Assessment and Risk Prediction of Chronic Kidney Disease and Kidney Fibrosis Using Non-Invasive Biomarkers.

Effective management of chronic kidney disease (CKD), a major health problem worldwide, requires accurate and timely diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for evaluating specific aspects of CKD have been proposed in the literature, many of which are based on a small number of samples. Based on the evidence presented in relevant studies, a comprehensive overview of the different biomarkers applicable for clinical implementation is lacking. This review aims to compile information on the non-invasive diagnostic, prognostic, and predictive biomarkers currently available for the management of CKD and provide guidance on the application of these biomarkers. We specifically focus on biomarkers that have demonstrated added value in prospective studies or those based on prospectively collected samples including at least 100 subjects. Published data demonstrate that several valid non-invasive biomarkers of potential value in the management of CKD are currently available.

Non-Invasive Biomarkers for Diagnosis, Risk Prediction, and Therapy Guidance of Glomerular Kidney Diseases: A Comprehensive Review.

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.

Differentiating primary and secondary FSGS using non-invasive urine biomarkers.

Background: Focal segmental glomerulosclerosis (FSGS) is divided into genetic, primary (p), uncertain cause, and secondary (s) forms. The subclasses differ in management and prognosis with differentiation often being challenging. We aimed to identify specific urine proteins/peptides discriminating between clinical and biopsy-proven pFSGS and sFSGS. Methods: Sixty-three urine samples were collected in two different centers (19 pFSGS and 44 sFSGS) prior to biopsy. Samples were analysed using capillary electrophoresis-coupled mass spectrometry. For biomarker definition, datasets of age-/sex-matched normal controls (NC, n = 98) and patients with other chronic kidney diseases (CKDs, n = 100) were extracted from the urinary proteome database. Independent specificity assessment was performed in additional data of NC (n = 110) and CKD (n = 170). Results: Proteomics data from patients with pFSGS were first compared to NC (n = 98). This resulted in 1179 biomarker (P < 0.05) candidates. Then, the pFSGS group was compared to sFSGS, and in a third step, pFSGS data were compared to data from different CKD etiologies (n = 100). Finally, 93 biomarkers were identified and combined in a classifier, pFSGS93. Total cross-validation of this classifier resulted in an area under the receiving operating curve of 0.95. The specificity investigated in an independent set of NC and CKD of other etiologies was 99.1% for NC and 94.7% for CKD, respectively. The defined biomarkers are largely fragments of different collagens (49%). Conclusion: A urine peptide-based classifier that selectively detects pFSGS could be developed. Specificity of 95%-99% could be assessed in independent samples. Sensitivity must be confirmed in independent cohorts before routine clinical application.

Revisiting aortic valve prosthesis choice in patients younger than 50 years: 10 years results of the AUTHEARTVISIT study.

OBJECTIVES: This population-based cohort study investigated mid-term outcome after surgical aortic valve replacement with a bioprosthetic or mechanical valve prosthesis in patients aged <50 years in a European social welfare state. METHODS: We analysed patient data from the main social insurance carriers in Austria (2010-2020). Subsequent patient-level record linkage with national health data provided patient characteristics and clinical outcome. Survival, reoperation, myocardial infarction, heart failure, embolic stroke or intracerebral haemorrhage, bleeding other than intracerebral haemorrhage and major adverse cardiac events were evaluated as outcomes. RESULTS: A total of 991 patients were analysed. Regarding demographics, no major differences between groups were observed. Multivariable Cox regression revealed no significant difference in overall survival (P = 0.352) with a median follow-up time of 6.2 years. Reoperation-free survival was decreased (hazard ratio = 1.560 [95% CI: 1.076-2.262], P = 0.019) and the risk for reoperation was increased (hazard ratio = 2.770 [95% CI: 1.402-5.472], P = 0.003) in patients who received bioprostheses. Estimated probability of death after reoperation was 0.23 (CL: 0.08-0.35) after 2 years and 0.34 (CL: 0.06-0.53) after 10 years over both groups. Regarding further outcomes, no significant differences between the two groups were observed. CONCLUSIONS: In patients below 50 years of age receiving aortic valve replacement, implantation of bioprostheses when compared to mechanical heart valve prostheses was associated with a significantly higher rate of reoperations and reduced reoperation-free survival. Nevertheless, we could not observe a difference in overall survival. However, long-term follow-up has to evaluate that a significantly lower rate of reoperations may translate in consistently improved long-term survival.

Glycosylation of bacterial antigens changes epitope patterns.

Introduction: Unlike glycosylation of proteins expressed in mammalian systems, bacterial glycosylation is often neglected in the development of recombinant vaccines. Methods: Here, we compared the effects of glycosylation of YghJ, an Escherichia coli protein important for mucus attachment of bacteria causing in urinary tract infections (UTIs). A novel method based on statistical evaluation of phage display for the identification and comparison of epitopes and mimotopes of anti-YghJ antibodies in the sera was used. This is the first time that the effect of glycosylation of a recombinant bacterial antigen has been studied at the peptide epitope level. Results: The study identifies differences in the immune response for (non)-glycosylated antigens in rabbits and pigs and compares them to a large group of patients with UTI, which have been diagnosed as positive for various bacterial pathogens. We identified glycosylation-specific peptide epitopes, a large immunological similarity between different UTI pathogens, and a broad peptide epitope pattern in patients and animals, which could result in a variable response in patients upon vaccination. Discussion: This epitope analysis indicates that the vaccination of rabbits and pigs raises antibodies that translate well into the human immune system. This study underlines the importance of glycosylation in bacterial vaccines and provides detailed immune diagnostic methods to understand individual immune responses to vaccines.

Use of Urea for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone: A Systematic Review.

Importance: Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are associated with significant mortality and morbidity. The effectiveness and safety of oral urea for SIADH are still debated. Objective: To evaluate the efficacy and safety of urea for the treatment of SIADH. Evidence Review: A systematic search of Medline and Embase was conducted for controlled and uncontrolled studies of urea for SIADH in adult patients. The primary outcome was serum sodium concentration after treatment. Secondary outcomes included the proportion of patients with osmotic demyelination syndrome (ODS), intracranial pressure, and resource use such as length of stay. Findings: Twenty-three studies involving 537 patients with SIADH were included, of which 462 were treated with urea. The pooled mean baseline serum sodium was 125.0 mmol/L (95% CI, 122.6-127.5 mmol/L). The median treatment duration with oral urea was 5 days. Urea increased serum sodium concentration by a mean of 9.6 mmol/L (95% CI, 7.5-11.7 mmol/L). The mean increase in serum sodium after 24 hours was 4.9 mmol/L (95% CI, 0.5-9.3 mmol/L). Adverse events were few, mainly consisting of distaste or dysgeusia, and no case of ODS was reported. Resource use was too infrequently reported to be synthesized. Conclusions and Relevance: In this systematic review of the use of urea in SIADH and despite the lack of randomized clinical trials, lower-quality evidence was identified that suggests that urea may be an effective, safe, and inexpensive treatment modality that warrants further exploration.

Recent Advances in Urinary Peptide and Proteomic Biomarkers in Chronic Kidney Disease: A Systematic Review.

Biomarker development, improvement, and clinical implementation in the context of kidney disease have been a central focus of biomedical research for decades. To this point, only serum creatinine and urinary albumin excretion are well-accepted biomarkers in kidney disease. With their known blind spot in the early stages of kidney impairment and their diagnostic limitations, there is a need for better and more specific biomarkers. With the rise in large-scale analyses of the thousands of peptides in serum or urine samples using mass spectrometry techniques, hopes for biomarker development are high. Advances in proteomic research have led to the discovery of an increasing amount of potential proteomic biomarkers and the identification of candidate biomarkers for clinical implementation in the context of kidney disease management. In this review that strictly follows the PRISMA guidelines, we focus on urinary peptide and especially peptidomic biomarkers emerging from recent research and underline the role of those with the highest potential for clinical implementation. The Web of Science database (all databases) was searched on 17 October 2022, using the search terms "marker *" OR biomarker * AND "renal disease" OR "kidney disease" AND "proteome *" OR "peptid *" AND "urin *". English, full-text, original articles on humans published within the last 5 years were included, which had been cited at least five times per year. Studies based on animal models, renal transplant studies, metabolite studies, studies on miRNA, and studies on exosomal vesicles were excluded, focusing on urinary peptide biomarkers. The described search led to the identification of 3668 articles and the application of inclusion and exclusion criteria, as well as abstract and consecutive full-text analyses of three independent authors to reach a final number of 62 studies for this manuscript. The 62 manuscripts encompassed eight established single peptide biomarkers and several proteomic classifiers, including CKD273 and IgAN237. This review provides a summary of the recent evidence on single peptide urinary biomarkers in CKD, while emphasizing the increasing role of proteomic biomarker research with new research on established and new proteomic biomarkers. Lessons learned from the last 5 years in this review might encourage future studies, hopefully resulting in the routine clinical applicability of new biomarkers.

Dynamics of urine proteomics biomarker and disease progression in patients with IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) frequently leads to kidney failure. The urinary proteomics-based classifier IgAN237 may predict disease progression at the time of kidney biopsy. We studied whether IgAN237 also predicts progression later in the course of IgAN. METHODS: Urine from patients with biopsy-proven IgAN was analyzed using capillary electrophoresis-mass spectrometry at baseline (IgAN237-1, n = 103) and at follow-up (IgAN237-2, n = 89). Patients were categorized as "non-progressors" (IgAN237 ≤0.38) and "progressors" (IgAN237 >0.38). Estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio slopes were calculated. RESULTS: Median age at biopsy was 44 years, interval between biopsy and IgAN237-1 was 65 months and interval between IgAN237-1 and IgAN237-2 was 258 days (interquartile range 71-531). IgAN237-1 and IgAN237-2 values did not differ significantly and were correlated (rho = 0.44, P < .001). Twenty-eight percent and 26% of patients were progressors based on IgAN237-1 and IgAN237-2, respectively. IgAN237 inversely correlated with chronic eGFR slopes (rho = -0.278, P = .02 for score-1; rho = -0.409, P = .002 for score-2) and with ±180 days eGFR slopes (rho = -0.31, P = .009 and rho = -0.439, P = .001, respectively). The ±180 days eGFR slopes were worse for progressors than for non-progressors (median -5.98 versus -1.22 mL/min/1.73 m2 per year for IgAN237-1, P < .001; -3.02 vs 1.08 mL/min/1.73 m2 per year for IgAN237-2, P = .0047). In multiple regression analysis baseline progressor/non-progressor according to IgAN237 was an independent predictor of eGFR180days-slope (P = .001). CONCLUSION: The urinary IgAN237 classifier represents a risk stratification tool in IgAN also later in the course of the dynamic disease. It may guide patient management in an individualized manner.

Antifibrotic Soluble Thy-1 Correlates with Renal Dysfunction in Chronic Kidney Disease.

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 Thy-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 ß, increase Thy-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.

Impact of first-line use of caplacizumab on treatment outcomes in immune thrombotic thrombocytopenic purpura.

BACKGROUND: The von Willebrand factor-directed nanobody caplacizumab has greatly changed the treatment of immune thrombotic thrombocytopenic purpura (iTTP) in recent years. Data from randomized controlled trials established efficacy and safety. OBJECTIVES: This study aims to address open questions regarding patient selection, tailoring of therapy duration, obstacles in prescribing caplacizumab in iTTP, effect on adjunct treatment, and outcomes in the real-world setting. METHODS: We report retrospective, observational cohorts of 113 iTTP episodes treated with caplacizumab and 119 historical control episodes treated without caplacizumab. We aggregated data from the caplacizumab phase II/III trials and real-world data from France, the United Kingdom, Germany, and Austria (846 episodes, 396 treated with caplacizumab, and 450 historical controls). RESULTS: Caplacizumab was efficacious in iTTP, independent of the timing of therapy initiation, but curtailed the time of active iTTP only when used in the first-line therapy within 72 hours after diagnosis and until at least partial ADAMTS13-activity remission. Aggregated data from multiple study populations showed that caplacizumab use resulted in significant absolute risk reduction of 2.87% for iTTP-related mortality (number needed to treat 35) and a relative risk reduction of 59%. CONCLUSION: Caplacizumab should be used in first line and until ADAMTS13-remission, lowers iTTP-related mortality and refractoriness, and decreases the number of daily plasma exchange and hospital stay. This trial is registered at www. CLINICALTRIALS: gov as #NCT04985318.

Predictive performance and clinical application of COV50, a urinary proteomic biomarker in early COVID-19 infection: a prospective multicentre cohort study.

BACKGROUND: The SARS-CoV-2 pandemic is a worldwide challenge. The CRIT-CoV-U pilot study generated a urinary proteomic biomarker consisting of 50 peptides (COV50), which predicted death and disease progression from SARS-CoV-2. After the interim analysis presented for the German Government, here, we aimed to analyse the full dataset to consolidate the findings and propose potential clinical applications of this biomarker. METHODS: CRIT-CoV-U was a prospective multicentre cohort study. In eight European countries (Austria, France, Germany, Greece, North Macedonia, Poland, Spain, and Sweden), 1012 adults with PCR-confirmed COVID-19 were followed up for death and progression along the 8-point WHO scale. Capillary electrophoresis coupled with mass spectrometry was used for urinary proteomic profiling. Statistical methods included logistic regression and receiver operating characteristic curve analysis with a comparison of the area under curve (AUC) between nested models. Hospitalisation costs were derived from the care facility corresponding with the Markov chain probability of reaching WHO scores ranging from 3 to 8 and flat-rate hospitalisation costs adjusted for the gross per capita domestic product of each country. FINDINGS: From June 30 to Nov 19, 2020, 228 participants were recruited, and from April 30, 2020, to April 14, 2021, 784 participants were recruited, resulting in a total of 1012 participants. The entry WHO scores were 1-3 in 445 (44%) participants, 4-5 in 529 (52%) participants, and 6 in 38 (4%) participants; and of all participants, 119 died and 271 had disease progression. The odds ratio (OR) associated with COV50 in all 1012 participants for death was 2·44 (95% CI 2·05-2·92) unadjusted and 1·67 (1·34-2·07) when adjusted for sex, age, BMI, comorbidities, and baseline WHO score; and for disease progression, the OR was 1·79 (1·60-2·01) when unadjusted and 1·63 (1·41-1·91) when adjusted (p<0·0001 for all). The predictive accuracy of the optimised COV50 thresholds was 74·4% (71·6-77·1%) for mortality (threshold 0·47) and 67·4% (64·4-70·3%) for disease progression (threshold 0·04). When adjusted for covariables and the baseline WHO score, these thresholds improved AUCs from 0·835 to 0·853 (p=0·033) for death and from 0·697 to 0·730 (p=0·0008) for progression. Of 196 participants who received ambulatory care, 194 (99%) did not reach the 0·04 threshold. The cost reductions associated with 1 day less hospitalisation per 1000 participants were million Euro (M€) 0·887 (5-95% percentile interval 0·730-1·039) in participants at a low risk (COV50 <0·04) and M€2·098 (1·839-2·365) in participants at a high risk (COV50 ≥0·04). INTERPRETATION: The urinary proteomic COV50 marker might be predictive of adverse COVID-19 outcomes. Even in people with mild-to-moderate PCR-confirmed infections (WHO scores 1-4), the 0·04 COV50 threshold justifies earlier drug treatment, thereby potentially reducing the number of days in hospital and associated costs. FUNDING: German Federal Ministry of Health.

Alternate-day dosing of caplacizumab for immune-mediated thrombotic thrombocytopenic purpura.

BACKGROUND: The anti-von Willebrand factor (VWF) nanobody caplacizumab directly prevents the fatal microthrombi formation in immune-mediated thrombotic thrombocytopenic purpura (iTTP), thereby adding a new therapeutic principle to the treatment of this disorder. However, real-world treatment modalities beyond clinical trials remain heterogeneous. METHODS: Here, we describe the risks and benefits of an alternate-day dosing regimen for caplacizumab by thoroughly analyzing the timing and outcome of this approach in a retrospective cohort of 25 iTTP patients treated with caplacizumab at seven different medical centers in Austria and Germany between 2018 and 2021. RESULTS: Alternate-day dosing of caplacizumab appeared feasible and led to persisting normal platelet counts in most patients. Five patients experienced iTTP exacerbations or relapses that led to the resumption of daily caplacizumab application. VWF activity was repeatedly measured in 16 of 25 patients and documented sufficient suppression by caplacizumab after 24 and 48 h in line with published pharmacodynamics. CONCLUSION: Extension of caplacizumab application intervals from daily to alternate-day dosing may be safely considered in selected patients after 3 to 4 weeks of daily treatment. Earlier modifications may be discussed in low-risk patients but require close monitoring for clinical and laboratory features of thrombotic microangiopathy.

Mechanical aortic valve prostheses offer a survival benefit in 50-65 year olds: AUTHEARTVISIT study.

BACKGROUND: The present population-based cohort study investigated long-term mortality after surgical aortic valve replacement (AVR) with bioprosthetic (B) or mechanical aortic valve prostheses (M) in a European social welfare state. METHODS: We analysed patient data from health insurance records covering 98% of the Austrian population between 2010 and 2018. Subsequent patient-level record linkage with national health data provided patient characteristics and clinical outcomes. Further reoperation, myocardial infarction, heart failure and stroke were evaluated as secondary outcomes. RESULTS: A total of 13,993 patients were analysed and the following age groups were examined separately: <50 years (727 patients: 57.77% M, 42.23% B), 50-65 years (2612 patients: 26.88% M, 73.12% B) and >65 years (10,654 patients: 1.26% M, 98.74% B). Multivariable Cox regression revealed that the use of B-AVR was significantly associated with higher mortality in patients aged 50-65 years compared to M-AVR (HR = 1.676 [1.289-2.181], p < 0.001). B-AVR also performed worse in a competing risk analysis regarding reoperation (HR = 3.483 [1.445-8.396], p = 0.005) and myocardial infarction (HR = 2.868 [1.255-6.555], p = 0.012). However, the risk of developing heart failure and stroke did not differ significantly after AVR in any age group. CONCLUSIONS: Patients aged 50-65 years who underwent M-AVR had better long-term survival, and a lower risk of reoperation and myocardial infarction. Even though anticoagulation is crucial in patients with M-AVR, we did not observe significantly increased stroke rates in patients with M-AVR. This evident survival benefit in recipients of mechanical aortic valve prostheses aged <65 years critically questions current guideline recommendations.

Molecular Mapping of Urinary Complement Peptides in Kidney Diseases.

Defective complement activation has been associated with various types of kidney disease. This led to the hypothesis that specific urine complement fragments may be associated with kidney disease etiologies, and disease progression may be reflected by changes in these complement fragments. We investigated the occurrence of complement fragments in urine, their association with kidney function and disease etiology in 16,027 subjects, using mass spectrometry based peptidomics data from the Human Urinary Proteome/Peptidome Database. Twenty-three different urinary peptides originating from complement proteins C3, C4 and factor B (CFB) could be identified. Most C3-derived peptides showed inverse association with estimated glomerular filtration rate (eGFR), while the majority of peptides derived from CFB demonstrated positive association with eGFR. Several peptides derived from the complement proteins C3, C4 and CFB were found significantly associated with specific kidney disease etiologies. These peptides may depict disease-specific complement activation and could serve as non-invasive biomarkers to support development of complement interventions through assessing complement activity for patients' stratification and monitoring of drug impact. Further investigation of these complement peptides may provide additional insight into disease pathophysiology and could possibly guide therapeutic decisions, especially when targeting complement factors.

Clinical Relevance of Elevated Soluble ST2, HSP27 and 20S Proteasome at Hospital Admission in Patients with COVID-19.

Although, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents one of the biggest challenges in the world today, the exact immunopathogenic mechanism that leads to severe or critical Coronavirus Disease 2019 (COVID-19) has remained incompletely understood. Several studies have indicated that high systemic plasma levels of inflammatory cytokines result in the so-called "cytokine storm", with subsequent development of microthrombosis, disseminated intravascular coagulation, and multiorgan-failure. Therefore, we reasoned those elevated inflammatory molecules might act as prognostic factors. Here, we analyzed 245 serum samples of patients with COVID-19, collected at hospital admission. We assessed the levels of heat shock protein 27 (HSP27), soluble suppressor of tumorigenicity-2 (sST2) and 20S proteasome at hospital admission and explored their associations with overall-, 30-, 60-, 90-day- and in-hospital mortality. Moreover, we investigated their association with the risk of ventilation. We demonstrated that increased serum sST2 was uni- and multivariably associated with all endpoints. Furthermore, we also identified 20S proteasome as independent prognostic factor for in-hospital mortality (sST2, AUC = 0.73; HSP27, AUC = 0.59; 20S proteasome = 0.67). Elevated sST2, HSP27, and 20S proteasome levels at hospital admission were univariably associated with higher risk of invasive ventilation (OR = 1.8; p < 0.001; OR = 1.1; p = 0.04; OR = 1.03, p = 0.03, respectively). These findings could help to identify high-risk patients early in the course of COVID-19.

CD99 and polymeric immunoglobulin receptor peptides deregulation in critical COVID-19: A potential link to molecular pathophysiology?

Identification of significant changes in urinary peptides may enable improved understanding of molecular disease mechanisms. We aimed towards identifying urinary peptides associated with critical course of COVID-19 to yield hypotheses on molecular pathophysiological mechanisms in disease development. In this multicentre prospective study urine samples of PCR-confirmed COVID-19 patients were collected in different centres across Europe. The urinary peptidome of 53 patients at WHO stages 6-8 and 66 at WHO stages 1-3 COVID-19 disease was analysed using capillary electrophoresis coupled to mass spectrometry. 593 peptides were identified significantly affected by disease severity. These peptides were compared with changes associated with kidney disease or heart failure. Similarities with kidney disease were observed, indicating comparable molecular mechanisms. In contrast, convincing similarity to heart failure could not be detected. The data for the first time showed deregulation of CD99 and polymeric immunoglobulin receptor peptides and of known peptides associated with kidney disease, including collagen and alpha-1-antitrypsin. Peptidomic findings were in line with the pathophysiology of COVID-19. The clinical corollary is that COVID-19 induces specific inflammation of numerous tissues including endothelial lining. Restoring these changes, especially in CD99, PIGR and alpha-1-antitripsin, may represent a valid and effective therapeutic approach in COVID-19, targeting improvement of endothelial integrity.

A urinary peptidomic profile predicts outcome in SARS-CoV-2-infected patients.

BACKGROUND: COVID-19 prediction models based on clinical characteristics, routine biochemistry and imaging, have been developed, but little is known on proteomic markers reflecting the molecular pathophysiology of disease progression. METHODS: The multicentre (six European study sites) Prospective Validation of a Proteomic Urine Test for Early and Accurate Prognosis of Critical Course Complications in Patients with SARS-CoV-2 Infection Study (Crit-COV-U) is recruiting consecutive patients (≥ 18 years) with PCR-confirmed SARS-CoV-2 infection. A urinary proteomic biomarker (COV50) developed by capillary-electrophoresis-mass spectrometry (CE-MS) technology, comprising 50 sequenced peptides and identifying the parental proteins, was evaluated in 228 patients (derivation cohort) with replication in 99 patients (validation cohort). Death and progression along the World Health Organization (WHO) Clinical Progression Scale were assessed up to 21 days after the initial PCR test. Statistical methods included logistic regression, receiver operating curve (ROC) analysis and comparison of the area under the curve (AUC). FINDINGS: In the derivation cohort, 23 patients died, and 48 developed worse WHO scores. The odds ratios (OR) for death per 1 standard deviation (SD) increment in COV50 were 3·52 (95% CI, 2·02-6·13, p <0·0001) unadjusted and 2·73 (1·25-5·95, p = 0·012) adjusted for sex, age, baseline WHO score, body mass index (BMI) and comorbidities. For WHO scale progression, the corresponding OR were 2·63 (1·80-3·85, p<0·0001) and 3·38 (1·85-6·17, p<0·0001), respectively. The area under the curve (AUC) for COV50 as a continuously distributed variable was 0·80 (0·72-0·88) for mortality and 0·74 (0·66-0·81) for worsening WHO score. The optimised COV50 thresholds for mortality and worsening WHO score were 0·47 and 0·04 with sensitivity/specificity of 87·0 (74·6%) and 77·1 (63·9%), respectively. On top of covariates, COV50 improved the AUC, albeit borderline for death, from 0·78 to 0·82 (p = 0·11) and 0·84 (p = 0·052) for mortality and from 0·68 to 0·78 (p = 0·0097) and 0·75 (p = 0·021) for worsening WHO score. The validation cohort findings were confirmatory. INTERPRETATION: This first CRIT-COV-U report proves the concept that urinary proteomic profiling generates biomarkers indicating adverse COVID-19 outcomes, even at an early disease stage, including WHO stages 1-3. These findings need to be consolidated in an upcoming final dataset. FUNDING: The German Federal Ministry of Health funded the study.

Weight-reduction and changes in renal function in CKD patients participating in a conservative multimodal obesity program.

INTRODUCTION: Due to the global epidemic of obesity, there is increasing interest in a distinct entity, called obesity-related nephropathy (ORN). Data on sustainable effects of weight reductions, with conservative, non-surgical treatment programs, on renal function in CKD patients are scarce. MATERIALS AND METHODS: We retrospectively investigated patients with CKD (eGFR ≤ 60 mL/min/1.73m2) from a non-surgical multimodality obesity treatment program over 12 months. RESULTS: We identified 17 obese patients with CKD (estimated glomerular filtration rate (eGFR) ≤ 60 mL/min at baseline). 76% were female, 41% had type II diabetes mellitus, and the mean age was 59.6 ± 8.4 years (mean ± SD). Mean serum creatinine and eGFR at baseline were 106.4 ± 17.6 µmol/L and 53.4 ± 5.8 mL/min, respectively. Mean weight and body mass index (BMI) were 134.9 ± 26.4 and 50.1 ± 10.5 kg/m2, respectively. All subjects lost weight, with average weight loss of -32.2 ± 15.1 kg (p < 0.001) by the end of 12 months (BMI at 12 months 38.1 ± 7.8 kg/m2 (-12.0 ± 6.0 kg/m2, p < 0.001). Average 12-month creatinine was 92.2 ± 23.3 µmol/L, representing a drop of 14.2 ± 15.6 µmol/L (p = 0.004). Average eGFR increased by 14.8 ± 18.0 mL/min to a 12-month value of 68.2 ± 19.3 mL/min (p = 0.002). There were no significant differences when comparing patients with and without diabetes mellitus. CONCLUSION: These results demonstrate the potential renal impact of a non-surgical multimodal obesity program on renal function in very obese patients with CKD. Weight loss intervention should be highly encouraged especially in obese CKD patients.

Diagnosis of Hereditary TTP Caused by Homozygosity for a Rare Complex ADAMTS13 Allele After Salmonella Infection in a 43-Year-Old Asylum Seeker.

A 43-year-old Armenian patient was diagnosed with salmonella infection and thrombotic microangiopathy (TMA). The clinical course was benign with resolution of all laboratory alterations after antibiotic treatment. Constantly deficient ADAMTS13 activity without ADAMTS13 inhibitors and evidence of homozygosity for a rare complex ADAMTS13 allele led to the diagnosis of congenital thrombotic thrombocytopenic purpura (cTTP). Half-life of ADAMTS13 after plasma infusion was calculated (27,6h) and double blinded plasma infusion as well as ergometric exercise with and without prior plasma infusion undertaken to investigate suspected smoldering TTP activity.