Little is known about sex- and age-specific variations and temporal trends in serum uric acid (SUA) concentrations, the prevalence of hyperuricemia and its association with metabolic risk factors in ...the general population. Between January 1, 1985 and June 30, 2005 146,873 participants (42% women) were recruited. Prevalence of hyperuricemia was estimated applying a common (SUA > 360 µmol/L) and sex-specific cut-off points (women > 340 µmol/L, men > 420 µmol/L). At baseline, mean age was 41.2 years in men and 51.5 years in women, mean SUA concentration was 314.8 µmol/L and 243.6 µmol/L, respectively. Applying a common cut-off point, the prevalence of hyperuricemia was 18.5% in men and 4.4% in women and by sex-specific cut-off points it was 15.1% and 13.8%, respectively. SUA levels increased by 6.7 µmol/L per decade in men, but remained constant in women until the age of 50 years with a sharp increase by approximately 22 µmol/L per decade thereafter. In men and women, hyperuricemia was associated with obesity, hypertriglyceridemia and elevated gamma-glutamyl transferase. With increasing age SUA levels and the prevalence of hyperuricemia rise in a sex-specific manner. Above the age of 65 years, the sex-specific prevalence of hyperuricemia in women outreaches that in men.
Uromodulin (Tamm-Horsfall protein) is produced in the kidney by cells of the thick ascending limb and distal tubule. Recent genetic studies suggest a role of uromodulin in chronic kidney disease. ...Mutations in the UMOD gene cause uromodulin storage disease. They code for amino acid substitutions that lead to misfolding of the molecule and its retention in the endoplasmic reticulum. Single nucleotide polymorphisms in the region of the UMOD gene have been shown to be associated with chronic kidney disease and reduced glomerular filtration rate. These polymorphisms affect uromodulin concentration in the urine, and lower genetically determined urinary uromodulin concentrations seem to protect against renal disease. Chronic kidney disease is associated with higher serum levels of uromodulin. From animal experiments and human studies it is hypothesized that uromodulin entering the renal interstitium either by basolateral secretion or urinary back-leakage in damaged tubuli interacts with and stimulates cells of the immune system and thereby causes inflammation and progression of chronic kidney disease.
Hemodialysis patients are at high risk for severe COVID-19. SARS-CoV-2 vaccination related safety and immunogenicity data in these patients are rare.
In this observational study ...SARS-CoV-2-seronegative hemodialysis patients were vaccinated with two doses of the Pfizer/BioNTech mRNA-BNT162b2 vaccine (COMIRNATY
30 µg) and followed for 90 days. Local and systemic side effects were assessed at every dialysis session during the first post-vaccination week after the first and second vaccine dose. Immunogenicity was determined four weeks after vaccination by quantifying anti-SARS-CoV-2 spike protein IgG antibodies (LIAISON
SARS-CoV-2-TrimericS IgG chemiluminescent immunoassay) expressed in binding activity units per milliliter (BAU/mL) adapted to the WHO International standard.
Fifty patients (32% women, 68% men) with a mean (SD) age of 67.6 (14.8) years were included. Mild local reactions occurred in 38% after the first injection, and in 29.2% with mild, in 2.1% with moderate and in 2.1% with severe degree after the second injection. Systemic reactive events occurred less often, with diarrhea (4% mild, 4% moderate) and fatigue (8% mild) being the most frequent ones. After the first injection 42% of the patients developed a positive response using the assay specific cut-off value of 33.8 binding activity units per milliliter (BAU/mL) with a median (Q1, Q3) anti-SARS-CoV-2 spike IgG concentration of 20.0 (11.7, 51.0) BAU/mL. After the second injection the percentage of seropositive patients increased to 97.9% with an anti-SARS-CoV-2 spike IgG concentration of 1075 (290.8, 1735) BAU/mL. Higher age and immunosuppression were associated with lower, calcitriol treatment and prior seroconversion to hepatitis B vaccination with significantly higher antibody concentration.
The mRNA-BNT162b2 SARS-CoV-2 vaccine appears to be safe and well-tolerated and shows a high immunogenicity in hemodialysis patients.
Background
Due to the waning humoral response after a two-dose SARS-CoV-2 mRNA vaccination, a third booster was recommended in hemodialyis patients. Data on a heterologous mRNA-vector regimen, which ...might improve immunogenicity, are very limited.
Methods
In this observational study 36 chronic hemodialysis patients (mean (SD) age 66.9 (15.9) years, 33.3% females) were followed up for 13 months. All patients were vaccinated twice using the mRNA-BNT162b2 vaccine, followed by a 3
rd
dose of the vector vaccine Ad26COVS1 eight months later. We assessed the humoral response by quantifying the anti-SARS-CoV-2 spike IgG antibody and neutralizing antibody concentrations. The cellular immune response was evaluated
via
SARS-CoV-2 spike protein-specific interferon-γ release assay.
Results
The seroconversion rate was 47.2%, 100%, 69.4% and 100% one month after the 1
st
dose, one and six months after the 2
nd
dose and four months after the heterologous 3
rd
dose. The median (Q1, Q3) anti-SARS-CoV-2 spike IgG concentrations at the same time were 28.7 (13.2, 69.4) BAU/ml, 1130.0 (594.5, 1735.0) BAU/ml, 89.7 (26.4, 203.8) BAU/ml, and 2080.0 (1062.5, 2080.0) BAU/ml. The percentage of patients with neutralizing antibodies was 58.3% after the 2
nd
dose and improved to 100% after the 3
rd
dose (
P <
0.001). A positive T-cell response was found in 50% of patients after the 3
rd
dose.
Conclusions
A third heterologous booster dose helped to sustain humoral immunity in almost all hemodialysis patients and induced a significant T-cellular response in half of them. Stimulating the immune response against SARS-CoV-2 by two different vaccine platforms seems to be a promising approach.
We investigated the association between metabolic factors and End-Stage Renal Disease (ESRD) and quantified the magnitude of their influence dependent on sex and time of exposure up to 20 years.
A ...prospective cohort study was conducted to determine risk factors for the development of ESRD. From 1988 to 2005 185,341 persons (53.9% women) participated in the "Vorarlberg Health Monitoring and Promotion Programme" (VHM&PP). Data on body mass index (BMI), fasting blood glucose (FBG), systolic (BPsys) and diastolic (BPdia) blood pressure, total cholesterol (TC), triglycerides (TG), gamma-glutamyltransferase (GGT) and smoking status were collected. Data of the population-based VHM&PP were merged with the Austrian Dialysis and Transplant Registry. Cox proportional hazards models were applied to calculate hazard ratios (HRs) for ESRD, stratified by sex and 5-year time intervals.
During a mean follow-up of 17.5 years 403 patients (39.1% women) developed ESRD. Significant risk factors were: BMI (per 1 kg/m2) HR 1.04 (95% CI 1.01-1.06), FBG (per 1 mmol/L) HR 1.09 (1.05-1.12), BPsys (per 5 mmHg) HR 1.10 (1.07-1.14), BPdia (per 5 mmHg) HR 1.09 (1.03-1.15), TG (per 1 mmol/L) HR 1.07 (1.02-1.13), TC (per 1 mmol/L) HR 1.22 (1.13-1.32). We observed a sex-specific risk pattern with an increased ESRD risk for men for increasing TG and smoking, and for women for increasing BMI and GGT. In time interval analyses BPsys and TC were associated with early ESRD onset, whereas BMI, FBG, BPdia and GGT were associated with later onset.
Anthropometric and metabolic factors are differentially associated with the long-term risk for ESRD in a sex- and time-dependent manner. Consideration of these patterns in preventive and therapeutic strategies could have an impact on ESRD incidence.
Complement research experienced a renaissance with the discovery of a third activation route, the lectin pathway. We developed a unique model of total lectin pathway deficiency, a mouse strain ...lacking mannan-binding lectin-associated serine protease-2 (MASP-2), and analyzed the role of MASP-2 in two models of postischemic reperfusion injury (IRI). In a model of transient myocardial IRI, MASP-2-deficient mice had significantly smaller infarct volumes than their wild-type littermates. Mice deficient in the downstream complement component C4 were not protected, suggesting the existence of a previously undescribed lectin pathway-dependent C4-bypass. Lectin pathway-mediated activation of C3 in the absence of C4 was demonstrated in vitro and shown to require MASP-2, C2, and MASP-1/3. MASP-2 deficiency also protects mice from gastrointestinal IRI, as do mAb-based inhibitors of MASP-2. The therapeutic effects of MASP-2 inhibition in this experimental model suggest the utility of anti-MASP-2 antibody therapy in reperfusion injury and other lectin pathway-mediated disorders.
Anti-glomerular basement membrane disease (GBM) disease is a rare autoimmune disease causing rapidly progressive glomerulonephritis and pulmonary haemorrhage. Recently, an association between ...COVID-19 and anti-glomerular basement membrane (anti-GBM) disease has been proposed. We report on a patient with recurrence of anti-GBM disease after SARS-CoV-2 infection.
The 31-year-old woman had a past medical history of anti-GBM disease, first diagnosed 11 years ago, and a first relapse 5 years ago. She was admitted with severe dyspnoea, haemoptysis, pulmonary infiltrates and acute on chronic kidney injury. A SARS-CoV-2 PCR was positive with a high cycle threshold. Anti-GBM autoantibodies were undetectable. A kidney biopsy revealed necrotising crescentic glomerulonephritis with linear deposits of IgG, IgM and C3 along the glomerular basement membrane, confirming a recurrence of anti-GBM disease. She was treated with steroids, plasma exchange and two doses of rituximab. Pulmonary disease resolved, but the patient remained dialysis-dependent. We propose that pulmonary involvement of COVID-19 caused exposure of alveolar basement membranes leading to the production of high avidity autoantibodies by long-lived plasma cells, resulting in severe pulmonary renal syndrome.
Our case supports the assumption of a possible association between COVID-19 and anti-GBM disease.
Anthropometric and metabolic risk factors for all-cause end-stage renal disease (ESRD) may vary in their impact depending on the specific primary renal disease.
In this Austrian population-based ...prospective cohort study (n = 185,341; 53.9% women) the following data were collected between 1985 and 2005: age, sex, body mass index (BMI), fasting blood glucose (FBG) from 1988, blood pressure, total cholesterol (TC), triglycerides (TG), gamma-glutamyl transferase (GGT) and smoking status. These data were merged with the Austrian Dialysis and Transplant Registry to identify ESRD patients. Cox proportional hazards models were applied to calculate hazard ratios (HR) for all-cause ESRD as well as for cause-specific ESRD due to the following primary renal diseases: autosomal dominant polycystic kidney disease (ADPKD), vascular nephropathy (VN), diabetic nephropathy (DN) and other diseases (OD).
During a mean follow-up of 17.5 years 403 participants developed ESRD (ADPKD 36, VN 97, DN 86, and OD 184). All parameters except TG and GGT were significantly associated with all-cause ESRD risk. Particular cause-specific ESRD risk factor patterns were found: for ADPKD increased risk from hypertension (HR 11.55); for VN from smoking (HR 1.81), hypertension (HR 2.37), TG (≥5.70 vs. <1.17 mmol/L: HR 9.27); for DN from smoking (HR 1.77), BMI (≥30 vs. 18.5-24.9 kg/m2: HR 7.55), FBG (≥6.94 vs. <5.55 mmol/L: HR 7.67), hypertension (HR 1.08), TG (≥5.70 vs. <1.17 mmol/L: HR 2.02), GGT (HR 2.14); and for OD from hypertension (HR 2.29), TG (≥5.70 vs. <1.17 mmol/L: HR 6.99) and TC (≥6.22 vs. <5.18 mmol/L: HR 1.56).
Particular anthropometric and metabolic ESRD risk factors differ in importance depending on the primary renal disease. This needs to be considered for future preventive and therapeutic strategies addressing cause-specific ESRD.
Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators ...factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.
Studies on the association between iron supplementation and mortality in dialysis patients are rare and conflicting.
In our observational single-center cohort study (INVOR study) we prospectively ...studied 235 incident dialysis patients. Time-dependent Cox proportional hazards models using all measured laboratory values for up to 7.6 years were applied to study the association between iron supplementation and all-cause mortality, cardiovascular and sepsis-related mortality. Furthermore, the time-dependent association of ferritin levels with mortality in patients with normal C-reactive protein (CRP) levels (<0.5 mg/dL) and elevated CRP levels (≧0.5 mg/dL) was evaluated by using non-linear P-splines to allow flexible modeling of the association.
One hundred and ninety-one (81.3%) patients received intravenous iron, 13 (5.5%) patients oral iron, whereas 31 (13.2%) patients were never supplemented with iron throughout the observation period. Eighty-two (35%) patients died during a median follow-up of 34 months, 38 patients due to cardiovascular events and 21 patients from sepsis. Baseline CRP levels were not different between patients with and without iron supplementation. However, baseline serum ferritin levels were lower in patients receiving iron during follow up (median 93 vs 251 ng/mL, p<0.001). Iron supplementation was associated with a significantly reduced all-cause mortality HR (95%CI): 0.22 (0.08-0.58); p = 0.002 and a reduced cardiovascular and sepsis-related mortality HR (95%CI): 0.31 (0.09-1.04); p = 0.06. Increasing ferritin concentrations in patients with normal CRP were associated with a decreasing mortality, whereas in patients with elevated CRP values ferritin levels>800 ng/mL were linked with increased mortality.
Iron supplementation is associated with reduced all-cause mortality in incident dialysis patients. While serum ferritin levels up to 800 ng/mL appear to be safe, higher ferritin levels are associated with increased mortality in the setting of concomitant inflammation.
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