Effective management of glomerular kidney disease, one of the main categories of chronic kidney disease (CKD), requires accurate diagnosis, prognosis of progression, assessment of therapeutic ...efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for the assessment of specific aspects of glomerular diseases have been reported in the literature. Though, the vast majority of these have not been implemented in clinical practice or are not available on a global scale due to limited access, missing medical infrastructure, or economical as well as political reasons. The aim of this review is to compile all currently available information on the diagnostic, prognostic, and predictive biomarkers currently available for the management of glomerular diseases, and provide guidance on the application of these biomarkers. As a result of the compiled evidence for the different biomarkers available, we present a decision tree for a non-invasive, biomarker-guided diagnostic path. The data currently available demonstrate that for the large majority of patients with glomerular diseases, valid biomarkers are available. However, despite the obvious disadvantages of kidney biopsy, being invasive and not applicable for monitoring, especially in the context of rare CKD etiologies, kidney biopsy still cannot be replaced by non-invasive strategies.
Kidney fibrosis is a major culprit in the development and progression of chronic kidney disease (CKD), ultimately leading to the irreversible loss of organ function. Thymocyte differentiation ...antigen-1 (Thy-1) controls many core functions of fibroblasts relevant to fibrogenesis but is also found in a soluble form (sThy-1) in serum and urine. We investigated the association of sThy-1 with clinical parameters in patients with CKD receiving hemodialysis treatment compared to individuals with a preserved renal function. Furthermore, Thy-1 tissue expression was detected in a mouse model of diabetic CKD (eNOS
; db/db) and non-diabetic control mice (eNOS
). Serum and urinary sThy-1 concentrations significantly increased with deteriorating renal function, independent of the presence of diabetes. Serum creatinine is the major, independent, and inverse predictor of serum sThy-1 levels. Moreover, sThy-1 is not only predicted by markers of renal function but is also itself an independent and strong predictor of markers of renal function, i.e., serum creatinine. Mice with severe diabetic CKD show increased
-1 mRNA and protein expression in the kidney compared to control animals, as well as elevated urinary sThy-1 levels. Pro-fibrotic mediators, such as interleukin (IL)-4, IL-13, IL-6 and transforming growth factor β, increase
-1 gene expression and release of sThy-1 from fibroblasts. Our data underline the role of Thy-1 in the control of kidney fibrosis in CKD and raise the opportunity that Thy-1 may function as a renal antifibrotic factor.
Non-invasive urinary peptide biomarkers are able to detect and predict chronic kidney disease (CKD). Moreover, specific urinary peptides enable discrimination of different CKD etiologies and offer an ...interesting alternative to invasive kidney biopsy, which cannot always be performed. The aim of this study was to define a urinary peptide classifier using mass spectrometry technology to predict the degree of renal interstitial fibrosis and tubular atrophy (IFTA) in CKD patients. The urinary peptide profiles of 435 patients enrolled in this study were analyzed using capillary electrophoresis coupled with mass spectrometry (CE-MS). Urine samples were collected on the day of the diagnostic kidney biopsy. The proteomics data were divided into a training (
= 200) and a test (
= 235) cohort. The fibrosis group was defined as IFTA ≥ 15% and no fibrosis as IFTA < 10%. Statistical comparison of the mass spectrometry data enabled identification of 29 urinary peptides with differential occurrence in samples with and without fibrosis. Several collagen fragments and peptide fragments of fetuin-A and others were combined into a peptidomic classifier. The classifier separated fibrosis from non-fibrosis patients in an independent test set (
= 186) with area under the curve (AUC) of 0.84 (95% CI: 0.779 to 0.889). A significant correlation of IFTA and FPP_BH29 scores could be observed Rho = 0.5,
< 0.0001. We identified a peptidomic classifier for renal fibrosis containing 29 peptide fragments corresponding to 13 different proteins. Urinary proteomics analysis can serve as a non-invasive tool to evaluate the degree of renal fibrosis, in contrast to kidney biopsy, which allows repeated measurements during the disease course.
Abstract
Background
There is evidence of pre-established vulnerability in individuals that increases the risk of their progression to severe disease or death, although the mechanisms causing this are ...still not fully understood. Previous research has demonstrated that a urinary peptide classifier (COV50) predicts disease progression and death from SARS-CoV-2 at an early stage, indicating that the outcome prediction may be partly due to vulnerabilities that are already present. The aim of this study is to examine the ability of COV50 to predict future non-COVID-19-related mortality, and evaluate whether the pre-established vulnerability can be generic and explained on a molecular level by urinary peptides.
Methods
Urinary proteomic data from 9193 patients (1719 patients sampled at intensive care unit (ICU) admission and 7474 patients with other diseases (non-ICU)) were extracted from the Human Urinary Proteome Database. The previously developed COV50 classifier, a urinary proteomics biomarker panel consisting of 50 peptides, was applied to all datasets. The association of COV50 scoring with mortality was evaluated.
Results
In the ICU group, an increase in the COV50 score of one unit resulted in a 20% higher relative risk of death adjusted HR 1.2 (95% CI 1.17–1.24). The same increase in COV50 in non-ICU patients resulted in a higher relative risk of 61% adjusted HR 1.61 (95% CI 1.47–1.76), consistent with adjusted meta-analytic HR estimate of 1.55 95% CI 1.39–1.73. The most notable and significant changes associated with future fatal events were reductions of specific collagen fragments, most of collagen alpha I (I).
Conclusion
The COV50 classifier is predictive of death in the absence of SARS-CoV-2 infection, suggesting that it detects pre-existing vulnerability. This prediction is mainly based on collagen fragments, possibly reflecting disturbances in the integrity of the extracellular matrix. These data may serve as a basis for proteomics-guided intervention aiming towards manipulating/ improving collagen turnover, thereby reducing the risk of death.
Multidrug-resistant Gram-negative bacteria (MDRGN) are found with rising prevalence in non-hemodialysis risk populations as well as hemodialysis (HD) cohorts in Asia, Europe and North America. At the ...same time, colonization and consecutive infections with such pathogens may increase mortality and morbidity of affected individuals. We aimed to monitor intestinal MDRGN colonization in a yet not investigated German HD population.
We performed cross-sectional point-prevalence testing with 12 months follow-up and selected testing of relatives in an out-patient HD cohort of n = 77 patients by using microbiological cultures from fresh stool samples, combined with Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF-MS) and antimicrobial susceptibility testing.
We detected MDRGN in 8 out of 77 patients (10.4%) and 1 out of 22 relatives (4.5%), indicating only colonization and no infections. At follow-up, 2 patients showed phenotypic persistence of MDRGN colonization, and in 6 other patients de-novo MDRGN colonization could be demonstrated. Pathogens included Escherichia coli and Klebsiella pneumoniae (with extended-spectrum beta-lactamase ESBL-production as well as fluoroquinolone resistance), Stenotrophomonas maltophilia and Enterobacter cloacae.
In a single-center study, MDRGN colonization rates were below those found in non-HD high-risk populations and HD units in the US, respectively. Reasons for this could be high hygiene standards and a strict antibiotic stewardship policy with evidence of low consumption of fluoroquinolones and carbapenems in our HD unit and the affiliated hospital.
Summary
Objective
Fibroblast growth factor (FGF)‐21 has recently been introduced as a circulating adipokine which reverses insulin resistance and obesity in rodents. In this study, regulation of ...FGF‐21 in renal dysfunction was elucidated in both chronic kidney disease (CKD) and acute kidney dysfunction (AKD).
Study design and methods
Serum concentrations of total FGF‐21 were quantified by enzyme‐linked immunosorbent assay in 499 patients with CKD stages 1–5 (study population 1). Furthermore, total FGF‐21 was determined before and within 30 h after unilateral nephrectomy, a model of AKD, in 32 patients (study population 2). FGF‐21 levels were correlated to anthropometric and biochemical parameters of renal function, glucose and lipid metabolism, as well as inflammation, in both studies.
Results
In study population 1, median interquartile range circulating FGF‐21 adjusted for age, gender and body mass index was significantly different between CKD stages with highest values detectable in stage 5 (stage 1: 86·4 132·9; 2: 206·4 223·1; 3: 289·8 409·3; 4: 591·3 789·0; 5: 1918·1 4157·0 ng/l). Furthermore, estimated glomerular filtration rate remained a strong independent and negative predictor of FGF‐21. In study population 2, FGF‐21 increased significantly postsurgically (325·0 984·0 ng/l) as compared to presurgical values (255·5 243·0 ng/l). Furthermore, relative changes of FGF‐21 were independently and positively predicted by relative changes of creatinine.
Conclusions
We demonstrate that circulating FGF‐21 is increased in both CKD and AKD. Our results suggest renal excretion as a major route for FGF‐21 elimination. The pathophysiological significance of these findings needs to be elucidated in more detail.
SARS‐CoV‐2 infection results in a mild‐to‐moderate disease course in most patients, allowing outpatient self‐care and quarantine. However, in ≈10% of cases a two‐ or three‐phasic critical disease ...course with starting from day 7 to 10 is observed. To facilitate and plan outpatient care, biomarkers prognosing such worsening at an early stage appear of outmost importance. In this accelerated article, the identification of urinary peptides significantly associated with SARS‐CoV‐2 infection, and the development of a multi‐marker urinary peptide based test, COVID20, that may enable prognosis of critical and fatal outcomes in COVID‐19 patients is reported. COVID20 is composed of 20 endogenous peptides mainly derived from various collagen chains that enable differentiating moderate or severe disease from critical state or death with 83% sensitivity at 100% specificity. Based on the performance in this pilot study, testing in a prospective study on 1000 patients has been initiated.
Previous trials have demonstrated clinically significant and durable reductions in arterial pressure from baroreflex activation therapy (BAT), resulting from electrical stimulation of the carotid ...sinus using a novel implantable device. A second-generation system for delivering BAT, the Barostim neo™ system, has been designed to deliver BAT with a simpler device and implant procedure.
BAT, delivered with the advanced system, was evaluated in a single-arm, open-label study of patients with resistant hypertension, defined as resting systolic blood pressure (SBP) ≥140 mm Hg despite treatment with ≥3 medications, including ≥1 diuretic. Stable medical therapy was required for ≥4 weeks before establishing pretreatment baseline by averaging two SBP readings taken ≥24 hours apart.
Thirty patients enrolled from seven centers in Europe and Canada. From a baseline of 171.7 ± 20.2/99.5 ± 13.9 mm Hg, arterial pressure decreased by 26.0 ± 4.4/12.4 ± 2.5 mm Hg at 6 months. In a subset (n = 6) of patients with prior renal nerve ablation, arterial pressure decreased by 22.3 ± 9.8 mm Hg. Background medical therapy for hypertension was unchanged during follow-up. Three minor procedure-related complications occurred within 30 days of implant. All complications resolved without sequelae.
BAT delivered with the second-generation system significantly lowers blood pressure in resistant hypertension with stable, intensive background medical therapy, consistent with studies of the first-generation system for electrical activation of the baroreflex, and provides a safety profile comparable to a pacemaker.
Patients with kidney failure (KF) have a high incidence of cardiovascular (CV) disease, partly driven by insufficient clearance of uremic toxins. Recent investigations have questioned the accepted ...effects of adverse lipid profile and CV risk in uremic patients. Therefore, we related a panel of uremic toxins previously associated with CV morbidity/mortality to a full lipid profile in a large, tri-national, cross-sectional cohort. Total, high-density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL), and remnant cholesterol, as well as triglyceride, levels were associated with five uremic toxins in a cohort of 611 adult KF patients with adjustment for clinically relevant covariates and other patient-level variables. Univariate analyses revealed negative correlations of total, non-HDL, and LDL cholesterol with all investigated uremic toxins. Multivariate linear regression analyses confirmed independent, negative associations of phenylacetylglutamine with total, non-HDL, and LDL cholesterol, while indole-3 acetic acid associated with non-HDL and LDL cholesterol. Furthermore, trimethylamine-N-Oxide was independently and negatively associated with non-HDL cholesterol. Sensitivity analyses largely confirmed findings in the entire cohort. In conclusion, significant inverse associations between lipid profile and distinct uremic toxins in KF highlight the complexity of the uremic milieu, suggesting that not all uremic toxin interactions with conventional CV risk markers may be pathogenic.
This study compared the immunogenicity and safety of a booster dose of HepB-CpG (HEPLISAV-B® vaccine) with HepB-Eng (Engerix-B®) and HepB-AS04 (Fendrix®) in patients receiving chronic hemodialysis. ...This was a multicenter, randomized, open-label, phase 3 study of adults receiving hemodialysis with antibodies to HBsAg (anti-HBs) <10 mIU/mL at study entry. The objective was to compare the seroprotection rate (SPR) induced by HepB-CpG with HepB-Eng or HepB-AS04. The SPR was defined as the percentage of patients with anti-HBs ≥10 mIU/mL post-vaccination. At 20 sites in Germany, 155 participants were randomized: HepB-CpG = 54; HepB-Eng = 50; and HepB-AS04 = 51. Of the 149 participants in the modified intention-to-treat population, 76.5% had not previously responded to at least one series of hepatitis B vaccine. Based on a post hoc analysis, the SPR in HepB-CpG recipients (52.8%; 95% confidence interval CI: 38.6%, 66.7%) was significantly higher than in HepB-Eng recipients (32.6%; 95% CI: 19.5%, 48.0%), and non-inferior to that in HepB-AS04 recipients (43.1%; 95% CI: 29.3%, 57.8%). Local post-injection reactions occurred in significantly fewer HepB-CpG (9.3%) than HepB-AS04 recipients (31.4%; p = .007) and at a similar rate to HepB-Eng recipients (8.2%). Systemic post-injection reactions in HepB-CpG recipients (18.5%) were similar to the HepB-AS04 group (19.6%) and higher than in the HepB-Eng group (12.2%). In this difficult-to-immunize population, a booster dose of HepB-CpG induced significantly higher levels of seroprotection than HepB-Eng with a similar safety profile. The higher levels of immunogenicity were not accompanied by higher levels of local post-injection reactions compared with HepB-AS04.
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