Proceedings of the 2022 UAB CRRT Academy: Non-Invasive Hemodynamic Monitoring to Guide Fluid Removal with CRRT and Proliferation of Extracorporeal Blood Purification Devices.

In 2022, we celebrated the 15th anniversary of the University of Alabama at Birmingham (UAB) Continuous Renal Replacement Therapy (CRRT) Academy, a 2-day conference attended yearly by an international audience of over 100 nephrology, critical care, and multidisciplinary trainees and practitioners. This year, we introduce the proceedings of the UAB CRRT Academy, a yearly review of select emerging topics in the field of critical care nephrology that feature prominently in the conference. First, we review the rapidly evolving field of non-invasive hemodynamic monitoring and its potential to guide fluid removal by renal replacement therapy (RRT). We begin by summarizing the accumulating data associating fluid overload with harm in critical illness and the potential for harm from end-organ hypoperfusion caused by excessive fluid removal with RRT, underscoring the importance of accurate, dynamic assessment of volume status. We describe four applications of point-of-care ultrasound used to identify patients in need of urgent fluid removal or likely to tolerate fluid removal: lung ultrasound, inferior vena cava ultrasound, venous excess ultrasonography, and Doppler of the left ventricular outflow track to estimate stroke volume. We briefly introduce other minimally invasive hemodynamic monitoring technologies before concluding that additional prospective data are urgently needed to adapt these technologies to the specific task of fluid removal by RRT and to learn how best to integrate them into practical fluid-management strategies. Second, we focus on the growth of novel extracorporeal blood purification devices, starting with brief reviews of the inflammatory underpinnings of multiorgan dysfunction and the specific applications of pathogen, endotoxin, and/or cytokine removal and immunomodulation. Finally, we review a series of specific adsorptive technologies, several of which have seen substantial clinical use during the COVID-19 pandemic, describing their mechanisms of target removal, the limited existing data supporting their efficacy, ongoing and future studies, and the need for additional prospective trials.

Inhibition of HSP 90 is associated with potent anti-tumor activity in Papillary Renal Cell Carcinoma.

BACKGROUND: There is no universally accepted treatment for patients with advanced papillary renal cell carcinoma (PRCC). The presence of activating mutations in MET, as well as gain of chromosome 7, where the MET gene is located, are the most common genetic alterations associated with PRCC, leading to the clinical evaluation of MET tyrosine kinase inhibitors (TKIs) in this cancer. However, TKIs targeting MET selectively, as well as multitargeted TKIs with activity against MET demonstrate modest efficacy in PRCC and primary and secondary treatment failure is common; other approaches are urgently needed to improve outcomes in these patients. METHODS: High throughput screening with small molecule libraries identified HSP90 inhibitors as agents of interest based on antitumor activity against patient derived PRCC cell lines. We investigated the activity of the orally available HSP90 inhibitor, SNX2112 in vitro, using 2D/3D PRCC cell culture models and in vivo, in mice tumor xenograft models. The molecular pathways mediating antitumor activity of SNX2112 were assessed by Western blot analysis, Flow cytometry, RNA-seq analysis, Real Time qPCR and imaging approaches. RESULTS: SNX2112 significantly inhibited cellular proliferation, induced G2/M cell cycle arrest and apoptosis in PRCC lines overexpressing MET. In contrast to TKIs targeting MET, SNX2112 inhibited both MET and known downstream mediators of MET activity (AKT, pAKT1/2 and pERK1/2) in PRCC cell lines. RNAi silencing of AKT1/2 or ERK1/2 expression significantly inhibited growth in PRCC cells. Furthermore, SNX2112 inhibited a unique set of E2F and MYC targets and G2M-associated genes. Interestingly, interrogation of the TCGA papillary RCC cohort revealed that these genes were overexpressed in PRCC and portend a poor prognosis. Finally, SNX-2112 demonstrated strong antitumor activity in vivo and prolonged survival of mice bearing human PRCC xenograft. CONCLUSIONS: These results demonstrate that HSP90 inhibition is associated with potent activity in PRCC, and implicate the PI3K/AKT and MEK/ERK1/2 pathways as important mediators of tumorigenesis. These data also provide the impetus for further clinical evaluation of HSP90, AKT, MEK or E2F pathway inhibitors in PRCC.

Reducing the drivers of drug demand in English towns by understanding risk and resilience in the community and developing a framework for partnership action: a mixed methods analysis.

BACKGROUND: Substance misuse has extensive effects on individuals and communities, ranging from the poor health of people who use drugs to the pressure placed on health care, social services, and the criminal justice system. Strategies to curtail the supply and demand of drugs and reduce these effects typically focus on supply, with less emphasis placed on the drivers of demand. We piloted and evaluated a public health approach for understanding the drivers and effects of substance misuse in a local area, and how these might be targeted for prevention through multi-agency partnership action. METHODS: A cross-sectional mixed methods analysis was conducted, using multi-agency data. 3 years of data provided by criminal justice agencies (police, youth justice, and probation), drug treatment services, social care, education, and hospitals were used to profile the local demand and effect of drugs on individuals and communities in a coastal town in southern England. The experiences of local professionals who support people who misuse drugs, or people affected by drug misuse, were collected via an online survey that was disseminated to relevant partnership organisations, including homelessness charities and drug treatment providers. A public health framework identifying relevant risk and resilience factors in the community was developed by combining the multi-agency data and survey responses The methodological efficacy of this approach to inform partnership action was evaluated via a survey with the project's stakeholders. FINDINGS: Community housing, mental health, and cycles entrenching substance misuse were identified as risk factors that increase individual-level, interpersonal-level, and community-level vulnerabilities to the harms of drug misuse, violence, and exploitation. Evaluation found this mixed-methods analysis for understanding risk and resilience to be a valuable approach to enable public health and community safety leaders to develop a framework for partnership action to reduce the negative effects of drug demand in the community. INTERPRETATION: Analysis of multi-agency data helped to further a shared understanding in local partners of the drivers and effects of drug demand at a local level; and, through a public health lens, clearly identified the role that local organisations can play in minimising the harms of substance misuse and exploitation. FUNDING: No funding received.

Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration-Resistant Prostate Cancer.

Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40. Pull-down studies using biotinylated-C86 found Hsp40 present in a multiprotein complex with full-length (FL-) AR, ARv7, and Hsp70 in CRPC cells. Treatment of CRPC cells with C86 or the allosteric Hsp70 inhibitor JG98 resulted in rapid protein destabilization of both FL-AR and ARv, including ARv7, concomitant with reduced FL-AR- and ARv7-mediated transcriptional activity. The glucocorticoid receptor, whose elevated expression in a subset of CRPC also leads to androgen-independent AR target gene transcription, was also destabilized by inhibition of Hsp40 or Hsp70. In vivo, Hsp40 or Hsp70 inhibition demonstrated single-agent and combinatorial activity in a 22Rv1 CRPC xenograft model. These data reveal that, in addition to recognized roles of Hsp40 and Hsp70 in FL-AR LBD remodeling, ARv lacking the LBD remain dependent on molecular chaperones for stability and function. Our findings highlight the feasibility and potential benefit of targeting the Hsp40/Hsp70 chaperone axis to treat prostate cancer that has become resistant to standard antiandrogen therapy.Significance: These findings highlight the feasibility of targeting the Hsp40/Hsp70 chaperone axis to treat CRPC that has become resistant to standard antiandrogen therapy. Cancer Res; 78(14); 4022-35. ©2018 AACR.

Mismatch in breast and detector size during screening and diagnostic mammography results in increased patient radiation dose.

RATIONALE AND OBJECTIVES: When using mammographic detectors of different sizes, it can be difficult to match patient breast size to optimal detector size. We studied whether a mismatch between breast size and optimal detector size resulted in increased radiation exposure. MATERIALS AND METHODS: All screening and diagnostic (Dx) mammography patients during a 6-week period in November-December 2009 (864 patients) were evaluated (institutional review board exemption for quality assurance studies). Data gathered included breast size (large or small), detector size used, number of views obtained, mean glandular dose (MGD) per breast, and patient waiting time. Average MGD and average waiting time was calculated for imaging performed on appropriately matched or mismatched breast size-detector size pairs. RESULTS: Screening mammography patients with large breasts imaged on a small detector received a significantly higher radiation dose (4.9 vs. 3.3 mGy, P < .05) and a greater number of views (5.9 vs. 4.6, P < .05) compared to optimally matched breast-detector pairs. Dx mammography patients with large breasts imaged on a small detector received a higher radiation dose (8.2 vs. 6.7 mGy, P < .05) compared to optimally matched breast-detector pairs, although without an increased number of views. Waiting times were longer for a large detector. CONCLUSIONS: A mismatch in breast-detector sizes results in a significantly greater radiation dose to patients with large breasts imaged on a small detector. Pressure to minimize patient waiting time may inadvertently result in increased radiation dose. Detector size should be matched to breast size whenever possible, but particularly for patients with larger breast sizes.

Ambulatory blood pressure monitoring and peri-hemodialysis blood pressures in a southeast US hemodialysis unit.

AIMS: End-stage renal disease (ESRD) patients on dialysis are perceived to have difficult-to-control blood pressure (BP) and commonly treated with complex antihypertensive regimens. Our hypothesis was that peri-dialysis BP will overestimate the true burden of hypertension in these patients. SUBJECTS AND METHODS: We performed 44-h ambulatory blood pressure monitoring (ABPM) in 43 patients recruited from the University of Mississippi outpatient dialysis unit. Data collected included routine peri-dialysis blood systolic blood pressure (SBP), diastolic blood pressure (DBP), weight gain, and demographic information. We investigated whether the pre-dialysis or post-dialysis blood pressure would better correspond to the ABPM results. RESULTS: The mean age of participants was 50.5 ± 12.05 years, 95% African-American, and 44% diabetic with an average dialysis vintage of 31.1 ± 30 months. The mean SBP and DBP were 164.6/87.9 mmHg ± 22.3/15 before dialysis, 151.5/81.3 mmHg ± 24.1/13 after dialysis and 136/80.6 mmHg ± 23.5/14.7 during ABPM. There were wide limits of agreements between peri-dialysis BP and ABPM, the largest with pre-dialysis SBP (28.5 ± 16.6 mmHg) and the least with post-dialysis DBP (0.7 ± 10 mmHg). With both peri-dialysis BP measurements as explanatory variables in a linear regression model, only the post-dialysis SBP (ß 0.716; p < 0.001) but not pre-dialysis SBP (ß 0.157; p = 0.276) had a significant independent association with ABPM systolic BP. For DBP, both pre-dialysis (ß 0.543; p = 0.001) and post-dialysis (ß 0.317; p = 0.037) values retained correlation with DBP on ABPM. CONCLUSION: Peri-dialysis measurements overestimated true BP burden in this Southeastern U.S. cohort of ESRD patients. When BP readings from outside the dialysis unit are notavailable, assessment of BP control should focus pre-dialysis on DBP and post-dialysison both SBP and DBP.

Radiofrequency and microwave tumor ablation in patients with implanted cardiac devices: is it safe?

PURPOSE: To identify malfunction of implanted cardiac devices during or after thermal ablation of tumors in lung, kidney, liver or bone, using radiofrequency (RF) or microwave (MW) energy. MATERIALS AND METHODS: After providing written consent, 19 patients (15 men and 4 women; mean age 78 years) with pacemakers or pacemaker/defibrillators underwent 22 CT image-guided percutaneous RF or MW ablation of a variety of tumors. Before and after each procedure, cardiac devices were interrogated and reprogrammed by a trained cardiac electrophysiology fellow. Possible pacer malfunctions included abnormalities on electrocardiographic (EKG) monitoring and alterations in device settings. Our institutional review board approved this Health Insurance Portability and Accountability Act-compliant study. Informed consent for participation in this retrospective study was deemed unnecessary by our review board. RESULTS: During 20 of 22 sessions, no abnormalities were identified in continuous, EKG tracings or pacemaker functions. However, in two sessions significant changes, occurred in pacemaker parameters: inhibition of pacing during RF application in one, session and resetting of mode by RF energy in another session. These changes did not, result in hemodynamic instability of either patient. MW ablation was not associated with, any malfunction. In all 22 sessions, pacemakers were undamaged and successfully reset to original parameters. CONCLUSION: RF or MW ablation of tumors in liver, kidney, bone and lung can be performed safely in patients with permanent intra-cardiac devices, but careful planning between radiology and cardiology is essential to avoid adverse outcomes.

Correlation of treatment time and ultrafiltration rate with serum albumin and C-reactive protein levels in patients with end-stage kidney disease receiving chronic maintenance hemodialysis: a cross-sectional study.

BACKGROUND: The relationship between treatment time, ultrafiltration rate (UFR) and inflammation has received limited exploration so far. METHODS: This is a cross-sectional cohort study of 12 hemodialysis clinics. Statistical models explored the association of multiple patient- and dialysis-specific covariates with low albumin (5 mg/dl) and calculated the ORs and 95% CIs. RESULTS: 616 patients with a mean age of 60.9 +/- 14.4 years participated in our study. Mean treatment time was 237.3 +/- 23.8 min and mean UFR was 7.0 +/- 4.0 ml/kg/h. In stepwise logistic regression, treatment time >4 h reduced the risk of low albumin (OR 0.397, 95% CI 0.235-0.672, p < 0.001). Congestive heart failure (OR 1.634, 95% CI 1.154-2.312, p = 0.006) and acute infection (OR 1.799, 95% CI 1.059-3.056, p = 0.03) were significant correlates of the risk of high CRP. There was no association between UFR and either CRP or albumin. CONCLUSION: Treatment time had a significant cross-sectional association with serum albumin but not with CRP.

Optimizing nutrition in patients with chronic kidney disease.

Nutrition is a crucial part of the treatment of patients with chronic kidney disease (CKD) because of its influence on morbidity and mortality. Nutrition status can be assessed using laboratory nutrition markers, the Subjective Global Assessment (SGA), anthropometric data, diet interviews and food diaries, and psychosocial assessment. Diet prescriptions need to be individualized based on each patient's degree of CKD and type of renal replacement therapy.