25-Hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)
D) need to be bound to carrier proteins to be transported to their target cells. The majority of either 25OHD or 1,25(OH)
D is bound ...to vitamin D-binding protein (DBP), a smaller fraction is bound to albumin and only very small amounts of 25OHD or 1,25(OH)
D are free. Albumin-bound 25OHD or 1,25(OH)
D is relatively easily available after dissociation from albumin. Thus, the sum of free and albumin-bound forms is called bioavailable 25OHD and bioavailable 1,25(OH)
D. Total 25OHD and 1,25(OH)
D are defined as the sum of free, albumin-bound and DBP-bound 25OHD and 1,25(OH)
D, respectively. This cross-sectional study in 427 pregnant women compared the correlation of the six vitamin D compounds with biomarkers of bone health, lipid metabolism, kidney function, endocrine parameters, and group B water-soluble vitamins. Among the 25OHD metabolites analysed, total 1,25(OH)
D showed clearly the best correlation with calcium, bone-specific alkaline phosphatase, adiponectin, LDL, HDL, urea, thyroxine, and group B water-soluble vitamins. When comparing the three 25OHD metabolites, both free 25OHD and bioavailable 25OHD showed overall good correlations with calcium, bone-specific alkaline phosphatase, adiponectin, LDL, HDL, urea, thyroxine, triiodothyronine, and group B water-soluble vitamins, The correlations of 1,25(OH)
D and 25OHD metabolites went always in opposite directions. Only PTH correlates always inversely with all six vitamin D compounds. In conclusion, free 25(OH)D and bioavailable 25(OH)D are more precise determinants of the vitamin D status than total 25(OH)D in normal pregnancy, whereas total 1,25(OH)
D is superior to free and bioavailable 1,25(OH)
D. Except for PTH, correlations of 25(OH)D and 1,25(OH)
D metabolites with typical clinical chemistry readouts go in opposite directions.
In established acute kidney injury (AKI), serum creatinine poorly differentiates prerenal from intrinsic AKI. In this study, we tested whether urinary neutrophil gelatinase-associated lipocalin ...(NGAL) distinguishes between intrinsic and prerenal AKI, and tested its performance in predicting a composite outcome that included progression to a higher RIFLE (Risk, Injury, Failure, Loss of function, End stage renal disease) class, dialysis, or death. Urinary NGAL was measured using a standardized clinical platform in 161 hospitalized patients with established AKI. Sixteen patients were excluded because of postrenal obstruction or insufficient clinical information. Of the remaining 145 patients, 75 had intrinsic AKI, 32 had prerenal AKI, and 38 patients could not be classified. Urinary NGAL levels effectively discriminated between intrinsic and prerenal AKI (area under the receiver-operating characteristic curve 0.87). An NGAL level over 104μg/l indicated intrinsic AKI (likelihood ratio 5.97), whereas an NGAL level <47μg/l made intrinsic AKI unlikely (likelihood ratio 0.2). Patients experiencing the composite outcome had significantly higher median urinary NGAL levels on inclusion. In logistic regression analysis, NGAL independently predicted the composite outcome when corrected for demographics, comorbidities, creatinine, and RIFLE class. Hence, urinary NGAL is useful in classifying and stratifying patients with established AKI.
BackgroundAntineutrophil cytoplasmic autoantibody-associated (ANCA-associated) vasculitidies (AAV) are life-threatening systemic autoimmune conditions. ANCAs directed against proteinase 3 (PR3) or ...myeloperoxidase (MPO) bind their cell surface-presented antigen, activate neutrophils, and cause vasculitis. An imbalance between PR3 and its major inhibitor α1-antitrypsin (AAT) was proposed to underlie PR3- but not MPO-AAV. We measured AAT and PR3 in healthy individuals and patients with AAV and studied protective AAT effects pertaining to PR3- and MPO-ANCA.MethodsPlasma and blood neutrophils were assessed for PR3 and AAT. WT, mutant, and oxidation-resistant AAT species were produced to characterize AAT-PR3 interactions by flow cytometry, immunoblotting, fluorescence resonance energy transfer assays, and surface plasmon resonance measurements. Neutrophil activation was measured using the ferricytochrome C assay and AAT methionine-oxidation by Parallel Reaction Monitoring.ResultsWe found significantly increased PR3 and AAT pools in patients with both PR3- and MPO-AAV; however, only in PR3-AAV did the PR3 pool correlate with the ANCA titer, inflammatory response, and disease severity. Mechanistically, AAT prevented PR3 from binding to CD177, thereby reducing neutrophil surface antigen for ligation by PR3-ANCA. Active patients with PR3-AAV showed critical methionine-oxidation in plasma AAT that was recapitulated by ANCA-activated neutrophils. The protective PR3-related AAT effects were compromised by methionine-oxidation in the AAT reactive center loop but preserved when 2 critical methionines were substituted with valine and leucine.ConclusionPathogenic differences between PR3- and MPO-AAV are related to AAT regulation of membrane-PR3, attenuating neutrophil activation by PR3-ANCA rather than MPO-ANCA. Oxidation-resistant AAT could serve as adjunctive therapy in PR3-AAV.FUNDINGThis work was supported by KE 576/10-1 from the Deutsche Forschungsgemeinschaft, SCHR 771/8-1 from the Deutsche Forschungsgemeinschaft, grant 394046635 - SFB 1365 from the Deutsche Forschungsgemeinschaft, and ECRC grants.
It was shown that hypertension delays SARS CoV-2 viral clearance and exacerbates airway hyperinflammation in the respiratory tract. However, it is unknown whether hypertension determines the ...long-term cellular and humoral response to SARS Cov2. Health care workers (HCWs) after an outbreak of SARS Cov-2 infections were analyzed. Infected HCWs were not vaccinated before blood collection. 5-14 months (median 7 months) after detection of SARS CoV-2 infection, blood was taken to analyze humoral response (S1 IgG and SARS CoV-2 neutralizing antibodies) and cellular (T cell responses to SARS-CoV-2 with Lymphocyte Transformation Test). To identify clinical factors that determine the immune response, a multivariate regression analysis was done considering age, BMI, sex, diabetes, hypertension, smoking, COPD, asthma and time between PCR positivity and blood collection as confounding factors. Infected hypertensive HCWs more often needed to be hospitalized than non-hypertensive HCWs, but were less likely to develop anosmia and myalgia. The long-term humoral and cellular immune response was significantly strengthened in hypertensive versus normotensive infected HCWs. Multivariate regression analysis revealed that hypertension was independently associated with the humoral response to SARS CoV-2 infection. Multivariate regression analysis using same confounding factors for the humoral response showed a clear trend for an association with the cellular response to SARS CoV-2 infection as well. In conclusion, SARS CoV-2 infection strengthened immune response to SARS CoV-2 infection in hypertensive HCWs independent of other risk factors.
Vitamin D contributes to blood pressure (BP) regulation. We compared the association of BP in diabetic patients with either total vitamin D - the standard way of analyzing the vitamin D status - or ...free vitamin D, because only free vitamin D passes the cell membrane and interacts with the nuclear vitamin D receptor (VDR). An analytical cross-sectional study was conducted with 178 diabetic patients with impaired kidney function. Free and total vitamin D concentrations were measured in all patients. Multiple linear regression analysis considering patient age, sex, body mass index, height, smoking and drinking situation, the use of antihypertensive drugs, cholecalciferol treatment, C-reactive protein and estimated glomerular filtration rate as confounding factors were conducted to compare the association of free and total vitamin D with systolic and diastolic blood pressure (SBP and DBP). Multiple linear regression analysis revealed that neither SBP nor DBP was correlated with total vitamin D (SBP, 95% CI -0.405 ~ 0.159, p = 0.390; DBP, 95% CI -0.131 ~ 0.142, p = 0.933) (Table 2). However, the concentration of free vitamin D was independently associated with SBP (95% CI -2.691 ~ -0.210; p = 0.022) (Table 3), but not with DBP (95% CI -0.934 ~ 0.285; p = 0.293). In conclusion, free - but not total - vitamin D serum concentrations in patients with diabetes and impaired kidney function are inversely correlated with SBP. This study suggests that free vitamin D measurements might be more clinically relevant - as compared to measurements of total vitamin D - to adjust vitamin D therapy in diabetic patients with impaired kidney function.
Vitamin D deficiency is very common in women of reproductive age. Studies in animals suggests a link between vitamin D and reproductive hormone biosynthesis. A systematic analysis of the correlation ...of reproductive hormones in reproductive-aged women with both total and free vitamin D was, however, not done so far. This cross-sectional study was performed in 351 healthy reproductive age Caucasian women (median age, 28.0 years; interquartile ranges, 24.7-31.0 years). We measured serum levels of both total and free 25(OH)D, endocrinological, hematological and biochemical parameters. Spearman's rank correlations were performed to assess the correlation between 25(OH)D metabolites and selected parameters. Total vitamin D and free vitamin D measurements correlated well (rho=0.912, p < 0.0001). Both total 25(OH)D and free 25(OH)D showed significant negative correlation with FAI (rho=-0.229, p<0.0001 and rho=-0.195, p<0.0001 for total and free 25(OH)D, respectively); LH (rho=-0.177, p=0.001 and rho=-0.114, p=0.04 for total and free 25(OH)D, respectively), testosterone (rho=-0.174, p=0.001 and rho=-0.190, p<0.0001 for total and free 25(OH)D, respectively) and AMH (rho=-0.130, p=0.015 and rho=-0.107, p=0.047 for total and free 25(OH)D, respectively). Our study showed comparable correlations of both total and free 25(OH)D with endocrinological parameters, i.e. inverse correlations with free androgen index, luteinizing hormone, testosterone, LH/FSH ratio, androstenedione and anti-Müllerian hormone, and also with hematological and biochemical parameters, i.e. inverse correlations with erythrocytes, hsCRP and leukocytes count, and positive correlation with transferrin saturation, mean corpuscular hemoglobin and mean corpuscular volume in healthy reproductive age women.
The CREDENCE trial testing canagliflozin and the EMPA-REG OUTCOME trial testing empagliflozin suggest different effects on acute kidney injury (AKI). AKI diagnosis was mainly made based on changes of ...serum creatinine (sCr) although this also reflect mode of action of SGLT-2 inhibitors. We analyzed both compounds in a rat AKI model. The renal ischemia-reperfusion injury (I/R) model was used. Four groups were analyzed: sham, I/R+placebo, I/R+canagliflozin (30 mg/kg/day), I/R+ empagliflozin (10 mg/kg/day). Glucose excretion was comparable in both treatment groups indicating comparable SGLT-2 inhibition. Comparing GFR surrogate markers after I/R (sCr and blood urea nitrogen (BUN)), sCr peaked 24 h after I/R, BUN after 48 h, respectively, in the placebo treated I/R group. At all investigated time points after I/R sCr and BUN was higher in the I/R + canagliflozin group as compared to placebo treated rats, whereas the empagliflozin group did not differ from the placebo group. I/R led to tubular dilatation and necrosis. Empagliflozin was able to reduce that finding whereas canagliflozin had no effect. Treatment with empagliflozin also resulted in a significant reduction in an improved inflammatory score (p = 0.006). Renal expression of kidney injury molecule-1 (KIM-1) increased after I/R and empagliflozin but not canagliflozin significantly alleviated KIM-1 expression. I/R reduced urinary miR-26a excretion. Empagliflozin but not canagliflozin was able to restore normal levels of urinary miR-26a. This study in an AKI model confirmed safety data in the EMPA-REG OUTCOME trial suggesting that empagliflozin might reduce AKI risk. The empagliflozin effects on KIM-1 and miR-26a might indicate beneficial regulation of inflammation. These data should stimulate clinical studies with AKI risk as primary endpoint.
Due to rare but major adverse reactions to the AstraZeneca adenoviral ChAdOx1-S-nCoV-19 vaccine (ChAd), German health authorities recommended adults under 60 who received one dose of ChAd, to receive ...a second dose of the BioNTech mRNA BNT162b2 vaccine (BNT) as a booster. Studies in the general population suggest an enhanced efficacy of the heterologous (ChAd-BNT) compared to the homologous (BNT-BNT) vaccination regimen. However, an analysis of the efficacy in patient populations with a high risk of severe COVID-19 due to acquired immunodeficiency is still missing. We therefore compared both vaccination regimens in healthy controls, patients with gynecological tumors after chemotherapy, patients on dialysis and patients with rheumatic diseases concerning the humoral and cellular immune response. The humoral and cellular immune response differed substantially in healthy controls compared to patients with acquired immunodeficiency. Overall, the most significant differences between the two immunization regimens were found in neutralizing antibodies. These were always higher after a heterologous immunization. Healthy controls responded well to both vaccination regimens. However, the formation of neutralizing antibodies was more pronounced after a heterologous immunization. Dialysis patients, on the other hand, only developed an adequate humoral and particularly cellular immune response after a heterologous immunization. Tumor and rheumatic patients also - to a weaker extent compared to dialysis patients - benefited from a heterologous immunization. In conclusion, the heterologous COVID-19 vaccination regimens (ChAd-BNT) seem to have an advantage over the homologous vaccination regimens, especially in immunocompromised patients such as patients with end-stage kidney disease treated with hemodialysis.
Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a sensitive and specific diagnostic test for acute kidney injury (AKI) in the Emergency Department (ED), but its economic impact has not ...been investigated. We hypothesized that uNGAL used in combination with serum creatinine (sCr) would reduce costs in the management of AKI in patients presenting to the ED in comparison to using sCr alone.
A cost simulation model was developed for clinical algorithms to diagnose AKI based on sCr alone vs. uNGAL plus sCr (uNGAL+sCr). A cost minimization analysis was performed to determine total expected costs for patients with AKI. uNGAL test characteristics were validated with eight-hundred forty-nine patients with sCr ≥1.5 from a completed study of 1635 patients recruited from EDs at two U.S. hospitals from 2007-8. Biomarker test, AKI work-up, and diagnostic imaging costs were incorporated.
For a hypothetical cohort of 10,000 patients, the model predicted that the expected costs were $900 per patient (pp) in the sCr arm and $950 in the uNGAL+sCr arm. uNGAL+sCr resulted in 1,578 fewer patients with delayed diagnosis and treatment than sCr alone (2,013 vs. 436 pts) at center 1 and 1,973 fewer patients with delayed diagnosis and treatment than sCr alone at center 2 (2,227 vs. 254 patients). Although initial evaluation costs at each center were $50 pp higher in with uNGAL+sCr, total costs declined by $408 pp at Center 1 and by $522 pp at Center 2 due to expected reduced delays in diagnosis and treatment. Sensitivity analyses confirmed savings with uNGAL + sCr for a range of cost inputs.
Using uNGAL with sCr as a clinical diagnostic test for AKI may improve patient management and reduce expected costs. Any cost savings would likely result from avoiding delays in diagnosis and treatment and from avoidance of unnecessary testing in patients given a false positive AKI diagnosis by use of sCr alone.
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