Prospective urinary albumin/creatinine ratio for diagnosis, staging, and organ response assessment in renal AL amyloidosis: results from a large cohort of patients

Abstract Objectives Quantification of 24 h-proteinuria is the gold standard for diagnosing, staging, and monitoring of patients with renal AL amyloidosis. However, 24 h-urine collection is cumbersome and may result in preanalytical error. In this prospective study, we investigated the role of urinary albumin/creatinine ratio (UACR) (cut-off: 300 mg/g) identifying renal involvement, evaluated a UACR-based staging system (UACR cut-off: 3,600 mg/g) and assessed whether UACR response (UACR decrease >30% without worsening in eGFR >25%) predicts renal outcome in 531 patients with newly-diagnosed AL amyloidosis. Methods From October 2013 paired 24 h-proteinuria and UACR (on first morning void) were measured in all newly-diagnosed patients with AL amyloidosis. Correlation between 24 h-proteinuria and UACR at baseline was assessed by Pearson's r test. Impact of UACR response on renal outcome was assessed in randomly created testing (n=354) and validation (n=177) cohorts. Results A strong linear correlation was found between 24 h-proteinuria and UACR at baseline (r=0.90; p<0.001). After a median follow-up of 31 months, 57 (11%) patients required dialysis. A UACR-based renal staging system identified three stages with significantly higher dialysis rate at 36 months comparing stage I with stage II and stage II with stage III. Achieving a renal response, according to a UACR-based criterion, resulted in lower dialysis rate in both testing and validation cohorts. Conclusions UACR is a reliable marker for diagnosis, prognosis, and organ response assessment in renal AL amyloidosis and can reliably replace 24 h-proteinuria in clinical trials and individual patients' management

Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis

© The Author(s) 2021.Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.This study was supported by a grant from CARIPLO “Molecular mechanisms of Ig toxicity in age-related plasma cell dyscrasias no. 2015-0591”, by a grant from the Black Swan Research Initiative from the International Myeloma Foundation “Automated multidimensional flow cytometry for high-sensitive screening and to monitor response in AL amyloidosis”, by a grant from CARIPLO “Structure–function relation of amyloid: understanding the molecular bases of protein misfolding diseases to design new treatments no. 2013-0964”, by a grant from the Amyloidosis Foundation “Investigating new therapies to treat AL amyloidosis”, and by a grant from Cancer Research UK, FCAECC and AIRC under the Accelerator Award 2017 Program “Early detection and intervention: understanding the mechanisms of transformation and hidden resistance of incurable hematological malignancies”, by a grant from CARIPLO “Harnessing the plasma cell secretory capacity against systemic light chain amyloidosis” (no. 2018-0257), by a grant from the Italian Ministry of Health “Towards effective, patient-tailored anti-plasma cell therapies in AL amyloidosis: predicting drug response and overcoming drug resistance” (GR-2018-12368387). This study has also supported the Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369, CB16/12/00400, and CB16/12/00489) and the Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI13/02196). G.P. is supported in part by the Bart Barlogie Young Investigator Award from the International Myeloma Society (IMS). P.M. is supported in part by a fellowship grant form Collegio Ghislieri (Pavia). We acknowledge the study coordinator and data manager Anna Carnevale Baraglia

The INSIEME seismic network: a research infrastructure for studying induced seismicity in the High Agri Valley (southern Italy)

International audienceAbstract. The High Agri Valley is a tectonically active area in southern Italy characterized by high seismic hazard related to fault systems capable of generating up to M=7 earthquakes (i.e. the 1857 Mw=7 Basilicata earthquake). In addition to the natural seismicity, two different clusters of induced microseismicity were recognized to be caused by industrial operations carried out in the area: (1) the water loading and unloading operations in the Pertusillo artificial reservoir and (2) the wastewater disposal at the Costa Molina 2 injection well. The twofold nature of the recorded seismicity in the High Agri Valley makes it an ideal study area to deepen the understanding of driving processes of both natural and anthropogenic earthquakes and to improve the current methodologies for the discrimination between natural and induced seismic events by collecting high-quality seismic data. Here we present the dataset gathered by the INSIEME seismic network that was installed in the High Agri Valley within the SIR-MIUR research project INSIEME (INduced Seismicity in Italy: Estimation, Monitoring, and sEismic risk mitigation). The seismic network was planned with the aim to study the two induced seismicity clusters and to collect a full range of open-access data to be shared with the whole scientific community. The seismic network is composed of eight stations deployed in an area of 17 km×11 km around the two clusters of induced microearthquakes, and it is equipped with triaxial weak-motion broadband sensors placed at different depths down to 50 m. It allows us to detect induced microearthquakes, local and regional earthquakes, and teleseismic events from continuous data streams transmitted in real time to the CNR-IMAA Data Centre. The network has been registered at the International Federation of Digital Seismograph Networks (FDSN) with code 3F. Data collected until the end of the INSIEME project (23 March 2019) are already released with open-access policy through the FDSN web services and are available from IRIS DMC (https://doi.org/10.7914/SN/3F_2016; Stabile and INSIEME Team, 2016). Data collected after the project will be available with the permanent network code VD (https://doi.org/10.7914/SN/VD, CNR IMAA Consiglio Nazionale delle Ricerche, 2019) as part of the High Agri Valley geophysical Observatory (HAVO), a multi-parametric network managed by the CNR-IMAA research institute