Race-free renal function estimation equations and potential impact on Black patients: Implications for cancer clinical trial enrollment.

BACKGROUND: Black patients face disparities in cancer outcomes. Additionally, Black patients are more likely to be undertreated and underrepresented in clinical trials. The recent recommendation to remove race from the estimated glomerular filtration rate (eGFR) results in lower eGFR values for Black patients. The ramifications of this decision, both intended and unintended, are still being elucidated in the medical community. Here, the authors analyze the removal of race from eGFR for Black patients with cancer, specifically with respect to clinical trial eligibility. METHODS: In a cohort of self-identified Black patients who underwent nephrectomy at a tertiary referral center from 2009 to 2021 (n = 459), eGFR was calculated with and without race in commonly used equations (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] and Modification of Diet in Renal Disease [MDRD]). The distribution of patients and changes within chronic kidney disease stages with different equations was considered. Theoretical exclusion at commonly observed clinical trial eGFR points was then simulated on the basis of the utilization of the race coefficient. RESULTS: The median eGFR from CKD-EPI was significantly higher with race (76 ml/min/1.73 m2 ) than without race (66 ml/min/1.73 m2 ; p < .0001). The median eGFR from MDRD was significantly higher with race (71.0 ml/min/1.73 m2 ) than without race (58 ml/min/1.73 m2 ; p < .0001). Observing results in the context of common clinical trial cutoff points, the authors found that 13%-22%, 6%-12%, and 2%-3% more Black patients would fall under common clinical trial cutoffs of 60, 45, and 30 ml/min, respectively, depending on the equation used. A subanalysis of stage III-IV patients only was similar. CONCLUSIONS: Race-free renal function equations may inadvertently result in increased exclusion of Black patients from clinical trials. This is especially concerning because of the underrepresentation and undertreatment that Black patients already experience. PLAIN LANGUAGE SUMMARY: Black patients experience worse oncologic outcomes and are underrepresented in clinical trials. Kidney function, as estimated by glomerular filtration rate equations, is a factor in who can and cannot be in a clinical trial. Race is a variable in some of these equations. For Black patients, removing race from these equations leads to the calculation of lower kidney function. Lower estimated kidney function may result in more black patients being excluded from clinical trials. The inclusion of all races in clinical trials is important for offering best care to everyone and for making results from clinical trials applicable to everyone.

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.

"Pushing Geographic Boundaries: Interfacility transport and remote extracorporeal membrane oxygenation cannulation of patients during COVID-19 pandemic".

Amidst the pandemic, geographical boundaries presented challenges to those in need of higher levels of care from referral centers. Authors sought to evaluate potential predictors of treatment success; assess our transport and remote cannulation process; and identify transport associated complications.Retrospective series of critically ill adults with COVID-19 transferred by our Extracorporeal Membrane Oxygenation (ECMO) team 24 March 2020 through 8 June 2021. Descriptive statistics and associated interquartile ranges (IQR) were used to summarize the data.Sixty-three patients with COVID associated acute respiratory distress syndrome (ARDS) requiring ECMO support were admitted to our ECMO center. Mean age was 44 years old (SD 12; IQR 36-56). 59% (n = 37) of patients were male. Average body mass index was 39.7 (SD 11.3; IQR 31-48.5). Majority of patients (77.8%; n = 35) had severe ARDS. Predictors of treatment success were not observed.Transport distances ranged from 2.2 to 236 miles (median 22.5 miles; IQR 8.3-79); round trip times from 18 to 476 min (median 83 min; IQR 44-194). No transport associated complications occurred. Median duration of ECMO support was 17 days (IQR 9.5-34.5). Length of stay in the Intensive Care Unit (median 36 days; IQR 17-49) and hospital (median 39 days; IQR 25-57) varied. Amongst those discharged, 60% survived.

Organizational and financial aspects of a continuous renal replacement therapy program.

Critically ill patients who develop severe acute kidney injury in the intensive care unit often require treatment with renal replacement therapies (RRTs). This complication is associated with severe morbidity and mortality and high costs, both during hospitalization and postdischarge. This article discusses the operational requirements to develop and conduct a RRT program, as well as the financial implications of this complex form of patient care. The management of these programs must occur in a context where a clear organizational and educational framework and a multidisciplinary team ensures safety, effectiveness, cost-control, and a clear quality control framework.

Optimal Role of the Nephrologist in the Intensive Care Unit.

As advances in Critical Care Medicine continue, critically ill patients are surviving despite the severity of their illness. The incidence of acute kidney injury (AKI) has increased, and its impact on clinical outcomes as well as medical expenditures has been established. The role, indications and technological advancements of renal replacement therapy (RRT) have evolved, allowing more effective therapies with less complications. With these changes, Critical Care Nephrology has become an established specialty, and ongoing collaborations between critical care physicians and nephrologist have improved education of multi-disciplinary team members and patient care in the ICU. Multidisciplinary programs to support these changes have been stablished in some hospitals to maximize the delivery of care, while other programs have continue to struggle in their ability to acquire the necessary resources to maximize outcomes, educate their staff, and develop quality initiatives to evaluate and drive improvements. Clearly, the role of the nephrologist in the ICU has evolved, and varies widely among institutions. This special article will provide insights that will hopefully optimize the role of the nephrologist as the leader of the acute care nephrology program, as clinician for critically ill patients, and as teacher for all members of the health care team.

Successful delivery of RRT in Ebola virus disease.

AKI has been observed in cases of Ebola virus disease. We describe the protocol for the first known successful delivery of RRT with subsequent renal recovery in a patient with Ebola virus disease treated at Emory University Hospital, in Atlanta, Georgia. Providing RRT in Ebola virus disease is complex and requires meticulous attention to safety for the patient, healthcare workers, and the community. We specifically describe measures to decrease the risk of transmission of Ebola virus disease and report pilot data demonstrating no detectable Ebola virus genetic material in the spent RRT effluent waste. This article also proposes clinical practice guidelines for acute RRT in Ebola virus disease.

The Use of TKM-100802 and Convalescent Plasma in 2 Patients With Ebola Virus Disease in the United States.

BACKGROUND: The current West Africa Ebola virus disease (EVD) outbreak has resulted in multiple individuals being medically evacuated to other countries for clinical management. METHODS: We report two patients who were transported from West Africa to the United States for treatment of EVD. Both patients received aggressive supportive care measures, as well as an investigational therapeutic (TKM-100802) and convalescent plasma. RESULTS: While one patient experienced critical illness with multi-organ failure requiring mechanical ventilation and renal replacement therapy, both patients recovered without serious long-term sequelae to date. CONCLUSIONS: It is unclear what role the experimental drug and convalescent plasma had in the recovery of these patients. Prospective clinical trials are needed to delineate the role of investigational therapies in the care of patients with EVD.

Critical Care for Multiple Organ Failure Secondary to Ebola Virus Disease in the United States.

OBJECTIVE: This report describes three patients with Ebola virus disease who were treated in the United States and developed for severe critical illness and multiple organ failure secondary to Ebola virus infection. The patients received mechanical ventilation, renal replacement therapy, invasive monitoring, vasopressor support, and investigational therapies for Ebola virus disease. DATA SOURCES: Patient medical records from three tertiary care centers (Emory University Hospital, University of Nebraska Medical Center, and Texas Health Presbyterian Dallas Hospital). STUDY SELECTION: Not applicable. DATA EXTRACTION: Not applicable. DATA SYNTHESIS: Not applicable. CONCLUSION: In the severe form, patients with Ebola virus disease may require life-sustaining therapy, including mechanical ventilation and renal replacement therapy. In conjunction with other reported cases, this series suggests that respiratory and renal failure may occur in severe Ebola virus disease, especially in patients burdened with high viral loads. Ebola virus disease complicated by multiple organ failure can be survivable with the application of advanced life support measures. This collective, multicenter experience is presented with the hope that it may inform future treatment of patients with Ebola virus disease requiring critical care treatment.

Vancomycin clearance in high-volume venovenous hemofiltration.

OBJECTIVE: To report the pharmacokinetic and pharmacodynamic properties of vancomycin in 4 patients undergoing high-volume continuous venovenous hemofiltration (CVVH). CASE SUMMARY: Data from 4 patients prescribed high-volume CVVH for acute renal failure treated with vancomycin were analyzed. Vancomycin plasma concentrations were measured 4 and 24 hours after the end of a 1-hour vancomycin infusion. The mean therapy fluid rate on initiation of vancomycin was 56.2 mL/kg/h (range 48.0-65.5). The mean loading dose of vancomycin was 18.3 mg/kg (range 14.7-19.7). Median vancomycin concentration 4 hours after the dose was 18.1 mg/L (range 13.1-30.0). At 24 hours after the dose, only 1 patient had a detectable vancomycin concentration (5.2 mg/L). DISCUSSION: There was a large variability in the clearance of vancomycin in this patient population. Current strategies for dosing vancomycin may lead to subtherapeutic trough concentrations. Vancomycin dosing in this patient population should be based on a detailed assessment of the CVVH prescription, vancomycin concentrations, and clinical needs and response. CONCLUSIONS: An initial vancomycin dose of 20-25 mg/kg with frequent monitoring and adjustment is recommended for patients receiving high-volume CVVH.

Fluid Management for Critically Ill Patients with Acute Kidney Injury Receiving Kidney Replacement Therapy: An International Survey.

BACKGROUND: In critically ill patients receiving KRT, high ultrafiltration rates and persistent fluid accumulation are associated with adverse outcomes. The purpose of this international survey was to evaluate current practices and evidence gaps related to fluid removal with KRT in critically ill patients. METHODS: This was a multinational, web-based survey distributed by seven networks comprising nephrologists and intensivists. Physicians involved in the care of critically ill patients were invited to complete a 39-question survey about fluid management practices on KRT. The survey was distributed from September 2021 to December 2021. RESULTS: There were 757 respondents from 96 countries (response rate of 65%). Most respondents practiced adult medicine (89%) and worked in an academic center (69%). The majority (91%) reported aiming for a 0.5- to 2-L negative fluid balance per day when fluid removal is indicated, although there was important variability in what respondents considered a safe maximal target. Intensivists were more likely than nephrologists to use adjunct volume status assessment methods ( i.e. , ultrasound, hemodynamic markers, and intra-abdominal pressure), while nephrologists were more likely to deploy cointerventions aimed at improving tolerance to fluid removal ( i.e. , osmotic agents and low-temperature dialysate). There was a broad consensus that rapid decongestion should be prioritized when fluid accumulation is present, but the prevention of hypotension was also reported as a competing priority. A majority (77%) agreed that performing trials that compare fluid management strategies would be ethical and clinically relevant. CONCLUSIONS: We have identified multiple areas of variability in current practice of fluid management for patients receiving KRT. Most nephrologists and intensivists agreed that several knowledge gaps related to fluid removal strategies should be investigated in future randomized controlled trials.

Effect of Blood Culture Contamination on Antibiotic Use in an Institution With Rapid Laboratory Methods and Phone-Based Clinical Follow-up of Blood Culture Results.

In a multivariate analysis of 30 574 blood culture (BC) results, BC contamination was associated with only a small increase in antibiotic length of therapy compared to no-growth BCs (difference, 0.36 days [95% confidence interval, .05-.67]; P = .02). Stewardship processes at our institution appear to be effective in reducing the impact of BC contamination.

Therapeutic drug monitoring of piperacillin-tazobactam using spent dialysate effluent in patients receiving continuous venovenous hemodialysis.

Sepsis and multisystem organ failure are common diagnoses affecting nearly three-quarters of a million Americans annually. Infection is the leading cause of death in acute kidney injury, and the majority of critically ill patients who receive continuous dialysis also receive antibiotics. Dialysis equipment and prescriptions have gradually changed over time, raising concern that current drug dosing recommendations in the literature may result in underdosing of antibiotics. Our research group directed its attention toward antibiotic dosing strategies in patients with acute renal failure (ARF), and we sought data confirming that patients receiving continuous dialysis and antibiotics actually were achieving therapeutic plasma drug levels during treatment. In the course of those investigations, we explored "fast-track" strategies to estimate plasma drug concentrations. As most antimicrobial antibiotics are small molecules and should pass freely through modern high-flux hemodialyzer filters, we hypothesized that continuous renal replacement therapy (CRRT) effluent could be used as the medium for drug concentration measurement by reverse-phase high-pressure liquid chromatography (HPLC). Here we present the first data demonstrating this approach for piperacillin-tazobactam. Paired blood and dialysate trough-peak-trough samples were drawn from 19 patients receiving piperacillin-tazobactam and continuous venovenous hemodialysis (CVVHD). Total, free, and dialysate drug concentrations were measured by HPLC. Dialysate drug levels predicted plasma free drug levels well (r(2) = 0.91 and 0.92 for piperacillin and tazobactam, respectively) in all patients. These data suggest a strategy for therapeutic drug monitoring that minimizes blood loss from phlebotomy and simplifies analytic procedures.

PARP14 regulates cyclin D1 expression to promote cell-cycle progression.

Cyclin D1 is an essential regulator of the G1-S cell-cycle transition and is overexpressed in many cancers. Expression of cyclin D1 is under tight cellular regulation that is controlled by many signaling pathways. Here we report that PARP14, a member of the poly(ADP-ribose) polymerase (PARP) family, is a regulator of cyclin D1 expression. Depletion of PARP14 leads to decreased cyclin D1 protein levels. In cells with a functional retinoblastoma (RB) protein pathway, this results in G1 cell-cycle arrest and reduced proliferation. Mechanistically, we found that PARP14 controls cyclin D1 mRNA levels. Using luciferase assays, we show that PARP14 specifically regulates cyclin D1 3'UTR mRNA stability. Finally, we also provide evidence that G1 arrest in PARP14-depleted cells is dependent on an intact p53-p21 pathway. Our work uncovers a new role for PARP14 in promoting cell-cycle progression through both cyclin D1 and the p53 pathway.

Reducing the impact of summer cattle grazing on water quality in the Sierra Nevada Mountains of California: a proposal.

The Sierra Nevada Mountain range serves as an important source of drinking water for the State of California. However, summer cattle grazing on federal lands affects the overall water quality yield from this essential watershed as cattle manure is washed into the lakes and streams or directly deposited into these bodies of water. This organic pollution introduces harmful microorganisms and also provides nutrients such as nitrogen and phosphorus which increase algae growth causing eutrophication of otherwise naturally oligotrophic mountain lakes and streams. Disinfection and filtration of this water by municipal water districts after it flows downstream will become increasingly costly. This will be compounded by increasing surface water temperatures and the potential for toxins release by cyanobacteria blooms. With increasing demands for clean water for a state population approaching 40 million, steps need to be implemented to mitigate the impact of cattle on the Sierra Nevada watershed. Compared to lower elevations, high elevation grazing has the greatest impact on the watershed because of fragile unforgiving ecosystems. The societal costs from non-point pollution exceed the benefit achieved through grazing of relatively few cattle at the higher elevations. We propose limiting summer cattle grazing on public lands to lower elevations, with a final goal of allowing summer grazing on public lands only below 1,500 m elevation in the Central and Northern Sierra and 2,000 m elevation in the Southern Sierra.

Adverse Events Associated With Radium-223 in Metastatic Prostate Cancer: Disproportionality Analysis of FDA Data Reflecting Worldwide Utilization.

BACKGROUND: Radionuclide radium-223 improves survival in men with metastatic castrate-resistant prostate cancer. The United States (US) Food and Drug Administration Adverse Events Reporting System (FAERS) is a post-market pharmacovigilance database valuable for adverse event (AE) assessments. We analyzed FAERS to identify disproportionate AE signals related to radium-223, and to explore radium-223's international utilization. MATERIALS AND METHODS: We identified 2182 radium-223 cases associated with AE(s) from 2013 to 2018. The duration of radium-223 therapy was calculated. Reporting odds ratio (ROR) and proportional reporting ratio (PRR), with 95% confidence intervals (CIs), were calculated for AEs of interest. ROR shows disproportionate signals if the lower limit of the 95% CI > 1. PRR shows disproportionate signals if PRR ≥ 2, χ2 statistic ≥ 4, and ≥ 3 AEs were reported. We identified any US Food and Drug Administration enforcement actions for radium-223. RESULTS: A majority (60.8%) of events occurred outside the US. Among patients with radium-223-associated AEs, the median therapy duration was only 56 days (corresponding to 2-3 treatment cycles). Disproportionate signals were detected for general health deterioration (ROR, 5.03; 95% CI, 4.23-5.98 and PRR, 4.94; 95% CI, 4.16-5.87), bone pain (ROR, 4.53; 95% CI, 3.67-5.59 and PRR, 4.48; 95% CI, 3.63-5.53), and hematologic AEs including anemia (ROR, 2.89; 95% CI, 2.55-3.27 and PRR, 2.80; 95% CI, 2.48-3.17), thrombocytopenia (ROR, 3.22; 95% CI, 2.77-3.74 and PRR, 3.16; 95% CI, 2.72-3.67), and pancytopenia/bone marrow failure (ROR, 4.83; 95% CI, 4.11-5.67 and PRR, 4.73; 95% CI, 4.03-5.55). There were no enforcement actions for radium-223. CONCLUSIONS: Patients with metastatic castrate-resistant prostate cancer experiencing AEs are only receiving one-half the prescription dose of radium-223 required for survival benefit. Radium-223 is associated with health deterioration, bone pain, and hematologic AEs. Real-world analyses are important for ongoing radium-223 risk-benefit assessments.