High-resolution African HLA resource uncovers HLA-DRB1 expression effects underlying vaccine response.

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.

Increased levels of a mycophenolic acid metabolite in patients with kidney failure negatively affect cardiomyocyte health.

Chronic kidney disease (CKD) significantly increases cardiovascular risk and mortality, and the accumulation of uremic toxins in the circulation upon kidney failure contributes to this increased risk. We thus performed a screening for potential novel mediators of reduced cardiovascular health starting from dialysate obtained after hemodialysis of patients with CKD. The dialysate was gradually fractionated to increased purity using orthogonal chromatography steps, with each fraction screened for a potential negative impact on the metabolic activity of cardiomyocytes using a high-throughput MTT-assay, until ultimately a highly purified fraction with strong effects on cardiomyocyte health was retained. Mass spectrometry and nuclear magnetic resonance identified the metabolite mycophenolic acid-ß-glucuronide (MPA-G) as a responsible substance. MPA-G is the main metabolite from the immunosuppressive agent MPA that is supplied in the form of mycophenolate mofetil (MMF) to patients in preparation for and after transplantation or for treatment of autoimmune and non-transplant kidney diseases. The adverse effect of MPA-G on cardiomyocytes was confirmed in vitro, reducing the overall metabolic activity and cellular respiration while increasing mitochondrial reactive oxygen species production in cardiomyocytes at concentrations detected in MMF-treated patients with failing kidney function. This study draws attention to the potential adverse effects of long-term high MMF dosing, specifically in patients with severely reduced kidney function already displaying a highly increased cardiovascular risk.

Sex-specific time trends of long-term graft survival after kidney transplantation - a registry-based study.

BACKGROUND: Sex-specific trends over time with respect to kidney graft survival have scarcely been described in earlier studies. The present study aimed to examine whether kidney graft survival differs between women and men over time. METHODS: This study was based on prospectively collected data extracted from a quality registry including all kidney transplant patients between January 1965 and September 2017 at the transplantation center of a university hospital in Sweden. The transplantation center serves a population of approximately 3.5 million inhabitants. Only the first graft for each patient was included in the study resulting in 4698 transplantations from unique patients (37% women, 63% men). Patients were followed-up until graft failure, death, or the end of the study. Death-censored graft survival analysis after kidney transplantation (KT) was performed using Kaplan-Meier analysis with log-rank test, and analysis adjusted for confounders was performed using multivariable Cox regression analysis. RESULTS: Median age at transplantation was 48 years (quartiles 36-57 years) and was similar for women and men. Graft survival was analyzed separately in four transplantation periods that represented various immunosuppressive regimes (1965-1985, 1986-1995, 1996-2005, and 2006-2017). Sex differences in graft survival varied over time (sex-by-period interaction, p = 0.026). During the three first periods, there were no significant sex differences in graft survival. However, during the last period, women had shorter graft survival (p = 0.022, hazard ratio (HR) 1.71, 95% confidence interval (CI) 1.1-2.7, adjusted for covariates). Biopsy-proven rejections were more common in women. CONCLUSIONS: In this registry-based study, women had shorter graft survival than men during the last observation period (years 2006-2017).

Transvenous lead extraction in children with bidirectional rotational dissection sheaths.

Objectives: Due to the limited longevity of endovascular leads, children require thoughtful lifetime lead management strategies including conservation of access vessel patency. Consequently, there is an increasing interest in transvenous lead extraction (TLE) in children, however, data on TLE and the use of powered mechanical dissection sheaths is limited. Methods: We performed a retrospective cohort study analyzing all children <18 years that underwent TLE in our institution from 2015 to 2022. Procedural complexity, results and complications were defined as recommended by recent consensus statements. Results: Twenty-eight children [median age 12.8 (interquartile range 11.3-14.6) years] were included. Forty-one leads were extracted [median dwell time 85 (interquartile range 52-102) months]. Extractions of 31 leads (76%) in 22 patients (79%) were complex, requiring advanced extraction tools including powered bidirectional rotational dissection sheaths in 14 children. There were no major complications. Complete procedural success was achieved in 18 (64%) and clinical success in 27 patients (96%), respectively. Procedural success and complexity varied between lead types. The Medtronic SelectSecure™ lead was associated with increased odds of extraction by simple traction (p = 0.006) and complete procedural success (p < 0.001) while the Boston Scientific Fineline™ II lead family had increased odds of partial procedural failure (p = 0.017). Conclusions: TLE with the use of mechanical powered rotational dissection sheaths is feasible and safe in pediatric patients. In light of rare complications and excellent overall clinical success, TLE should be considered an important cornerstone in lifetime lead management in children. Particular lead types might be more challenging and less successful to extract.

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.

Glomerular macrophage index (GMI) in kidney transplant biopsies is associated with graft outcome.

BACKGROUND: Macrophages in renal transplants have been shown to participate in antibody-mediated rejection and are associated with impaired renal function. We calculated the glomerular macrophage index (GMI) in a large transplant biopsy cohort, studied its quantity in different diagnostic groups, to clarify its possible impact on graft survival. METHODS: GMI, defined as the mean number of macrophages in 10 glomeruli, was prospectively quantified in 1440 renal transplant biopsies over a 10-year period. The main histopathological diagnoses were grouped into eight disease entities, and GMI was compared to normal transplant biopsies as the reference group. The impact of GMI on graft survival was analyzed. RESULTS: GMI was highest in chronic (mean 9.4) and active (9.7) antibody mediated rejections (ABMR), mixed rejections (7.6), and recurrent or de novo glomerulonephritis (7.5) and differed significantly from normal transplants (1.3) in almost all diagnostic groups. Hazard ratios for graft loss were significantly increased for all biopsies with GMI ≥1.9 compared to GMI < .5 (reference group) in an adjusted Cox regression model and increased with higher GMI levels. Biopsies with GMI ≥ 4.6 had < 60% 10-year graft-survival, compared to > 80% with GMI ≤ 1.8. CONCLUSION: GMI levels were predictive of graft loss independent of histological diagnoses and may guide clinicians to decide follow-up and therapy.

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.

The association between long-term glycemic control and all-cause mortality is different among older versus younger patients with diabetes mellitus and maintenance hemodialysis treatment.

AIMS: Knowledge about association between glycated hemoglobin (HbA1c) and risk of all-cause mortality in patients with diabetes mellitus on maintenance hemodialysis (HD)-treatment is sparse. The study aims to investigate association between HbA1c and all-cause mortality in patients with diabetes and maintenance HD-treatment, separately for two age groups- above and below 75 years. METHODS: 2487 patients (mean age 66 years, 66 % men) were separated in two age groups: ≤75 years (n = 1810) and > 75 years (n = 677) and followed up between 2008 and 2018. Hazard ratios (HR) and 95 % confidence intervals (CI) for associations between HbA1c and all-cause mortality were calculated using Cox-regression-models. RESULTS: 1295 (52 %) patients died and 473 (70 %) among the patients above 75 years old. In the multivariate analysis, HbA1c5-6 % was used as reference. In patients ≤ 75 years old, only increased HbA1c > 9.7 %, HR2.03(CI1.43-2.89) was associated with increased risk of all-cause mortality. In patients > 75 years, HbA1c ≤ 5 %, HR1.67(CI1.16-2.40); HbA1c6.9-7.8 %, HR1.41(CI1.03-1.93) and HbA1c8.7-9.7 %, HR1.79 (CI1.08-2.96) were associated with increased risk of all-cause mortality. CONCLUSIONS: We found a J-shaped association between HbA1c and mortality only in diabetic HD-patients > 75 years. This probably indicates that in an old population of diabetic HD-patients, both intensive glucose control and hyperglycemia could be harmful and associated with higher risk of death.

Intra-Micellar and Extra-Micellar Oxidation in Phosphate and Histidine Buffers Containing Polysorbate 80.

Polysorbate is a key excipient included in formulations of therapeutic proteins to help prevent aggregation and surface adsorption. The stability of both polysorbate and therapeutic proteins can be compromised by oxidative degradation. In general, polysorbate is added to formulations at concentrations above the critical micelle concentration (cmc). To date, however, few experiments have quantitatively addressed the extent of extra- and intra-micellar oxidation of polysorbate in pharmaceutically relevant buffers. This study utilizes 2,2'-azobis(2-methylpropionamidine)dihydrochloride (AAPH), a peroxyl radical-generating initiator, C11-BODIPY(581/591), a lipid peroxidation probe, and fluorescence spectroscopy to reveal that both intra- and extra-micellar oxidation proceed in pharmaceutically relevant phosphate and histidine buffers. It is further demonstrated that the relative extent of oxidation observed in the intra- and extra-micellar compartments is similar irrespective of the buffer system.

Revascularization of Left Subclavian to Common Carotid Artery Prepares for Covered Stent Implantation in Patients With Complex Aortic Coarctation.

Seven adult patients underwent a two-stage treatment of complex coarctation (CoA), including surgical revascularization of the left subclavian artery (LSA) to left common carotid artery (LCCA), followed by transcatheter covered stent implantation. The majority of patients (5 of 7, 71%) received 1 covered stent (covered Cheatham Platinum stent: 8 zig/45 mm [n = 2], 10 zig/60 mm [n = 1], 10 zig/65 mm [n = 1]; BeGraft: 24/48 mm [n = 2]). In 1 patient (14%), the implantation of 2 covered stents (BeGraft 20/48 mm) was necessary. During a median follow-up of 2.4 years (interquartile range, 0.1 to 4.9 years), complications occurred in 3 of 7 patients (43%), including an asymptomatic but severe stenosis of the LSA bypass (n = 1), a recoarctation with a mild endoleak (n = 1), and a severe endoleak (n = 1). Surgical revascularization of the LSA to the LCCA can successfully prepare for covered stent implantation in complex CoA in adult patients. This two-stage approach was feasible and safe with complications occurring in 3 of 7 patients (43%). All complications were managed by catheter reintervention only.

Enzymatic removal of sialic acid enables iCIEF stability monitoring of charge variants of a highly sialylated bispecific antibody.

Antibody-based therapeutic proteins have highly complex molecular structures. The final therapeutic protein product may contain a wide range of charge variants. Accurate analysis of this charge variant composition is critical to determine manufacturing process consistency and protein stability and ultimately helps to ensure that patients receive a safe and efficacious product. Here, a highly sialylated bispecific antibody (bsAb-1) challenged the ability to monitor stability by imaged capillary isoelectric focusing (iCIEF). This challenge was overcome by optimization of the iCIEF master mix buffer (adjustment of urea concentration, addition of l-arginine) and enzymatic removal of sialic acid. The method was qualified by assessing linearity, precision, LOD, LOQ, accuracy, and robustness in accordance with ICH guidance. Main species loss detectability increased up to approximately fivefold compared to the iCIEF method without desialylation when monitoring changes in stressed samples. Importantly, the results of the iCIEF method with desialylation correlated with results obtained through LC-MS tryptic peptide mapping and enabled analysis of formulation development stability samples. Finally, this analytical method shows the potential to assess low-concentration formulation development samples down to a sample concentration of 0.1 mg/ml.

Histological diagnosis from kidney transplant biopsy can contribute to prediction of graft survival.

AIM: The primary aim of this study was to in depth examine if the histological findings in a transplanted kidney biopsy can predict the prognosis for the graft and the patient. The secondary aim was to extend knowledge of the impact of time elapsed on biopsy findings. METHODS: Data from 1462 patients were merged from a kidney transplantation registry and a biopsy registry during 1 January 2007 and 30 September 2017. Kaplan-Meier analysis and multivariate Cox-regression analysis were performed and hazard ratios (HR) with 95% confidence intervals (CI) were presented. RESULTS: Compared to normal biopsy findings, graft survival after biopsy (gsaBiopsy) was shorter for patients with glomerular diseases (HR 8.2, CI:3.2-21.1), rejections (HR 4.2, CI:1.7-10.3), chronic changes including IFTA (HR 3.2, CI:1.3-8.0), acute tubular injuries (HR 3.0, CI:1.2-7.8), and borderline changes (HR 2.9, CI:1.1-7.6). Sub-analysis of rejections showed shorter gsaBiopsy for chronic TCMR (HR 4.7, CI:1.9-11.3), active ABMR (HR 3.6, CI:1.7-7.7) and chronic ABMR (HR 3.5, CI:2.0-6.0). Patients with TCMR Banff grade II (HR 0.35, CI:0.20-0.63) and grade I (HR 0.52, CI:0.29-0.93) had a better gsaBiopsy compared to all other types of rejections. CONCLUSION: Shorter gsaBiopsy was noted in kidneys with glomerular diseases, rejections, acute tubular injuries and borderline changes. TCMR Banff rejections grade I and II were associated with a better prognosis.

Long-term glycemic variability and the risk of mortality in diabetic patients receiving peritoneal dialysis.

BACKGROUND: The large amount of glucose in the dialysate used in peritoneal dialysis (PD) likely affects the glycemic control. The aim of this study was to investigate the association between HbA1c variability, as a measure of long-term glycemic variability, and the risk of all-cause mortality in diabetic patients with PD. METHODS: 325 patients with diabetes and ESRD were followed (2008-2018) in the Swedish Renal Registry. Patients were separated in seven groups according to level of HbA1c variability. The group with the lowest variability was denoted the reference. The ratio of the standard deviation (SD) to the mean of HbA1c, HbA1c (SD)/HbA1c (mean), i.e. the coefficient of variation (CV), was defined as HbA1c variability. Hazard ratios (HR) and 95% confidence intervals (CI) were examined using Cox regression analyses. RESULTS: During follow-up, 170 (52%) deaths occurred. The highest mortality was among patients with the second highest HbA1c variability, CV≥2.83 [n = 44 of which 68% patients died]. In the multivariate analyses where lowest HbA1c variability (CV≤0.51) was used as the reference group, HbA1c CV 2.83-4.60 (HR 3.15, 95% CI 1.78-5.55; p<0.001) and CV> 4.6 (HR 2.48, 95% CI 1.21-5.11; p = 0.014) were associated with increased risk of death. CONCLUSION: The high risk of all-cause mortality in patients with diabetes and PD increased significantly with elevated HbA1c variability, as measure of long-term glycemic control. This indicates that stable glycemia is associated with an improvement of survival; whereas more severe glycemic fluctuations, possibly caused by radical changes in dialysis regimes or peritonitis, are associated with a higher risk of mortality in diabetic patients with PD.

Right atrial myxoma as the first manifestation of granulomatosis with polyangiitis, and a possible association with vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6): a case report and review of the literature.

BACKGROUND: Granulomatosis with polyangiitis and myxomas are rare conditions previously described to co-exist. Cardiac masses are often presumed to be myxomas rather than lesions of granulomatosis with polyangiitis. CASE PRESENTATION: We present a review of the symptoms for the two diagnoses along with the first verified case. CONCLUSIONS: Two possible risk factors for developing myxomas (VEGF and IL-6) are explored and discussed.

Coronary Interventions in Pediatric Congenital Heart Disease.

Coronary artery lesions represent rare conditions in pediatric congenital heart disease and mainly include coronary artery stenoses (CAS) or coronary artery fistulae (CAF). Due to the small vessel size, pediatric percutaneous coronary interventions (PCI) are demanding and studies concerning long-term results are missing. In this retrospective study, we analyzed indications, procedural details, and post-procedural outcomes in pediatric patients who underwent PCI in our institution. For CAS treatment, procedural success was defined as efficient coronary revascularization with a significant improvement of coronary perfusion. CAF treatment was considered successful, when no residual shunt was detectable. From 1995 to 2020, 32 pediatric patients aged ≤ 18 years received interventional treatment for CAS (n = 24/32) or CAF (n = 8/32). Reasons for CAS were post-surgical (n = 15/24) or post-transplant (n = 9/24). Interventional treatment strategies included coronary angioplasty (20/43), stent placement (10/43), and a combination of both (13/43). In-hospital mortality occurred in 6/24 patients and late mortality in 5/24 patients leading to an overall 5-year survival of 62.5%. Early mortality mainly occurred due to post-ischemic myocardial failure. CAF occlusion was performed using coil embolization (n = 3), placement of vascular plugs (n = 3), a combination of both (n = 1), or a combination of coil embolization and a covered stent (n = 1). Treatment of coronary fistulae was successful in all patients with excellent post-procedural results and no follow-up death. PCI in pediatric patients with congenital heart disease can be performed safely and effectively. However, the overall 5-year survival probability of patients with CAS is reduced due to severe ischemic myocardial damage.

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.

Urine proteomics for prediction of disease progression in patients with IgA nephropathy.

BACKGROUND: Risk of kidney function decline in immunoglobulin A (IgA) nephropathy (IgAN) is significant and may not be predicted by available clinical and histological tools. To serve this unmet need, we aimed at developing a urinary biomarker-based algorithm that predicts rapid disease progression in IgAN, thus enabling a personalized risk stratification. METHODS: In this multicentre study, urine samples were collected in 209 patients with biopsy-proven IgAN. Progression was defined by tertiles of the annual change of estimated glomerular filtration rate (eGFR) during follow-up. Urine samples were analysed using capillary electrophoresis coupled mass spectrometry. The area under the receiver operating characteristic curve (AUC) was used to evaluate the risk prediction models. RESULTS: Of the 209 patients, 64% were male. Mean age was 42 years, mean eGFR was 63 mL/min/1.73 m2 and median proteinuria was 1.2 g/day. We identified 237 urine peptides showing significant difference in abundance according to the tertile of eGFR change. These included fragments of apolipoprotein C-III, alpha-1 antitrypsin, different collagens, fibrinogen alpha and beta, titin, haemoglobin subunits, sodium/potassium-transporting ATPase subunit gamma, uromodulin, mucin-2, fractalkine, polymeric Ig receptor and insulin. An algorithm based on these protein fragments (IgAN237) showed a significant added value for the prediction of IgAN progression [AUC 0.89; 95% confidence interval (CI) 0.83-0.95], as compared with the clinical parameters (age, gender, proteinuria, eGFR and mean arterial pressure) alone (0.72; 95% CI 0.64-0.81). CONCLUSIONS: A urinary peptide classifier predicts progressive loss of kidney function in patients with IgAN significantly better than clinical parameters alone.

Risk factors for biopsy complications in initial versus subsequent biopsies in native and transplant kidneys.

BACKGROUND: Few studies exist about risk factors for complications in subsequent biopsies. PURPOSE: To explore risk factors for complications in initial versus subsequent biopsies in native and transplant kidneys, which may predict biopsy complications. MATERIAL AND METHODS: In a multicenter study, 2830 native kidney biopsies (4.3% subsequent) were analyzed for major complications (1251 of these were also analyzed for minor) and 667 transplant kidney biopsies (29% subsequent) were analyzed for major and minor complications. No death or nephrectomy were described. Fisher's exact test, Student's t-test, chi-square analyses, and univariate and multiple binary logistic regression analyses were employed; P < 0.05 was considered significant. RESULTS: In initial native kidney biopsies, the frequency of major complications was higher in women compared to men (odds ratio 1.6, 95% confidence interval 1.1-2.2), in younger patients (50 vs. 54 years, P = 0.007), and in patients with lower weight (78 vs. 82 kg, P = 0.005). In subsequent native kidney biopsies, patients with major complications had a higher systolic blood pressure (145 vs. 132 mmHg, P = 0.03). In initial transplant kidney biopsies, biopsies with major complications had less glomeruli in the biopsy (17 vs. 24, P = 0.046). In subsequent transplant kidney biopsies, patients with major complications had a higher mean arterial pressure (112 vs. 98 mmHg, P = 0.002). In subsequent native kidney biopsies, there was a higher number of SLE-nephritis (12% vs. 4.6%, P = 0.001) compared to initial biopsies. CONCLUSION: The different types of risk factors for complications in initial versus subsequent renal biopsies could be important for the clinicians to improve patients' safety.

Clinical parameters predicting complications in native kidney biopsies.

BACKGROUND: Renal biopsies are essential in nephrology but they are invasive and complications can occur. The aim of this study was to explore clinical parameters that can be used as predictors for biopsy complications. METHODS: Clinical parameters such as demographics, biopsy indications, serology, comorbidities and clinical chemistry were retrieved from a regional biopsy registry between 2006 and 2015 and from a nationwide registry between 2015 and 2017. Clinical data before biopsy were compared with data on major biopsy complications. Fisher's exact and χ 2 tests were used and odds ratios (ORs) with 95% confidence intervals (CIs) were presented. Univariate and multiple binary logistic regression analyses were performed with complications as outcome. A two-sided P-value <0.05 was considered significant. RESULTS: In total, 2835 consecutive native kidney biopsies were analysed (39% women and 61% men, median age 57 years). No death and nephrectomy due to biopsy complications were registered. The frequency of major biopsy complications was 5.65%. In the multiple logistic regression, the risk for complications increased in women [OR 1.51 (95% CI 1.08-2.11)] and decreased with age: 45-64 years age group [OR 0.66 (95% CI 0.44-0.99)] and >74 years age group [OR 0.51 (95% CI 0.27-0.96)]. Among comorbidities, patients with diabetes mellitus type 2 [OR 2.07 (95% CI 1.15-3.72)] and non-ischaemic heart disease [OR 3.20 (95% CI 1.64-6.25)] had a higher risk for major biopsy complications. CONCLUSIONS: Female gender, younger age (≤44 years), diabetes mellitus type 2 and non-ischaemic heart disease were found as risk factors for major biopsy complications.