Glomerular transcriptomics predicts long term outcome and identifies therapeutic strategies for patients with assumed benign IgA nephropathy.

Some patients diagnosed with benign IgA nephropathy (IgAN) develop a progressive clinical course, not predictable by known clinical or histopathological parameters. To assess if gene expression can differentiate between progressors and non-progressors with assumed benign IgAN, we tested microdissected glomeruli from archival kidney biopsy sections from adult patients with stable clinical remission (21 non-progressors) or from 15 patients that had undergone clinical progression within a 25-year time frame. Based on 1 240 differentially expressed genes from patients with suitable sequencing results, we identified eight IgAN progressor and nine non-progressor genes using a two-component classifier. These genes, including APOL5 and ZXDC, predicted disease progression with 88% accuracy, 75% sensitivity and 100% specificity on average 21.6 years before progressive disease was clinically documented. APOL lipoproteins are associated with inflammation, autophagy and kidney disease while ZXDC is a zinc-finger transcription factor modulating adaptive immunity. Ten genes from our transcriptomics data overlapped with an external genome wide association study dataset, although the gene set enrichment test was not statistically significant. We also identified 45 drug targets in the DrugBank database, including angiotensinogen, a target of sparsentan (dual antagonist of the endothelin type A receptor and the angiotensin II type 1 receptor) currently investigated for IgAN treatment. Two validation cohorts were used for substantiating key results, one by immunohistochemistry and the other by nCounter technology. Thus, glomerular mRNA sequencing from diagnostic kidney biopsies from patients with assumed benign IgAN can differentiate between future progressors and non-progressors at the time of diagnosis.

Prognostic significance of chronic myocardial injury diagnosed by three different cardiac troponin assays in patients admitted with suspected acute coronary syndrome.

OBJECTIVES: Chronic myocardial injury (CMI) is defined as stable concentrations of cardiac troponin T or I (cTnT or cTnI) above the assay-specific 99th percentile upper reference limit (URL) and signals poor outcome. The clinical implications of diagnosing CMI are unclear. We aimed to assess prevalence and association of CMI with long-term prognosis using three different high-sensitivity cTn (hs-cTn) assays. METHODS: A total of 1,292 hospitalized patients without acute myocardial injury had cTn concentrations quantified by hs-cTn assays by Roche Diagnostics, Abbott Diagnostics and Siemens Healthineers. The median follow-up time was 4.1 years. The prevalence of CMI and hazard ratios for mortality and cardiovascular (CV) events were calculated based on the URL provided by the manufacturers and compared to the prognostic accuracy when lower percentiles of cTn (97.5, 95 or 90), limit of detection or the estimated bioequivalent concentrations between assays were used as cutoff values. RESULTS: There was no major difference in prognostic accuracy between cTnT and cTnI analyzed as continuous variables. The correlation between cTnT and cTnI was high (r=0.724-0.785), but the cTnT assay diagnosed 3.9-4.5 times more patients with having CMI based on the sex-specific URLs (TnT, n=207; TnI Abbott, n=46, TnI Siemens, n=53) and had higher clinical sensitivity and AUC at the URL. CONCLUSIONS: The prevalence of CMI is highly assay-dependent. cTnT and cTnI have similar prognostic accuracy for mortality or CV events when measured as continuous variables. However, a CMI diagnosis according to cTnT has higher prognostic accuracy compared to a CMI diagnosis according to cTnI.

Use of corticosteroids in Norwegian patients with immunoglobulin a nephropathy progressing to end-stage kidney disease: a retrospective cohort study.

BACKGROUND: Despite several clinical trials, the use of corticosteroid therapy for treating immunoglobulin A nephropathy (IgAN) remains controversial. We aimed to describe the use of corticosteroid therapy combined with supportive therapy in Norwegian patients with IgAN who had progressed to end-stage kidney disease. METHODS: We conducted a retrospective cohort study using data from the Norwegian Renal Registry. Overall, 143 patients with primary IgAN who progressed to end-stage kidney disease were divided into two groups: the corticosteroid group, who had been treated with corticosteroids and supportive therapy, and the non-corticosteroid group, which had underwent only supportive therapy. The kidney function, time to end-stage kidney disease, and adverse effects were described. The observation period lasted from the diagnostic kidney biopsy until the initiation of kidney replacement therapy. RESULTS: Of the 143 included patients, 103 underwent supportive therapy alone, and 40 were treated with corticosteroids. Most patients (94%) were treated with renin-angiotensin-system blockade, and all patients reached end-stage kidney disease after a median of 5 years (interquartile range; 2-9 years). Time from diagnosis until end-stage kidney disease was similar in the two study groups (p = 0.98). During 6 months of corticosteroid therapy, median eGFR declined from 21 (interquartile range; 13-46) mL/min/1.73 m2 to 20 (interquartile range; 12-40) mL/min/1.73 m2, and median proteinuria decreased from 5.5 g/24 h to 3.0 g/24 h. Most patients (87.5%) treated with corticosteroids reported adverse events. In our linear regression analysis investigating the time to ESKD, we found that age (ß = -0.079, p = 0.008) and proteinuria at diagnosis (ß = -0.50, p = 0.01) exhibited statistically significant associations with a delay in the progression to ESKD. CONCLUSIONS: In this cohort of Norwegian patients with IgAN, corticosteroid therapy did not affect the time from diagnosis until end-stage kidney disease among a cohort of patients who all reached end-stage kidney disease. The treatment was also associated with adverse effects.

Epstein-Barr in a Patient Presenting with Right Upper Quadrant Pain: A Case Report from the Emergency Department.

BACKGROUND: Right upper quadrant abdominal pain and elevated cholestasis blood tests are usually associated with bacterial calculous cholecystitis. However, viral infections, such as Epstein-Barr virus (EBV) can also manifest with a similar clinical picture and is an important differential diagnosis. CASE REPORT: This case report discusses a young woman presenting to the emergency department with acute right upper quadrant abdominal pain. The initial assessment revealed a positive Murphy's sign, elevated white blood count, and a cholestatic pattern on liver function tests, leading one to suspect bacterial calculous cholecystitis and initiating antibiotic therapy. However, clinical examination also revealed tonsillar exudates and differential white blood cell count revealed monocytosis and lymphocytosis rather than a high neutrophil count. The patient tested positive for EBV. Furthermore, ultrasound and magnetic resonance imaging revealed gallbladder wall edema with no gallstones, leading one to conclude that the clinical manifestation and laboratory results were due to an EBV infection. Antibiotic therapy was ceased and the patient did not require surgical intervention. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Calculous bacterial cholecystitis usually entails antibiotic therapy and cholecystectomy. It is important to be aware of the differential diagnosis of EBV, as it usually does not require either of these and resolves spontaneously.

Diagnostic utility of oropharyngeal swabs as an alternative to lower respiratory tract samples for PCR-based syndromic testing in patients with community-acquired pneumonia.

Syndromic PCR-based analysis of lower respiratory tract (LRT) samples in patients with community-acquired pneumonia (CAP) improves the bacterial yield and time-to-results compared to culture-based methods. However, obtaining adequate sputum samples can be challenging and is frequently not prioritized in the emergency department (ED). In this study, we assess the concordance of microbiological detections between oropharyngeal- (OP) and LRT samples from patients presenting to the ED with CAP using a syndromic PCR-based respiratory panel [Biofire FilmArray Pneumonia plus (FAP plus)]. Paired OP- and high-quality LRT samples were collected from 103 patients with confirmed CAP, who had been included in a randomized controlled trial (NCT04660084) or a subsequent observational study at Haukeland University Hospital, and analyzed using the FAP plus. The LRT samples were obtained mainly by sputum induction (88%). Using the LRT samples as a reference standard, the positive percent agreement (PPA), negative percent agreement (NPA), and overall percent agreement for the most common bacterial pathogens in CAP, Streptococcus pneumoniae and Haemophilus influenzae, were 85%, 99% and 95%, and 86%, 98% and 93%, respectively. For Moraxella catarrhalis, the PPA was lower (74%), while the NPA was 100%. For bacteria that are less likely causes of uncomplicated CAP (e.g., Staphylococcus aureus and Enterobacterales) the results were more divergent. In conclusion, the FAP plus detects the most common CAP pathogens S. pneumoniae and H. influenzae from OP samples with high PPAs and excellent NPAs when compared with LRT samples. For these pathogens, the PPAs for OP samples were higher than previous reports for nasopharyngeal samples. This suggests that analysis of OP samples with syndromic PCR panels could represent an alternative approach for rapid microbiological testing in the ED, especially in patients where LRT samples are difficult to obtain. Divergent results for bacteria that are less likely to cause uncomplicated CAP do, however, emphasize the need for clinical evaluation of positive test results.

Growth Differentiation Factor 15: A Prognostic Marker in Patients with Acute Chest Pain without Acute Myocardial Infarction.

BACKGROUND: Acute chest pain is associated with an increased risk of death and cardiovascular events even when acute myocardial infarction (AMI) has been excluded. Growth differentiation factor-15 (GDF-15) is a strong prognostic marker in patients with acute chest pain and AMI, but the prognostic value in patients without AMI is uncertain. This study sought to investigate the ability of GDF-15 to predict long-term prognosis in patients presenting with acute chest pain without AMI. METHODS: In total, 1320 patients admitted with acute chest pain without AMI were followed for a median of 1523 days (range: 4 to 2208 days). The primary end point was all-cause mortality. Secondary end points included cardiovascular (CV) death, future AMI, heart failure hospitalization, and new-onset atrial fibrillation (AF). RESULTS: Higher concentrations of GDF-15 were associated with increased risk of death from all causes (median concentration in non-survivors vs survivors: 2124 pg/mL vs 852 pg/mL, P < 0.001), and all secondary end points. By multivariable Cox regression, GDF-15 concentration ≥4th quartile (compared to <4th quartile) remained an independent predictor of all-cause death (adjusted hazard ratio (HR): 2.75; 95% CI, 1.69-4.45, P < 0.001), CV death (adjusted HR: 3.74; 95% CI, 1.31-10.63, P = 0.013), and heart failure hospitalization (adjusted HR: 2.60; 95% CI, 1.11-6.06, P = 0.027). Adding GDF-15 to a model consisting of established risk factors and high-sensitivity cardiac troponin T (hs-cTnT) led to a significant increase in C-statistics for prediction of all-cause mortality. CONCLUSIONS: Higher concentrations of GDF-15 were associated with increased risk of mortality from all causes and risk of future CV events.

Validation of two IgA nephropathy risk-prediction tools using a cohort with a long follow-up.

BACKGROUND: Recently, two immunoglobulin A (IgA) nephropathy-prediction tools were developed that combine clinical and histopathologic parameters. The International IgAN Prediction Tool predicts the risk for 50% declines in the estimated glomerular filtration rate or end-stage kidney disease up to 80 months after diagnosis. The IgA Nephropathy Clinical Decision Support System uses artificial neural networks to estimate the risk for end-stage kidney disease. We aimed to externally validate both prediction tools using a Norwegian cohort with a long-term follow-up. METHODS: We included 306 patients with biopsy-proven primary IgA nephropathy in this study. Histopathologic samples were retrieved from the Norwegian Kidney Biopsy Registry and reclassified according to the Oxford Classification. We used discrimination and calibration as principles for externally validating the prognostic models. RESULTS: The median patient follow-up was 17.1 years. A cumulative, dynamic, time-dependent receiver operating characteristic analysis showed area under the curve values ranging from 0.90 at 5 years to 0.83 at 20 years for the International IgAN Prediction Tool, while time-naive analysis showed an area under the curve value at 0.83 for the IgA Nephropathy Clinical Decision Support System. The International IgAN Prediction Tool was well calibrated, while the IgA Nephropathy Clinical Decision Support System tends to underestimate risk for patients at higher risk and overestimates risk in the lower risk categories. CONCLUSIONS: We have externally validated two prediction tools for IgA nephropathy. The International IgAN Prediction Tool performed well, while the IgA Nephropathy Clinical Decision Support System has some limitations.

Aiming toWards Evidence baSed inTerpretation of Cardiac biOmarkers in patients pResenting with chest pain using Point of Care Testing (WESTCOR-POC): study design.

OBJECTIVES: Patients presenting with symptoms suggestive of acute coronary syndrome (ACS) contribute to a high workload and overcrowding in the Emergency Department (ED). Accelerated diagnostic protocols for non-ST-elevation myocardial infarction have proved challenging to implement. One obstacle is the turnaround time for analyzing high-sensitivity cardiac troponin (hs-cTn). In the WESTCOR-POC study (Clinical Trials number NCT05354804) we aim to evaluate safety and efficiency of a 0/1 h hs-cTn algorithm utilizing a hs-cTnI point of care (POC) instrument in comparison to central laboratory hs-cTnT measurements. DESIGN: This is a prospective single-center randomized clinical trial aiming to include 1500 patients admitted to the ED with symptoms suggestive of ACS. Patients will receive standard investigations following the European Society of Cardiology 0/1h protocols for centralized hs-cTnT measurements or the intervention using a 0/1h POC hs-cTnI algorithm. Primary end-points are 1) Safety; death, myocardial infarction or acute revascularization within 30 days 2) Efficiency; length of stay in the ED, 3) Cost- effectiveness; total episode cost, 4) Patient satisfaction, 5) Patient symptom burden and 6) Patients quality of life. Secondary outcomes are 12-months death, myocardial infarction or acute revascularization, percentage discharged after 3 and 6 h, total length of hospital stay and all costs related to hospital contact within 12 months. CONCLUSION: Results from this study may facilitate implementation of POC hs-cTn testing assays and accelerated diagnostic protocols in EDs, and may serve as a valuable resource for guiding future investigations for the use of POC high sensitivity troponin assays in outpatient clinics and prehospital settings.

Diagnostic Performance of Novel Troponin Algorithms for the Rule-Out of Non-ST-Elevation Acute Coronary Syndrome.

BACKGROUND: The European Society of Cardiology (ESC) rule-out algorithms use cutoffs optimized for exclusion of non-ST elevation myocardial infarction (NSTEMI). We investigated these and several novel algorithms for the rule-out of non-ST elevation acute coronary syndrome (NSTE-ACS) including less urgent coronary ischemia. METHOD: A total of 1504 unselected patients with suspected NSTE-ACS were included and divided into a derivation cohort (n = 988) and validation cohort (n = 516). The primary endpoint was the diagnostic performance to rule-out NSTEMI and unstable angina pectoris during index hospitalization. The secondary endpoint was combined MI, all-cause mortality (within 30 days) and urgent (24 h) revascularization. The ESC algorithms for high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) were compared to different novel low-baseline (limit of detection), low-delta (based on the assay analytical and biological variation), and 0-1-h and 0-3-h algorithms. RESULTS: The prevalence of NSTE-ACS was 24.8%, 60.0% had noncardiac chest pain, and 15.2% other diseases. The 0-1/0-3-h algorithms had superior clinical sensitivity for the primary endpoint compared to the ESC algorithm (validation cohort); hs-cTnT: 95% vs 63%, and hs-cTnI: 87% vs 64%, respectively. Regarding the secondary endpoint, the algorithms had similar clinical sensitivity (100% vs 94%-96%) but lower clinical specificity (41%-19%) compared to the ESC algorithms (77%-74%). The rule-out rates decreased by a factor of 2-4. CONCLUSION: Low concentration/low-delta troponin algorithms improve the clinical sensitivity for a combined endpoint of NSTEMI and unstable angina pectoris, with the cost of a substantial reduction in total rule-out rate. There was no clear benefit compared to ESC for diagnosing high-risk events.

The changing spectrum of microbial aetiology of respiratory tract infections in hospitalized patients before and during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic was met with strict containment measures. We hypothesized that societal infection control measures would impact the number of hospital admissions for respiratory tract infections, as well as, the spectrum of pathogens detected in patients with suspected community acquired pneumonia (CAP). METHODS: This study is based on aggregated surveillance data from electronic health records of patients admitted to the hospitals in Bergen Hospital Trust from January 2017 through June 2021, as well as, two prospective studies of patients with suspected CAP conducted prior to and during the COVID-19 pandemic (pre-COVID cohort versus COVID cohort, respectively). In the prospective cohorts, microbiological detections were ascertained by comprehensive PCR-testing in lower respiratory tract specimens. Mann-Whitney's U test was used to analyse continuous variables. Fisher's exact test was used for analysing categorical data. The number of admissions before and during the outbreak of SARS-CoV-2 was compared using two-sample t-tests on logarithmic transformed values. RESULTS: Admissions for respiratory tract infections declined after the outbreak of SARS-CoV-2 (p < 0.001). The pre-COVID and the COVID cohorts comprised 96 and 80 patients, respectively. The proportion of viruses detected in the COVID cohort was significantly lower compared with the pre-COVID cohort [21% vs 36%, difference of 14%, 95% CI 4% to 26%; p = 0.012], and the proportion of bacterial- and viral co-detections was less than half in the COVID cohort compared with the pre-COVID cohort (19% vs 45%, difference of 26%, 95% CI 13% to 41%; p < 0.001). The proportion of bacteria detected was similar (p = 0.162), however, a difference in the bacterial spectrum was observed in the two cohorts. Haemophilus influenzae was the most frequent bacterial detection in both cohorts, followed by Streptococcus pneumoniae in the pre-COVID and Staphylococcus aureus in the COVID cohort. CONCLUSION: During the first year of the COVID-19 pandemic, the number of admissions with pneumonia and the microbiological detections in patients with suspected CAP, differed from the preceding year. This suggests that infection control measures related to COVID-19 restrictions have an overall and specific impact on respiratory tract infections, beyond reducing the spread of SARS-CoV-2.

Utilizing the MEST score for prognostic staging in IgA nephropathy.

BACKGROUND: The Oxford classification/MEST score is an established histopathologic scoring system for patients with IgA nephropathy (IgAN). The objective of this study was to derive a prognostic model for IgAN based on the MEST score and histopathologic features. METHODS: A total of 306 patients with biopsy-proven primary IgAN were included. Histopathologic samples were retrieved from the Norwegian Kidney Biopsy Registry and reclassified according to the Oxford classification. The study endpoint was end-stage renal disease (ESRD). Patients were subclassified into three risk models based on histologic features (Model A), a composite score calculated from the adjusted hazard ratio values (Model B), and on quartiles (Model C). RESULTS: The mean follow-up time was 16.5 years (range 0.2-28.1). In total, 61 (20%) patients reached ESRD during the study period. Univariate analysis of M, E, S, T and C lesions demonstrated that all types were associated with an increased risk of ESRD; however, a multivariate analysis revealed that only S, T and C lesions were associated with poor outcomes. Statistical analysis of 15-year data demonstrated that Models A and B were as predictive as the MEST score, with an area-under-the-curve at 0.85. The Harrel c index values were 0.81 and 0.80 for the MEST score and Models A and B, respectively. In the present cohort, adding C lesions to the MEST score did not improve the models prognostic value. CONCLUSIONS: Patients can be divided into risk classes based on their MEST scores. Histopathologic data provide valuable prognostic information at the time of diagnosis. Model B was the most suitable for clinical practice because it was the most user-friendly.

Proteinase-3 and myeloperoxidase serotype in relation to demographic factors and geographic distribution in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

Background: In anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, antigen specificity varies between myeloperoxidase (MPO) and proteinase 3 (PR3). This has been reported to vary in relation to age, gender, geography and extrarenal manifestations. However, studies are difficult to compare as criteria for inclusion vary. The aim of this study was to investigate the relationship between ANCA serotype, latitude, ultraviolet (UV) radiation levels, age, gender and renal function at diagnosis in a large study with uniform inclusion criteria. Methods: Patients with biopsy-proven ANCA-associated glomerulonephritis were identified from regional or nationwide registries in 14 centres in Norway, Sweden, the UK, the Czech Republic, Croatia, Italy and the USA during the period 2000-13. UV radiation levels for 2000-13 in Europe were obtained from the Swedish Meteorological and Hydrological Institute. Results: A total of 1408 patients (45.2% PR3-ANCA) were included in the study. In univariable analysis, PR3-ANCA was significantly associated with male gender {odds ratio [OR] 2.12 [95% confidence interval (CI) 1.71-2.62]}, younger age [OR per year 0.97 (95% CI 0.96-0.98)] and higher glomerular filtration rate [OR per mL/min 1.01 (95% CI 1.01-1.02); P < 0.001] at diagnosis but not with latitude or UV radiation. In multivariable logistic regression analysis, latitude and UV radiation also became significant, with higher odds for PR3-ANCA positivity at northern latitudes/lower UV radiation levels. However, the latitudinal difference in MPO:PR3 ratio is smaller than differences previously reported concerning microscopic polyangiitis and granulomatosis with polyangiitis. Conclusions: The ratio between PR3-ANCA and MPO-ANCA varies in glomerulonephritis with respect to age, gender, renal function and geographic latitude/UV radiation levels.

Aiming toWards Evidence baSed inTerpretation of Cardiac biOmarkers in patients pResenting with chest pain-the WESTCOR study: study design.

Objectives. The main aim of the Aiming toWards Evidence baSed inTerpretation of Cardiac biOmarkers in patients pResenting with chest pain (WESTCOR-study) (Clinical Trials number NCT02620202) is to improve diagnostic pathways for patients presenting to the Emergency department (ED) with acute chest pain. Design. The WESTCOR-study is a two center, cross-sectional and prospective observational study recruiting unselected patients presenting to the ED with suspected non-ST elevation acute coronary syndrome (NSTE-ACS). Patient inclusion started September 2015 and we plan to include 2250 patients, finishing in 2019. The final diagnosis will be adjudicated by two independent cardiologists based on all available information including serial high sensitivity cardiac troponin measurements, coronary angiography, coronary CT angiography and echocardiography. The study includes one derivation cohort (N = 985) that will be used to develop rule out/rule in algorithms for NSTEMI and NSTE-ACS (if possible) using novel troponin assays, and to validate established NSTEMI algorithms, with and without clinical scoring systems. The study further includes one subcohort (n = 500) where all patients are examined with coronary CT angiography independent of biomarker status, aiming to assess the associations between biomarkers and the extent and severity of coronary atherosclerosis. Finally, an external validation cohort (N = 750) will be included at Stavanger University Hospital. Prospective studies will be based on the merged cohorts. Conclusion. The WESTCOR study will provide new diagnostic algorithms for early inclusion and exclusion of NSTE-ACS and insights in the associations between cardiovascular biomarkers, CT-angiographic findings and short and long-term clinical outcomes.

Long-term outcome in 145 patients with assumed benign immunoglobulin A nephropathy.

BACKGROUND: Patients with immunoglobulin A nephropathy (IgAN) who present with mild to moderate proteinuria and normal renal function are assumed to have excellent short-term renal prognosis, but the long-term prognosis is uncertain. METHODS: Patients were selected from the Norwegian Kidney Biopsy Registry based on the following criteria: diagnostic renal biopsy performed in the period 1988-99, with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and proteinuria <1 g/24 h at the time of biopsy. Patients were invited for a nephrological examination with a review of medical history and investigation of blood pressure, urinary findings and eGFR. RESULTS: A total of 145 patients attended the examination, performed by the first author, after a median of 22 (interquartile range 19-25) years after diagnosis. At the examination, 27 patients (18.6%) had a ≥50% decrease in GFR, of whom 4 (2.8%) had developed end-stage renal disease (ESRD). The mean duration from renal biopsy to ≥ 50% decrease in GFR was 17.3 ± 5.1 years in our cohort. Clinical remission was observed in 42 (29.0%) patients. Renal biopsies were re-examined utilizing the Oxford classification criteria. Mesangial hypercellularity was found in 12.3%, endocapillary proliferation was detected in 10.7% and segmental glomerulosclerosis was observed in 23.8%. All biopsies were scored as T0 (tubular atrophy in < 25% of the cortical area). None of the clinical or histopathological variables recorded at the time of biopsy could identify patients with progressive disease. Cumulative risks of ≥50% decrease in eGFR were 2.1% after 10 years, 4.1% after 15 years, 13.9% after 20 years and 24.7% after 25 years. CONCLUSIONS: We have shown that 18.6% of patients with assumed benign IgAN had progressive disease after a median duration of 22 years and that these patients could not be predicted at the time of biopsy. Our study demonstrates that an extended follow-up period is needed when assessing prognosis in this group of patients.

Clinical decision support system for end-stage kidney disease risk estimation in IgA nephropathy patients.

BACKGROUND: The progression of IgA nephropathy (IgAN) to end-stage kidney disease (ESKD) depends on several factors that are not quite clear and tangle the risk assessment. We aimed at developing a clinical decision support system (CDSS) for a quantitative risk assessment of ESKD and its timing using available clinical data at the time of renal biopsy. METHODS: We included a total of 1040 biopsy-proven IgAN patients with long-term follow-up from Italy (N = 546), Norway (N = 441) and Japan (N = 53). Of these, 241 patients reached ESKD: 104 Italian [median time to ESKD = 5 (3-9) years], 134 Norwegian [median time to ESKD = 6 (2-11) years] and 3 Japanese [median time to ESKD = 3 (2-12) years]. We independently trained and validated two cooperating artificial neural networks (ANNs) for predicting first the ESKD status and then the time to ESKD (defined as three categories: ≤ 3 years, between > 3 and 8 years and over 8 years). As inputs we used gender, age, histological grading, serum creatinine, 24-h proteinuria and hypertension at the time of renal biopsy. RESULTS: The ANNs demonstrated high performance for both the prediction of ESKD (with an AUC of 89.9, 93.3 and 100% in the Italian, Norwegian and Japanese IgAN population, respectively) and its timing (f-measure of 90.7% in the cohort from Italy and 70.8% in the one from Norway). We embedded the two ANNs in a CDSS available online (www.igan.net). Entering the clinical parameters at the time of renal biopsy, the CDSS returns as output the estimated risk and timing of ESKD for the patient. CONCLUSIONS: This CDSS provides useful additional information for identifying 'high-risk' IgAN patients and may help stratify them in the context of a personalized medicine approach.

Addition of eGFR and Age Improves the Prognostic Absolute Renal Risk-Model in 1,134 Norwegian Patients with IgA Nephropathy.

BACKGROUND: Predicting outcome in individual patients with IgA nephropathy (IgAN) is difficult but important. For this purpose, the absolute renal risk (ARR) model has been developed in a French cohort to calculate the risk of end-stage renal disease (ESRD) and death. ARR (0-3) is scored in individual IgAN patients based on the presence of proteinuria ≥1 g/24 h, hypertension, and severe histopathological lesions (1 point per risk factor). We have validated the ARR model in a Norwegian cohort of IgAN patients and tested whether adding data on initial estimated glomerular filtration rate (eGFR) and age improved prediction. METHODS: IgAN patients diagnosed between 1988 and 2012 were identified in the Norwegian Kidney Biopsy Registry, and endpoints were identified by record linkage with the Norwegian Renal Registry (ESRD) and the Population Registry (deaths). RESULTS: We identified 1,134 IgAN patients. The mean duration of follow-up was 10.2 years (range 0.0 to 25.7 years). Two hundred and fifty one patients developed ESRD and there were 69 pre-ESRD deaths. The ARR model significantly stratified the IgAN cohort according to risk of ESRD/death. The inclusion of eGFR and age significantly improved the ARR prognostic model; in the receiver operator characteristics (ROC) analysis, area under the curve (AUC) at 10-years of follow-up increased from 0.79 to 0.89, p < 0.001. CONCLUSIONS: ARR is a suitable prognostic model for stratifying IgAN patients according to the risk of ESRD or death. Including initial eGFR and age in the model substantially improved its accuracy in our nationwide cohort.

Improved prognosis in Norwegian patients with glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies.

BACKGROUND: Glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased mortality and a high risk of end-stage renal disease (ESRD). Here, we investigated whether the prognosis has improved over the last 25 years. METHODS: Patients were identified in the Norwegian Kidney Biopsy Registry. We included all patients with pauci-immune crescentic glomerulonephritis and a positive ANCA test from 1988 to 2012. Deaths and ESRD in the cohort were identified through record linkage with the Norwegian Population Registry (deaths) and the Norwegian Renal Registry (ESRD). Outcomes of patients diagnosed in 1988-2002 were compared with outcomes of patients diagnosed in 2003-12. RESULTS: A cohort of 455 patients with ANCA-associated glomerulonephritis was identified. The mean follow-up was 6.0 years (range, 0.0-23.4). During the study period, 165 (36%) patients died and 124 (27%) progressed to ESRD. Compared with patients diagnosed in 1988-2002, those diagnosed in 2003-12 had higher mean initial estimated glomerular filtration rates (37 versus 27 mL/min/1.73 m(2)) and lower risk of ESRD (1-year risk: 13 versus 19%; 10-year risk: 26 versus 37%). The composite endpoint, ESRD or death within 0-1 year after diagnosis, was reduced from 34 to 25%. In patients over 60 years old, 1-year mortality fell from 33 to 20%. CONCLUSIONS: In Norwegian patients with ANCA-associated glomerulonephritis, prognosis was significantly better in 2003-12 compared with 1988-2002. This improvement was probably partly due to a shorter diagnostic delay, and better therapeutic management in older patients.

Prognostic value of growth differentiation factor-15 3 months after an acute chest pain admission.

OBJECTIVE: Growth differentiation factor-15 (GDF-15) is a predictor of death and cardiovascular events when measured during index hospitalisation in patients with acute chest pain. This study investigated the prognostic utility of measuring GDF-15 3 months after an admission with suspected non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS: GDF-15 was measured at baseline and 3 months after admission in 758 patients admitted with suspected NSTE-ACS. Patients were followed for a median of 1540 (IQR: 1087-1776) days after the 3-month visit. The primary endpoint was all-cause mortality, while the secondary composite endpoint included all-cause mortality, incident myocardial infarction and heart failure hospitalisation during follow-up. RESULTS: In patients with GDF-15 ≥1200 pg/mL (n=248), 18% died and 25% met the composite endpoint. In patients with GDF-15 <1200 pg/mL (n=510), 1.7% died and 4% met the composite endpoint. The GDF-15 concentration (log2 transformed) at 3 months was significantly associated with all-cause mortality (adjusted HR: 2.2, 95% CI: 1.4 to 3.3, p<0.001) and the composite endpoint (adjusted HR: 1.9, 95% CI: 1.4 to 2.7, p<0.001), independently of traditional risk factors and baseline troponin T. A 10% change in GDF-15 concentration from baseline to the 3-month visit was associated with increased risk of all-cause mortality (HR: 1.06, 95% CI: 1.01 to 1.13, p=0.031), adjusting for baseline GDF-15 concentrations. CONCLUSIONS: High GDF-15 concentrations 3 months after admission for suspected NSTE-ACS are associated with long-term mortality and cardiovascular events, independent of traditional risk factors and troponin T. A change in GDF-15 concentration can provide prognostic information.

Microbial aetiology of community-acquired pneumonia in hospitalised adults: A prospective study utilising comprehensive molecular testing.

OBJECTIVES: This study aimed to describe the microbial aetiology of community-acquired pneumonia (CAP) in adults admitted to a tertiary care hospital and assess the impact of syndromic polymerase chain reaction (PCR) panels on pathogen detection. METHODS: Conducted at Haukeland University Hospital, Norway, from September 2020 to April 2023, this prospective study enrolled adults with suspected CAP. We analysed lower respiratory tract samples using both standard-of-care tests and the BIOFIRE® FILMARRAY® Pneumonia Plus Panel (FAP plus). The added value of FAP Plus in enhancing the detection of clinically relevant pathogens, alongside standard-of-care diagnostics, was assessed. RESULTS: Of the 3238 patients screened, 640 met the inclusion criteria, with 384 confirmed to have CAP at discharge. In these patients, pathogens with proven or probable clinical significance were identified in 312 (81.3%) patients. Haemophilus influenzae was the most prevalent pathogen, found in 118 patients (30.7%), followed by SARS-CoV-2 in 74 (19.3%), and Streptococcus pneumoniae in 64 (16.7%). Respiratory viruses were detected in 186 (48.4%) patients. The use of FAP plus improved the pathogen detection rate from 62.8% with standard-of-care methods to 81.3%. CONCLUSIONS: Pathogens were identified in 81% of CAP patients, with Haemophilus influenzae and respiratory viruses being the most frequently detected pathogens. The addition of the FAP plus panel, markedly improved pathogen detection rates compared to standard-of-care diagnostics alone.

Diagnostic Stewardship in Community-Acquired Pneumonia With Syndromic Molecular Testing: A Randomized Clinical Trial.

Importance: Lower respiratory tract (LRT) infections, including community-acquired pneumonia (CAP), are a leading cause of hospital admissions and mortality. Molecular tests have the potential to optimize treatment decisions and management of CAP, but limited evidence exists to support their routine use. Objective: To determine whether the judicious use of a syndromic polymerase chain reaction (PCR)-based panel for rapid testing of CAP in the emergency department (ED) leads to faster, more accurate microbiological test result-based treatment. Design, Setting, and Participants: This parallel-arm, single-blinded, single-center, randomized clinical superiority trial was conducted between September 25, 2020, and June 21, 2022, in the ED of Haukeland University Hospital, a large tertiary care hospital in Bergen, Norway. Adult patients who presented to the ED with suspected CAP were recruited. Participants were randomized 1:1 to either the intervention arm or standard-of-care arm. The primary outcomes were analyzed according to the intention-to-treat principle. Intervention: Patients randomized to the intervention arm received rapid syndromic PCR testing (BioFire FilmArray Pneumonia plus Panel; bioMérieux) of LRT samples and standard of care. Patients randomized to the standard-of-care arm received standard microbiological diagnostics alone. Main Outcomes and Measures: The 2 primary outcomes were the provision of pathogen-directed treatment based on a microbiological test result and the time to provision of pathogen-directed treatment (within 48 hours after randomization). Results: There were 374 patients (221 males [59.1%]; median (IQR) age, 72 [60-79] years) included in the trial, with 187 in each treatment arm. Analysis of primary outcomes showed that 66 patients (35.3%) in the intervention arm and 25 (13.4%) in the standard-of-care arm received pathogen-directed treatment, corresponding to a reduction in absolute risk of 21.9 (95% CI, 13.5-30.3) percentage points and an odds ratio for the intervention arm of 3.53 (95% CI, 2.13-6.02; P < .001). The median (IQR) time to provision of pathogen-directed treatment within 48 hours was 34.5 (31.6-37.3) hours in the intervention arm and 43.8 (42.0-45.6) hours in the standard-of-care arm (mean difference, -9.4 hours; 95% CI, -12.7 to -6.0 hours; P < .001). The corresponding hazard ratio for intervention compared with standard of care was 3.08 (95% CI, 1.95-4.89). Findings remained significant after adjustment for season. Conclusions and Relevance: Results of this randomized clinical trial indicated that routine deployment of PCR testing for LRT pathogens led to faster and more targeted microbial treatment for patients with suspected CAP. Rapid molecular testing could complement or replace selected standard, time-consuming, laboratory-based diagnostics. Trial Registration: ClinicalTrials.gov Identifier: NCT04660084.