Abstract: Dasatinib has been associated with nephrotoxicity. We sought to examine the incidence of proteinuria on dasatinib and determine potential risk factors that may increase dasatinib-associated glomerular injury. Methods We examined glomerular injury through urine albumin-creatinine ratio (UACR) in 82 patients with chronic myelogenous leukemia who were on tyrosine-kinase inhibitor therapy for at least 90 days. t tests were used to compare mean differences in UACR, while regression analysis was used to assess the effects of drug parameters on proteinuria development while on dasatinib. We assayed plasma dasatinib pharmacokinetics using tandem mass spectroscopy and further described a case study of a patient who experienced nephrotic-range proteinuria while on dasatinib. Results Participants treated with dasatinib ( n =32) had significantly higher UACR levels (median 28.0 mg/g; interquartile range, 11.5–119.5) than participants treated with other tyrosine-kinase inhibitors ( n =50; median 15.0 mg/g; interquartile range, 8.0–35.0; P 〈 0.001). In total, 10% of dasatinib users exhibited severely increased albuminuria (UACR 〉 300 mg/g) versus zero in other tyrosine-kinase inhibitors. Average steady-state concentrations of dasatinib were positively correlated with UACR ( ρ =0.54, P = 0.03) and duration of treatment ( P = 0.003). There were no associations with elevated BP or other confounding factors. In the case study, kidney biopsy revealed global glomerular damage with diffuse foot process effacement that recovered on termination of dasatinib treatment. Conclusions Exposure to dasatinib was associated with a significant chance of developing proteinuria compared with other similar tyrosine-kinase inhibitors. Dasatinib plasma concentration significantly correlated with higher risk of developing proteinuria while receiving dasatinib. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_09_08_CJN0000000000000219.mp3

Abstract: 〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 Chronic smoking and hypertension may lead to smoking-related nodular glomerulopathy (SRNG), a well-recognized entity that clinically and pathologically mimics nodular diabetic nephropathy (DN). However, like DN, diffuse mesangial sclerosis may occur in this setting without nodules. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 The clinicopathologic features of 10 non-diabetic patients with a long smoking history diagnosed from 2003-2012 showing diffuse mesangial glomerulosclerosis (6) or SRNG (4) were analyzed. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Nine of 10 patients were men, aged 58-80 with a 20-58 pack-year smoking history. None of the patients manifested diabetes, but all of them had hypertension. Numerous other cardiovascular comorbidities were present. At biopsy, the mean creatinine was 1.9 mg/dl (range 1.4-3) and the mean proteinuria was 3.9 g/24 h. The renal pathologic findings were similar in all patients except mesangial nodules in SRNG. Global glomerulosclerosis was seen in 6-72% of glomeruli (mean 31%), glomerulomegaly in all cases, and a range of interstitial fibrosis in 10-70% (mean 43%). Moderate (40%) and severe (50%) arteriosclerosis and arteriolar hyalinosis (80%) were also observed. Glomerular hilar or mesangial neovascularization was prominent. Endothelial swelling, subendothelial widening, and new basement membrane formation suggesting chronic healing thrombotic microangiopathy (TMA) was noted in 80%. No immune complexes were localized. 〈 b 〉 〈 i 〉 Conclusions: 〈 /i 〉 〈 /b 〉 Kidney biopsies from patients with proteinuria and chronic renal insufficiency in the setting of prolonged smoking and hypertension show either diffuse or nodular mesangial glomerulosclerosis. Chronic glomerular mesangial and endothelial injury associated with smoking leads to a chronic TMA appearance in the appropriate setting, even in the absence of mesangial nodule formation.

Abstract: A substantial proportion of patients with severe COVID-19 pneumonia develop thrombosis (both venous and arterial) via an undefined mechanism. Systemic elevation of high levels of D-dimer, a marker of coagulation activation and thrombolysis, is evident in almost all advanced COVID-19 patients and is associated with disease severity and mortality. However, the extrinsic factors that initiate blood coagulation in COVID-19 is not clear. Because tissue factor (TF) is the prime initiator of the extrinsic coagulation cascade, and because it is expressed and exposed under inflammatory conditions leading to vascular damage, we tested the hypothesis that higher TF expression is responsible for thrombi formation in the lungs of patients with severe COVID-19. To this end, we examined autopsy lung tissues from five COVID-19 pneumonia patients with acute respiratory syndrome (ARDS) who required ICU hospitalization, with 4 of the 5 patients requiring mechanical ventilation before they died, and five controls with acute ARDS caused by bacterial pneumonia, one with a prior influenza infection, and all on mechanical ventilation. Histological findings revealed all the COVID-19 lungs had characteristics of ARDS, including DAD with hyaline deposition and inflammatory cell invasion. Immunofluorescence staining showed TF expression throughout all lung tissues and in many blood vessels that were filled with thrombi with either fibrin, activated platelets, or both. TF expression was significantly higher in COVID-19 than control ARDS lung tissues (1.2 ± 0.3% in COVID-19 vs. 0.52 ± 0.2% in ARDS controls (p=0.004). Fibrin-enriched thrombi areas were higher in COVID-19 cases than in controls (1.6 ± 0.36% vs. 0.94 ± 0.4%; p=0.008) and correlated with TF expression (R2=0.4, p=0.02). Platelet factor 4 (PF4)-enriched thrombi areas were also higher in COVID-19 lung, but this trend was not statistically significant (0.94 ± 0.4% in COVID-19 and 0.54 ± 0.3% in controls; p=0.09), although it did, however, correlate with TF expression (R2=0.4, p=0.02). Many thrombi were in close proximity to TF-expressing areas in both COVID-19 and ARDS pneumonia controls. Dual RNA in situ hybridization with SARS-CoV-2 and TF fluorescence probes showed variable viral and TF mRNA expression. Increased TF mRNA expression was seen in COVID-19 vs. control lung (0.77 ± 0.4 % vs. 0.31 ± 0.15 %, p=0.05). TF mRNA expression correlated with viral mRNA in COVID-19 patients (R2=0.78, p=0.01). High-resolution images identified both sporadic and clustered SARS-CoV-2, and some areas co-localized with TF mRNA expression. We conclude that higher TF expression might be responsible for fibrin formation and platelet activation in the lungs of both COVID-19 and ARDS controls. Our observation of higher TF expression in COVID-19 patients was documented by two very sensitive methods, RNA in situ hybridization and immunostaining with very specific antibodies against TF and mRNA probes. Its correlation with SARS-CoV-2 mRNA suggests that SARS-CoV-2 infection induces both de novo gene transcription and protein synthesis in the lungs of COVID-19 patients. Thus, TF-initiated extrinsic coagulation might be responsible for the critical thrombi formation observed in many COVID-19 cases, rendering TF a potential therapeutic target. Disclosures Laurence: Alexion Pharmaceuticals: Honoraria, Research Funding.

Abstract: Background: Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell dyscrasias in which deposition of immunoglobulin light and/or heavy chains results in organ dysfunction, most commonly affecting the kidneys. MIDD can present with new onset hypertension, hematuria, renal insufficiency and proteinuria. The rarity of MIDD contributes to the uncertainty regarding optimal therapy (typically targeting the clonal plasma cells), and the relationship between hematologic response and renal outcome. We report here the experience at Memorial Sloan Kettering Cancer Center and New York Presbyterian Hospital/Weill Cornell Medical Center. Methods: An electronic query of pathology records was performed to identify patients with a biopsy-proven diagnosis of MIDD. Patients were eligible for inclusion in this analysis if they had received treatment and had been subsequently followed at either institution. A retrospective review of clinical records extracted patients' baseline characteristics and treatment history. Hematologic responses were assessed according to International Myeloma Working Group uniform response criteria (Kumar, S. et al 2016 Lancet Oncol 17(8): e328-346) and renal organ responses were evaluated based on changes in serum creatinine (SCr), and proteinuria, a modification of criteria previously reported (Kourelis, T. V., et al 2016, Am J Hematol 91(11): 1123-1128.; Nasr, S.H. et al. 2009, J Am Soc Nephrol 20(9): 2055-2064. The primary objective was to determine the rate of hematologic response after initial therapy. Secondary objectives included: (i) Estimation of renal response rate; (ii) Identification of risk factors associated with renal response using the Wilcoxon Rank Sum and Fisher's Exact Tests. Results: Among 54 patients identified who were diagnosed and started treatment between 1/1999 and 1/2016, 29 met criteria for inclusion. Baseline characteristics at diagnosis included: Median age of 50 (range, 32-79); 17 (59%) were male; 22 (75%) had hypertension. Renal parameters at diagnosis: median SCr of 2.4 mg/dl (range, 0.4-19), median CrCl 23 ml/min (range, 4-131), median proteinuria 2383.7mg/24h (range 4.7-13,000), nephrotic-range proteinuria syndrome in 13 (45%), hematuria in 4/25 pts (16%; 4 unknown), 7 were on hemodialysis (HD) prior to initiation of therapy, and 26 (90%) patients had monoclonal kappa light chain deposits. Hematologic parameters included median free light chain ratio of 67.9 (2.8-1179.0), detectable M-spike in 11 pts with a mean level of 0.6 g/dL and median bone marrow plasmacytosis of 20% (range, 0-90%). Induction treatment regimens included bortezomib in 18 (62%), lenalidomide in 6 (21%), cyclophosphamide in 8 (28%), and 21 (73%) underwent autologous stem cell transplant (ASCT) during the course of their treatment. Outcomes are shown in Table 1. Hematologic response among the 29 pts at completion of first line therapy included an overall response rate (ORR) of 93% with sCR (N=14, 48%); CR (N=5, 17%), VGPR (N=6, 20%), PR (N=2, 6.9%), Not available (N=2, 7%). Renal response (Table 1) among 29 patients included CR (N=9, 31%), PR (N=14, 48%) and End Stage Renal Disease (ESRD) (N=6, 21%). Among 7 patients on HD at baseline, 3 remained on HD despite treatment, while 4 stopped HD after treatment, 2 as a result of the treatment and 2 after renal transplant. 3 patients progressed to ESRD and required HD during treatment. Baseline beta-2 microglobulin (B2M), SCr, and eGFR at diagnosis were factors associated with renal response (p 〈 0.05). Hematologic response (CR vs. non-CR) was not associated with renal response (p=0.68) in this cohort. Conclusions: In this cohort, we observed a high rate of hematologic response (65.5% reaching CR) to upfront treatment regimens. A majority of patients received bortezomib-based regimens and ASCT. We observed a large proportion of patients whose renal impairment from MIDD improved significantly after receiving therapy directed at the underlying clonal neoplasm, with 75.8% reaching PR or better, nearly a third of patients achieving a renal CR, and 2/7 patients on HD at diagnosis discontinuing HD after treatment. Our experience presented here serves to inform the treatment approach of patients with MIDD. Given the scarcity of outcome data in MIDD, especially in the era of novel anti-myeloma therapy, prospective studies to optimize the management of these patients are needed. Disclosures Rossi: Celgene: Consultancy. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Korde:Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding. Lesokhin:Squibb: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Janssen: Research Funding; Serametrix, inc.: Patents & Royalties: Royalties. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hassoun:Oncopeptides AB: Research Funding.

Abstract: Substance use disorders (SUD) are associated with cognitive deficits that are not always addressed in current treatments, and this hampers recovery. Cognitive training and remediation interventions are well suited to fill the gap for managing cognitive deficits in SUD. We aimed to reach consensus on recommendations for developing and applying these interventions. Design, Setting and Participants We used a Delphi approach with two sequential phases: survey development and iterative surveying of experts. This was an on‐line study. During survey development, we engaged a group of 15 experts from a working group of the International Society of Addiction Medicine (Steering Committee). During the surveying process, we engaged a larger pool of experts ( n  = 54) identified via recommendations from the Steering Committee and a systematic review. Measurements Survey with 67 items covering four key areas of intervention development: targets, intervention approaches, active ingredients and modes of delivery. Findings Across two iterative rounds (98% retention rate), the experts reached a consensus on 50 items including: (i) implicit biases, positive affect, arousal, executive functions and social processing as key targets of interventions; (ii) cognitive bias modification, contingency management, emotion regulation training and cognitive remediation as preferred approaches; (iii) practice, feedback, difficulty‐titration, bias modification, goal‐setting, strategy learning and meta‐awareness as active ingredients; and (iv) both addiction treatment work‐force and specialized neuropsychologists facilitating delivery, together with novel digital‐based delivery modalities. Conclusions Expert recommendations on cognitive training and remediation for substance use disorders highlight the relevance of targeting implicit biases, reward, emotion regulation and higher‐order cognitive skills via well‐validated intervention approaches qualified with mechanistic techniques and flexible delivery options.