matched controls at follow up. CONCLUSIONS: Compared with women without preterm birth, those with spontaneous preterm birth had slightly higher concentrations of fibrinogen, both at mid-pregnancy and a decade after pregnancy. Additionally, we found slightly higher concentration of triglycerides at follow up in women with previous spontaneous preterm birth. The relevance of this finding is uncertain but might indicate potential pathophysiological mechanisms in common between spontaneous preterm birth and cardiovascular disease.

Analysis of HbA1c using microfluidic card (Capitainer qDBS card) as a pre-step before determination of the HbA1c value with an immunological method.

The objective of the study was to evaluate Capitainer's quantitative dried blood spots (qDBS) card for Hemoglobin A1c (HbA1c) testing. qDBS cards can be used for at-home sampling for HbA1c determination in a Swedish laboratory setting. A total of 153 routine requested HbA1c samples were used in this evaluation of microfluidic cards (qDBS). The HbA1c was extracted from the disc and HbA1c was determined at cobas 6000 instruments with immunological technology. The results were compared with results from traditional venous HbA1c testing. The reproducibility of using this elution procedure was 4.0% measured as coefficient of variation at a HbA1c concentration of 51 mmol/mol. Analytical performance specifications for HbA1c < 52 mmol/mol using DBS card (c501) compared with assigned values from Capillarys 3 was (y) = 1.03 x Capillarys 3(x) - 0.87; R2 = 0.97. There is a good agreement between HbA1c determined by traditional HbA1c testing and determination from Capitainer's qDBS cards. This shows that the technology could be used for out-of doctor's office testing.

Pediatric reference intervals for serum folate and cobalamin based on a European population without exposure to folic acid fortification.

The aim of the present study was to define pediatric reference intervals for serum cobalamin and folate utilizing data generated from a population not exposed to food fortified with folic acid. Folate and cobalamin results analyzed by electrochemiluminescence immunoassay (Roche Cobas) were obtained from 2375 children (2 months to 17.99 years of age). The serum samples were collected between 2011 and 2015 as part of the LIFE (Leipzig Research Centre for Civilization Diseases) Child cohort study in Germany, where folic acid fortification of food is not mandated. These results were used to generate age- and gender-specific reference intervals presented as non-parametric 2.5 and 97.5 percentiles. Because of a subsequent restandardisation of the Roche folate assay in 2016, folate values were recalculated accordingly for adaptation to results obtained using the present calibration. In both genders, folate concentrations decreased continuously with age, whereas cobalamin concentrations peaked at five years of age and then declined. Teenage females had higher concentrations of cobalamin in the age group 12-17.99 years.

A regulatory element associated to NAFLD in the promoter of DIO1 controls LDL-C, HDL-C and triglycerides in hepatic cells.

BACKGROUND: Genome-wide association studies (GWAS) have identified genetic variants linked to fat metabolism and related traits, but rarely pinpoint causative variants. This limitation arises from GWAS not considering functional implications of noncoding variants that can affect transcription factor binding and potentially regulate gene expression. The aim of this study is to investigate a candidate noncoding functional variant within a genetic locus flagged by a GWAS SNP associated with non-alcoholic fatty liver disease (NAFLD), a condition characterized by liver fat accumulation in non-alcohol consumers. METHODS: CRISPR-Cas9 gene editing in HepG2 cells was used to modify the regulatory element containing the candidate functional variant linked to NAFLD. Global gene expression in mutant cells was assessed through RT-qPCR and targeted transcriptomics. A phenotypic assay measured lipid droplet accumulation in the CRISPR-Cas9 mutants. RESULTS: The candidate functional variant, rs2294510, closely linked to the NAFLD-associated GWAS SNP rs11206226, resided in a regulatory element within the DIO1 gene's promoter region. Altering this element resulted in changes in transcription factor binding sites and differential expression of candidate target genes like DIO1, TMEM59, DHCR24, and LDLRAD1, potentially influencing the NAFLD phenotype. Mutant HepG2 cells exhibited increased lipid accumulation, a hallmark of NAFLD, along with reduced LDL-C, HDL-C and elevated triglycerides. CONCLUSIONS: This comprehensive approach, that combines genome editing, transcriptomics, and phenotypic assays identified the DIO1 promoter region as a potential enhancer. Its activity could regulate multiple genes involved in the NAFLD phenotype or contribute to defining a polygenic risk score for enhanced risk assessment in NAFLD patients.

Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression.

AIMS/HYPOTHESIS: Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycaemic traits. However, little is known about the function of the zinc finger transcription factor Ras-responsive element binding protein 1 (RREB1) in glucose homeostasis or how changes in its expression and/or function influence diabetes risk. METHODS: A zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo. Using transcriptomic and cellular phenotyping of a human beta cell model (EndoC-ßH1) and human induced pluripotent stem cell (hiPSC)-derived beta-like cells, we investigated how loss of RREB1 expression and activity affects pancreatic endocrine cell development and function. Ex vivo measurements of human islet function were performed in donor islets from carriers of RREB1 type 2 diabetes risk alleles. RESULTS: CRISPR/Cas9-mediated loss of rreb1a and rreb1b function in zebrafish supports an in vivo role for the transcription factor in beta cell mass, beta cell insulin expression and glucose levels. Loss of RREB1 also reduced insulin gene expression and cellular insulin content in EndoC-ßH1 cells and impaired insulin secretion under prolonged stimulation. Transcriptomic analysis of RREB1 knockdown and knockout EndoC-ßH1 cells supports RREB1 as a novel regulator of genes involved in insulin secretion. In vitro differentiation of RREB1KO/KO hiPSCs revealed dysregulation of pro-endocrine cell genes, including RFX family members, suggesting that RREB1 also regulates genes involved in endocrine cell development. Human donor islets from carriers of type 2 diabetes risk alleles in RREB1 have altered glucose-stimulated insulin secretion ex vivo, consistent with a role for RREB1 in regulating islet cell function. CONCLUSIONS/INTERPRETATION: Together, our results indicate that RREB1 regulates beta cell function by transcriptionally regulating the expression of genes involved in beta cell development and function.

The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation.

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous glomerular filtration rate (GFR)-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by the identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterized by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules <1 kDa dominating the glomerular filtrate, for example water, urea and creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterized by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.

Serum calprotectin correlates more strongly with inflammation and disease activity in ACPA positive than ACPA negative rheumatoid arthritis.

OBJECTIVES: The aim of the present study was to evaluate performance of serum and synovial fluid levels of the granulocyte protein calprotectin as inflammatory biomarker in rheumatoid arthritis (RA) patients with knee synovitis. METHODS: 76 RA patients with ongoing knee synovitis were included. Data on disease activity score with 28 joints and their subcomponents and radiological destruction of the affected knee were collected. White blood cell count, C-reactive protein, anti-citrullinated peptide antibodies (ACPA) against cyclic citrullinated peptide version 2 (anti-CCP2), IgM rheumatoid factor (RF) and calprotectin were analysed in parallel in circulation and in synovial fluid (SF). Counts of polynuclear and mononuclear cells were measured in SF. RESULTS: Serum (S) calprotectin correlated stronger than SF-calprotectin with inflammatory markers and disease activity. Instead, SF-calprotectin showed a strong correlation to SF counts of white blood cells, and especially to polymorphonuclear cell counts (Spearman's rho = 0.72, p< 0.001). S-calprotectin showed markedly stronger correlation with inflammatory markers and disease activity in ACPA positive as compared with ACPA negative RA patients; a similar difference was observed for patients with and without IgM RF. CONCLUSION: The particularly strong association between circulating calprotectin and inflammation in ACPA positive RA is a new argument for a specific role for polymorphonuclear granulocytes/neutrophils in this RA subset. Measurement of calprotectin in SF does not convey any additional benefit compared with measurement in the circulation in RA patients with knee synovitis.

Multilayer integration in silicon nitride: decoupling linear and nonlinear functionalities for ultralow loss photonic integrated systems.

Silicon nitride is an excellent material platform for its extremely low loss in a large wavelength range, which makes it ideal for the linear processing of optical signals on a chip. Moreover, the Kerr nonlinearity and the lack of two-photon absorption in the near infrared enable efficient nonlinear optics, e.g., frequency comb generation. However, linear and nonlinear operations require distinct engineering of the waveguide core geometry, resulting in a tradeoff between optical loss and single-mode behavior, which hinders the development of high-performance, ultralow-loss linear processing blocks on a single layer. Here, we demonstrate a dual-layer photonic integration approach with two silicon-nitride platforms exhibiting ultralow optical losses, i.e., a few dB/m, and individually optimized to perform either nonlinear or linear processing tasks. We demonstrate the functionality of this approach by integrating a power-efficient microcomb with an arrayed waveguide grating demultiplexer to filter a few frequency comb lines in the same monolithically integrated chip. This approach can significantly improve the integration of linear and nonlinear optical elements on a chip and opens the way to the development of fully integrated processing of Kerr nonlinear sources.

Plasma cytokine levels in spinal surgery with sevoflurane or total intravenous propofol anesthesia - A post hoc analysis of a randomized controlled trial.

Surgical tissue trauma stimulates an inflammatory response resulting in increased levels of cytokines which could contribute to acute kidney injury (AKI). It is not clear if anesthetic modality affects this response. We aimed to investigate the role of anesthesia in a healthy surgical population on the inflammatory response and the correlation to plasma creatinine. This study is a post hoc analysis of a published randomized clinical trial. We analyzed plasma from patients who underwent elective spinal surgery randomized to either total intravenous propofol anesthesia (n = 12) or sevoflurane anesthesia (n = 10). The plasma samples were collected before anesthesia, during anesthesia, and 1 h after surgery. Plasma cytokine levels after surgery were analyzed for correlations with duration of surgical insult and change in plasma creatinine concentration. The cytokine interleukin-6 (IL-6) was increased after surgery compared with preoperatively. IL-6 was higher in the sevoflurane group than the propofol group after surgery. No patient developed AKI, but plasma creatinine was increased postoperatively in the sevoflurane group. There was a significant association between surgical time and plasma IL-6 postoperatively. No significant correlation between change in plasma creatinine and IL-6 was detected. The cytokines IL-4, IL-13, Eotaxin, Interferon γ-Induced Protein 10 (IP-10), Granulocyte Colony-Stimulating Factor (G-CSF), Macrophage Inflammatory Protein-1ß (MIP-1ß), and Monocyte Chemoattractant Protein 1 (MCP-1) were lower postoperatively than before surgery independent of anesthetic modality. This post hoc analysis revealed that plasma IL-6 was increased after surgery and more so in the sevoflurane group than the propofol group. Postoperative plasma IL-6 concentration was associated with surgical time.

Increased plasma levels of soluble programmed death ligand 1 (sPD-L1) and fibroblast growth factor 23 (FGF-23) in patients with Graves' ophthalmopathy in comparison to hyperthyroid patients without Graves' ophthalmopathy.

BACKGROUND: Management of Graves' ophthalmopathy (GO) is still a challenge in Graves' disease (GD). Moreover, 40% of GD patients show radiological muscle enlargement without clinically apparent GO. Delayed treatment of GO may lead to deterioration in prognosis. METHODS: Thirty GD patients with overt hyperthyroidism were included in this study, 17 of whom either had GO at diagnosis or developed GO during the study period. Samples were collected at the beginning of the study, at 6 months, and at 24 months. Plasma samples were analyzed for 92 cytokines using the Olink Target 96 inflammation panel. RESULTS: After adjustment for multiplicity testing using the false discovery rate approach, soluble programmed death ligand 1 (sPD-L1) and fibroblast growth factor 23 (FGF-23) were significantly elevated in GO patients. CONCLUSION: Using a broad cytokine panel we show that patients with Graves' ophthalmopathy have elevated PD-L1 and FGF-23 levels. The findings support previous suggestions that PD-L1 may serve as a treatment target.

Urine Galectin-3 binding protein reflects nephritis activity in systemic lupus erythematosus.

BACKGROUND: Lupus nephritis (LN) is a major and severe organ involvement in systemic lupus erythematosus (SLE), whose diagnosis and treatment necessitate to perform kidney biopsy, which is an invasive procedure. Non-invasive urine biomarkers are an active area of investigation to support LN diagnosis and management. OBJECTIVE: To investigate the role of urinary galectin-3 binding protein (u-Gal-3BP) as a candidate biomarker of renal disease in biopsy proven LN. PATIENTS AND METHODS: Levels of u-Gal-3BP were investigated in a cross-sectional fashion by ELISA in 270 subjects: 86 LN patients, 63 active SLE patients with no kidney involvement, 73 SLE patients with inactive disease and 48 age and sex-matched population-based controls (PBC). Moreover, urine samples were analysed separately by ELISA for additional markers of kidney pathology: neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), kidney injury molecule-1 (KIM-1) and galectin-3 (Gal-3). The concentrations of all studied molecules were normalized to urine creatinine levels. In 10 patients, post-treatment levels of the biomarkers were measured. RESULTS: Normalized u-Gal-3BP levels were higher in LN patients compared to the other groups (p < .0001). Comparing different LN classes, u-Gal-3BP levels were higher among patients with proliferative (class III/IV) and membranous (class V) as compared to mesangial (class II) forms (p = .04). In proliferative forms, u-Gal-3BP levels correlated with the activity index in renal biopsies (r = 0.42, p = .004). Moreover, in a subset of 10 patients with repeated kidney biopsy and urine sampling before and after induction treatment, a significant decrease of u-Gal-3BP was observed (p = .03). Among the other markers, KIM-1 was also able to discriminate LN from the other groups, while NGAL, OPN and Gal-3 could not in this cohort. CONCLUSION: Given its ability to discriminate LN patients from active non-renal and inactive SLE patients, the observed correlation with the activity index in renal biopsies, and its levels declining following treatment, u-Gal-3BP shows promise as a non-invasive urinary biomarker to help detecting and to monitor renal involvement in SLE patients and should be validated in larger cohorts.

Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil and Africa.

BACKGROUND: A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts. METHODS: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed. RESULTS: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males. CONCLUSION: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study.

Interlaboratory variation for NT-proBNP among Swedish laboratories in an external quality program 2011-2021.

OBJECTIVES: NT-proBNP is frequently used for ruling out heart failure. Different cut-offs are used depending on the clinical context, e.g. an acute or chronic condition. Medical decision limits have been suggested at 125 and 300 ng/L or 400 ng/L in international guidelines. However, there is limited standardization between NT-proBNP methods and using the same blood sample might cause different treatment of patients. METHODS: Data from the external quality assessment program for NT-proBNP from Equalis, Sweden, were extracted for the period 2011-2021, and categorized according to manufacturer. Manufacturer median NT-proBNP values were compared to total median values. CV% was calculated for each manufacturer and in comparison to different levels of NT-proBNP. RESULTS: Roche was the most common method, and its median results were closest to the median consensus results. When looking at the total CV at NT-proBNP levels in the range of 0-500 ng/L, the total CV varied from 4 to 27%. During 2019-2021, Siemens (Immulite, Centaur, Atellica) yielded results 16-20% above the consensus median depending on sample level. Similarly, Abbott was 5-7% above, while Roche and Siemens Stratus were 1% respectively 6-10% below the consensus median. CONCLUSIONS: The introduction of new manufacturers and methods in 2017 have caused the agreement between manufacturers to decline. This highlights the need for a common calibrator and reference materials, particularly since medical decision limits in guidelines, e.g. European Society of Cardiology 2021, which are mostly based on Roche methods, do not take these method differences into account.

Reference Intervals for Plasma Free Kappa and Lambda Chains and Kappa/Lambda Ratio using PENIA.

BACKGROUND: Determination of free light chains is used increasingly for patients with multiple myeloma and other plasma cell dyscrasias. The aim of the present study was to define reference intervals for free kappa and lambda chains and kappa/lambda ratio in lithium heparin plasma and compare the test results with cystatin C based estimated glomerular filtration rate. METHODS: Free kappa and lambda chains were measured in Liheparin plasma from 222 healthy blood donors using free light chain reagents and a BNII nephelometer from Siemens Diagnostics. RESULTS: Calculated reference intervals for kappa chain, free was 4.73 mg/L (90% confidence interval 4.00 - 5.45) - 22.66 mg/L (20.33 - 24.98), for lambda chain, free was 4.33 mg/L (3.70 - 4.95) - 29.28 mg/L (26.96 - 31.59), and for Kappa/Lambda Chain ratio 0.59 (0.56 - 0.62) - 1.46 (1.37 - 1.56). There was no need for gender or age specific reference intervals. Cystatin C based estimated glomerular filtration rate had a significant effect on the levels of free light chains. CONCLUSIONS: The study presents reference intervals for plasma free light chains and compared results of estimated glomerular filtration rate with free light chains of kappa and lambda.