Conserved long noncoding RNA TILAM promotes liver fibrosis through interaction with PML in HSCs.

BACKGROUND AND AIMS: Fibrosis is the common end point for all forms of chronic liver injury, and the progression of fibrosis leads to the development of end-stage liver disease. Activation of HSCs and their transdifferentiation into myofibroblasts results in the accumulation of extracellular matrix proteins that form the fibrotic scar. Long noncoding RNAs regulate the activity of HSCs and provide targets for fibrotic therapies. APPROACH AND RESULTS: We identified long noncoding RNA TILAM located near COL1A1 , expressed in HSCs, and induced with liver fibrosis in humans and mice. Loss-of-function studies in human HSCs and human liver organoids revealed that TILAM regulates the expression of COL1A1 and other extracellular matrix genes. To determine the role of TILAM in vivo, we annotated the mouse ortholog ( Tilam ), generated Tilam- deficient green fluorescent protein-reporter mice, and challenged these mice in 2 different models of liver fibrosis. Single-cell data and analysis of single-data and analysis of Tilam-deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Tilam -deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Furthermore, loss of Tilam expression attenuated the development of fibrosis in the setting of in vivo liver injury. Finally, we found that TILAM interacts with promyelocytic leukemia nuclear body scaffold protein to regulate a feedback loop by which TGF-ß2 reinforces TILAM expression and nuclear localization of promyelocytic leukemia nuclear body scaffold protein to promote the fibrotic activity of HSCs. CONCLUSIONS: TILAM is activated in HSCs with liver injury and interacts with promyelocytic leukemia nuclear body scaffold protein to drive the development of fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end-stage liver disease.

Signals From Inflamed Perivascular Adipose Tissue Contribute to Small Vessel Dysfunction in Women Living With the Human Immunodeficiency Virus.

INTRODUCTION: People living with the human immunodeficiency virus (PWH) have microvascular disease. Since perivascular adipose tissue (PVAT) regulates microvascular function and adipose tissue is inflamed in PWH, we tested the hypothesis that PWH have inflamed PVAT that impairs the function of their small vessels. METHODS: Subcutaneous small arteries were dissected with or without (+ or -) PVAT from a gluteal skin biopsy from 11 women with treated HIV (WWH) aged < 50 years and 10 matched women without HIV and studied on isometric myographs. Nitric oxide (NO) and reactive oxygen species (ROS) were measured by fluorescence microscopy. Adipokines and markers of inflammation and ROS were assayed in PVAT. RESULTS: PVAT surrounding the small arteries in control women significantly (P < 0.05) enhanced acetylcholine (Ach)-induced endothelium dependent relaxation and NO and reduced contractions to thromboxane and endothelin-1. However, these effects of PVAT were reduced significantly (P < 0.05) in WWH whose PVAT released less adiponectin but more markers of ROS and inflammation. Moderation of contractions by PVAT were correlated positively with adipose adiponectin. CONCLUSION: PVAT from WWH has oxidative stress, inflammation and reduced release of adiponectin that may contribute to enhanced contractions and therefore could promote small artery dysfunction.

KDOQI US Commentary on the 2021 KDIGO Clinical Practice Guideline for the Management of Glomerular Diseases.

The KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases represents the first update to this set of recommendations since the initial set of KDIGO guideline recommendations was published in 2012. The pace of growth in our molecular understanding of glomerular disease has quickened and a number of newer immunosuppressive and targeted therapies have been introduced since the original set of guideline recommendations, making such an update necessary. Despite these updates, many areas of controversy remain. In addition, further updates since the publication of KDIGO 2021 have occurred which this guideline does not encompass. With this commentary, the KDOQI work group has generated a chapter-by-chapter companion opinion article that provides commentary specific to the implementation of the KDIGO 2021 guideline in the United States.

Efficacy of venetoclax plus rituximab for relapsed CLL: 5-year follow-up of continuous or limited- duration therapy.

We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months and then received venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry (<10-4 cutoff) were allowed, but not required, to discontinue therapy, while remaining in the study and could be retreated with VenR upon progression. Median follow-up for all patients (N = 49) was 5.3 years. Five-year rates (95% CI) for overall survival, progression-free survival, and duration of response were 86% (72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71%; 95% CI, 39-88) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all >2 years off venetoclax (range, 2.1-6.4). Four patients were retreated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit.

Quantification of the role of lead foil in flattening filter free beam reference dosimetry.

PURPOSE: To quantify the potential error in outputs for flattening filter free (FFF) beams associated with use of a lead foil in beam quality determination per the addendum protocol for TG-51, we examined differences in measurements of the beam quality conversion factor kQ when using or not using lead foil. METHODS: Two FFF beams, a 6 MV FFF and a 10 MV FFF, were calibrated on eight Varian TrueBeams and two Elekta Versa HD linear accelerators (linacs) according to the TG-51 addendum protocol by using Farmer ionization chambers [TN 30013 (PTW) and SNC600c (Sun Nuclear)] with traceable absorbed dose-to-water calibrations. In determining kQ , the percentage depth-dose at 10 cm [PDD(10)] was measured with 10×10 cm2 field size at 100 cm source-to-surface distance (SSD). PDD(10) values were measured either with a 1 mm lead foil positioned in the path of the beam [%dd(10)Pb ] or with omission of a lead foil [%dd(10)]. The %dd(10)x values were then calculated and the kQ factors determined by using the empirical fit equation in the TG-51 addendum for the PTW 30013 chambers. A similar equation was used to calculate kQ for the SNC600c chamber, with the fitting parameters taken from a very recent Monte Carlo study. The differences in kQ factors were compared for with lead foil vs. without lead foil. RESULTS: Differences in %dd(10)x with lead foil and with omission of lead foil were 0.9 ± 0.2% for the 6 MV FFF beam and 0.6 ± 0.1% for the 10 MV FFF beam. Differences in kQ values with lead foil and with omission of lead foil were -0.1 ± 0.02% for the 6 MV FFF and -0.1 ± 0.01% for the 10 MV FFF beams. CONCLUSION: With evaluation of the lead foil role in determination of the kQ factor for FFF beams. Our results suggest that the omission of lead foil introduces approximately 0.1% of error for reference dosimetry of FFF beams on both TrueBeam and Versa platforms.

Fostamatinib for the treatment of warm antibody autoimmune hemolytic anemia: Phase 2, multicenter, open-label study.

Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults with chronic immune thrombocytopenia (ITP). This phase 2 study evaluated the response to fostamatinib, administered at 150 mg BID orally with or without food in adults with wAIHA and active hemolysis with hemoglobin (Hgb) <10 g/dL who had failed at least one prior treatment. Hemoglobin levels and safety assessments were performed at visits every 2 weeks. The primary endpoint was Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by week 24 without rescue therapy or red blood cell transfusion. Eleven of 24 (46%) patients achieved the primary endpoint. Increases in median Hgb were detected at week 2 and sustained over time. Median lactate dehydrogenase levels and reticulocyte counts generally declined over time with little change in median haptoglobin levels. The most common adverse events (AEs) were diarrhea (42%), fatigue (42%), hypertension (27%), dizziness (27%), and insomnia (23%). AEs were manageable and consistent with the fostamatinib safety database of over 3900 patients across multiple diseases (rheumatoid arthritis, B-cell lymphoma, COVID-19, and ITP). No new safety signals were detected. Fostamatinib may be a promising therapeutic option for wAIHA. A randomized, double-blind, phase 3 study is nearing completion.

Estradiol treatment or modest exercise improves hepatic health and mitochondrial outcomes in female mice following ovariectomy.

We recently reported that compared with males, female mice have increased hepatic mitochondrial respiratory capacity and are protected against high-fat diet-induced steatosis. Here, we sought to determine the role of estrogen in hepatic mitochondrial function, steatosis, and bile acid metabolism in female mice and investigate potential benefits of exercise in the absence or presence of estrogen via ovariectomy (OVX). Female C57BL mice (n = 6 per group) were randomly assigned to sham surgery (sham), ovariectomy (OVX), or OVX plus estradiol replacement therapy (OVX + Est). Half of the mice in each treatment group were sedentary (SED) or had access to voluntary wheel running (VWR). All mice were fed a high-fat diet (HFD) and were housed at thermoneutral temperatures. We assessed isolated hepatic mitochondrial respiratory capacity using the Oroboros O2k with both pyruvate and palmitoylcarnitine as substrates. As expected, OVX mice presented with greater hepatic steatosis, weight gain, and fat mass gain compared with sham and OVX + Est animals. Hepatic mitochondrial coupling (basal/state 3 respiration) with pyruvate was impaired following OVX, but both VWR and estradiol treatment rescued coupling to levels greater than or equal to sham animals. Estradiol and exercise also had different effects on liver electron transport chain protein expression depending on OVX status. Markers of bile acid metabolism and excretion were also impaired by ovariectomy but rescued with estradiol add-back. Together our data suggest that estrogen depletion impairs hepatic mitochondrial function and liver health, and that estradiol replacement and modest exercise can aid in rescuing this phenotype.NEW & NOTEWORTHY OVX induces hepatic steatosis in sedentary mice which can be prevented by modest physical activity (VWR) and/or estradiol treatment. Estrogen impacts hepatic mitochondrial coupling in a substrate-specific manner. OVX mice have impaired fecal bile acid excretion, which was rescued with estradiol treatment.

Hemodialysis Emergencies: Core Curriculum 2021.

Since maintenance hemodialysis (HD) first became available in the United States in 1962, there has been tremendous growth in the population of patients with kidney failure. HD has become a routine treatment carried out in outpatient clinics, hospitals, nursing facilities, and in patients' homes. Although it is a complex procedure, HD is quite safe. Serious complications are uncommon due to the use of modern HD machines and water treatment systems as well as the development of strict protocols to monitor various aspects of the HD treatment. The practicing nephrologist must be knowledgeable about life-threatening complications that can occur during HD and be able to recognize, manage, and prevent them. This installment in the AJKD Core Curriculum in Nephrology reviews the pathogenesis, management, and prevention of 9 HD emergencies. The HD emergencies covered include dialyzer reactions, dialysis disequilibrium syndrome, uremic/dialysis-associated pericarditis, air embolism, venous needle dislodgement, vascular access hemorrhage, hemolysis, dialysis water contamination, and arrhythmia episodes.

Improving Primary Care Delivery for Patients Receiving Maintenance Hemodialysis.

The beneficial impact of primary care, focused on all aspects of a patient's health (rather than a disease-specific focus) is well established. Recognized benefits include greater receipt of preventive care and counseling, lower use of emergency care and hospitalization for ambulatory care-sensitive conditions, and decreased early mortality. Although the importance of primary care and care coordination at the primary care/specialty interface is well recognized, the role of primary care within traditional and emerging care models for patients receiving in-center maintenance hemodialysis remains ill-defined. In this perspective article, we will describe: (1) the role of primary care for patients receiving maintenance hemodialysis and the current evidence regarding the receipt of primary care among these patients; (2) the key challenges to delivery of primary care in these complex cases, including suboptimal care coordination between nephrology and primary care providers, the intensity of dialysis care, and the limited capacity of nephrologists and primary care providers to meet the broad health needs of hemodialysis patients; (3) potential strategies for improving the delivery of primary care for patients receiving hemodialysis; and (4) future research requirements to improve primary care delivery for this high-risk population.

Cirmtuzumab blocks Wnt5a/ROR1 stimulation of NF-κB to repress autocrine STAT3 activation in chronic lymphocytic leukemia.

Coculture of nurse-like cells (NLCs) with chronic lymphocytic leukemia (CLL) cells induced leukemia cell phosphorylation of STAT3 (pSTAT3), which could be blocked by anti-Wnt5a antibodies or the anti-ROR1 monoclonal antibody, cirmtuzumab. Time-course studies revealed Wnt5a could induce activation of NF-κB within 30 minutes, but required more than 3 hours to induce pSTAT3. Culture of isolated CLL cells for 24 hours revealed Wnt5a-induced expression of interleukin 6 (IL-6), IL-8, CCL2, CCL3, CCL4, and CXCL1, which in turn could induce pSTAT3 in unstimulated CLL cells within 30 minutes. We found that Wnt5a could induce CLL cell expression of NF-κB target genes, including IL-6, and that this effect could be blocked by cirmtuzumab or drugs that inhibit NF-κB. Examination of CLL cells and plasma collected from patients treated with cirmtuzumab revealed reduced levels of phosphorylated p65 and diminished expression of NF-κB and STAT3 target genes in CLL cells, as well as lower plasma levels of IL-6, in the samples after therapy. Collectively, these studies indicate that Wnt5a/ROR1-dependent signaling contributes to CLL cell activation of NF-κB, which in turn causes autocrine IL-6-induced activation of pSTAT3. As such, this study demonstrates that cirmtuzumab can inhibit leukemia cell activation of both NF-κB and STAT3 in patients with CLL.

Outcomes in revisional bariatric surgery: a high-volume single institution experience.

BACKGROUND: This study aims to evaluate outcomes of adjustable gastric band (AGB) conversion to sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB), SG conversion to RYGB and RYGB revision procedures. METHODS: Patients undergoing secondary bariatric surgery between 2009 and 2017 were retrospectively identified from a prospective database. Primary outcomes were weight loss and improvement in comorbidities. For weight loss, percent of total body weight loss (%TWL) and percentage of excess BMI loss (%EBMIL) were included. Comorbidities included were hemoglobin A1C (HbA1C), cardiovascular risk (CV) and hypertension. RESULTS: 266 Secondary bariatric procedures were analyzed. There were four Grade IIIb complications within 30 days. There was greater %EBMIL at 12 and 24 months in the AGB to RYGB group, and in %TWL at 24 months compared to AGB to SG group (p < 0.05). Only AGB to RYGB had significantly continued improvement in these two parameters at 24 months compared to at 6 months post-operatively-%EBMIL and %TWL tapered off in the other procedures. There was significantly lower CV risk in dyslipidemic patients at 24 months in the AGB to RYGB compared to the AGB to SG group. In the SG to RYGB patients, there was significant improvement in CV risk in dyslipidemic patients at 24 months compared to baseline. There was significant improvement in HbA1C in diabetics in AGB to RYGB patients at 6 and 12 months, in AGB to SG patients at 12 months, and in SG to RYGB patients at 12 and 24 months compared to baseline. In RYGB revision and SG to RYGB patients, there was a relative increase in the number of patients being normotensive at 24 months compared to baseline. CONCLUSION: Secondary bariatric surgery is a complex and challenging procedure that may improve weight loss and cardiovascular risk for certain procedures but further studies will be necessary.

Higher Prevalence of Concurrent Thrombocytopenia in Patients Receiving Continuous Renal Replacement Therapy in the Cardiac Intensive Care Unit.

INTRODUCTION: Thrombocytopenia (TCP) is a common finding in patients receiving continuous renal replacement therapy (CRRT). OBJECTIVE: The purpose of this study was to assess the nature of TCP in patients receiving CRRT. METHODS: This is a single-center case-control observational study of 795 patients involving over 166,950 h of delivered CRRT at Johns Hopkins Hospital. Concurrent TCP in patients receiving CRRT was defined as a decrease in platelet count of ≥50% any time within 72 h of initiation of CRRT with strict exclusion criteria. RESULTS: There was a higher incidence of TCP in the cardiac intensive care unit (CICU) (22.5%) compared to medical ICU (MICU) (13.1%). Using logistic regression, the odds of developing concurrent TCP in patients receiving CRRT was 2.46 (95% CI 1.32-3.57, p < 0.05) times higher in the CICU compared with the MICU. There was no difference in the incidence of severe or profound TCP or timing of acute TCP between the CICU and MICU. CONCLUSION: Safe delivery of dialysis care in the ICU is paramount and creating awareness of potential risks such as concurrent TCP in patients receiving CRRT should be part of this care.

Understanding Preferences for Lifestyle-Focused Visual Text Messages in Patients With Cardiovascular and Chronic Respiratory Disease: Discrete Choice Experiment.

BACKGROUND: Supporting healthy lifestyle changes is a key aim of cardiovascular and pulmonary rehabilitation programs. SMS text messaging programs have demonstrated effectiveness in cardiovascular disease risk reduction, weight loss, increasing physical activity, and smoking cessation. The optimization of SMS text messaging programs may deliver greater population benefits as mobile phone use becomes ubiquitous. Visual messaging (ie, image-based messages) has the potential to communicate health messages via digital technology and result in enhanced engagement. OBJECTIVE: This study aims to determine and understand patient preferences for lifestyle-focused visual text messages that support cardiovascular and pulmonary rehabilitation. METHODS: A discrete choice experiment was conducted in a 4-stage iterative process to elicit patient preferences for visual message features. Attribute and level development yielded 3 attributes (purpose, image type, and web address), and 16 choice sets were subsequently constructed according to a full factorial design. Patients participating in cardiovascular and pulmonary rehabilitation were surveyed (on the web) for their preferences regarding the visual message choice sets. Respondents were asked to choose among 16 pairs of visual messages regarding key lifestyle behaviors, namely, physical activity and nutrition. The data were analyzed using a conditional logit model. RESULTS: There was a total of 1728 observations from 54 unique respondents. Two factors that were associated with patient preference were gain-framed purpose compared with no purpose (odds ratio [OR] 1.93, 95% CI 1.40-2.65) and real images compared with cartoon images (OR 1.26, 95% CI 1.04-1.54). A loss-framed purpose was less preferred than no purpose (OR 0.55, 95% CI 0.42-0.74). Overall, patients preferred positive images that were colorful and engaged with text that supported the image and had a preference for images of real people rather than cartoons. CONCLUSIONS: A discrete choice experiment is a scientific method for eliciting patient preferences for a visual messaging intervention that is designed to support changes in lifestyle behaviors. SMS text messaging programs that use visual aids may result in greater patient satisfaction by using a gain frame, using real images, and avoiding a loss frame. Further research is needed to explore the feasibility of implementation and the health and behavioral outcomes associated with such visual messaging programs.

Burnout and Emotional Well-Being among Nephrology Fellows: A National Online Survey.

BACKGROUND: Physician burnout and emotional distress are associated with work dissatisfaction and provision of suboptimal patient care. Little is known about burnout among nephrology fellows. METHODS: Validated items on burnout, depressive symptoms, and well being were included in the American Society of Nephrology annual survey emailed to US nephrology fellows in May to June 2018. Burnout was defined as an affirmative response to two single-item questions of experiencing emotional exhaustion or depersonalization. RESULTS: Responses from 347 of 808 eligible first- and second-year adult nephrology fellows were examined (response rate=42.9%). Most fellows were aged 30-34 years (56.8%), male (62.0%), married or partnered (72.6%), international medical graduates (62.5%), and pursuing a clinical nephrology fellowship (87.0%). Emotional exhaustion and depersonalization were reported by 28.0% and 14.4% of the fellows, respectively, with an overall burnout prevalence of 30.0%. Most fellows indicated having strong program leadership (75.2%), positive work-life balance (69.2%), presence of social support (89.3%), and career satisfaction (73.2%); 44.7% reported a disruptive work environment and 35.4% reported depressive symptoms. Multivariable logistic regression revealed a statistically significant association between female gender (odds ratio [OR], 1.90; 95% confidence interval [95% CI], 1.09 to 3.32), poor work-life balance (OR, 3.97; 95% CI, 2.22 to 7.07), or a disruptive work environment (OR, 2.63; 95% CI, 1.48 to 4.66) and burnout. CONCLUSIONS: About one third of US nephrology fellows surveyed reported experiencing burnout and depressive symptoms. Further exploration of burnout-especially that reported by female physicians, as well as burnout associated with poor work-life balance or a disruptive work environment-is warranted to develop targeted efforts that may enhance the educational experience and emotional well being of nephrology fellows.

Interrelationships Between Coating Uniformity and Efficiency in Pan Coating Processes.

The relationships between coating uniformity and efficiency were explored for tablet coating processes in pan coaters. The factors affecting the size of the spray zone were modeled using one-dimensional deposition analysis of spray droplets. This model was incorporated into the analytical model developed for coating uniformity by Choi et al. (AAPS PharmSciTech 22(7), 2021) that farther elucidated the effects of tablet shape and bed porosity. The results were compared with literature data on coating efficiency. The variables examined included tablet shape and size, coating time, pan speed, atomizing and pattern air flow rates, bed porosity, spray rate, batch size, coating solution concentration, spray gun-to-bed distance, and pan diameter. It is shown that, except for pan diameter and atomizing air flow rate, variables that improve coating efficiency adversely affected coating uniformity and vice versa. Implications of these relationships are discussed to improve formulation, process, and equipment designs.

Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy.

B-cell receptor pathway inhibitors (BCRis) have transformed treatment of chronic lymphocytic leukemia (CLL); however, the efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRis is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi before enrollment. Venetoclax was initiated at 20 mg daily, followed by intrapatient ramp-up to 400 mg daily. Primary objectives included efficacy (objective response rate [ORR]) and safety of venetoclax. The study enrolled 36 patients who previously received idelalisib (ORR, 67% [24/36]); 2 patients achieved complete remission, and 1 had complete remission with incomplete bone marrow recovery. Median progression-free survival (PFS) has not yet been reached; estimated 12-month PFS was 79%. The most common adverse events (AEs; all grades) were neutropenia (56%), diarrhea (42%), upper respiratory tract infection (39%), thrombocytopenia (36%), nausea (31%), fatigue (28%), cough (22%), rash (22%), and anemia (22%). Grade 3 or 4 AEs were primarily hematologic (neutropenia [50%], thrombocytopenia [25%], and anemia [17%]). No patients experienced tumor lysis syndrome. Venetoclax demonstrated promising clinical activity and favorable tolerability in patients with CLL whose disease progressed during or after idelalisib therapy. This trial was registered at www.clinicaltrials.gov as #NCT02141282.

Novel Coating Uniformity Models for Tablet Pan Coaters.

Novel mathematical models were developed to predict inter-tablet coating uniformity in terms of coefficients of variation (CV) and acceptance values (AV) for cylindrical tablet pan coaters, operating in batch and continuous modes. The models, based on binomial coating spray and tablet movement distribution functions and on bed geometry, yielded equations and results that are in good agreement with previously reported experimental data, most empirical expressions, and more computationally intensive models. The new model equations are readily useable for process analysis, optimization, scale-up, and manufacturing design and control.

The Use of Erythropoiesis-Stimulating Agents in Patients With CKD and Cancer: A Clinical Approach.

Erythropoiesis-stimulating agents (ESAs) have been used to manage anemia in chronic kidney disease (CKD) to reduce transfusion requirements and anemia symptoms. Lack of objective benefit of normalizing hemoglobin (Hb) levels and increased evidence of ESA-induced complications in persons with anemia has resulted in clinicians generally attempting to maintain Hb levels in the 10- to 11-g/dL range. In 2000, concerns in patients with cancer arose attributable to associations of ESA use with increased mortality, thrombotic complications, and cerebrovascular accidents led to a change in US Food and Drug Administration oncology guidelines regarding limitation of ESA use for chemotherapy-induced anemia. No guidance was rendered for individuals with CKD and cancer. Persons with CKD with remote or active malignancy should receive the lowest ESA doses possible that achieve a maximum Hb level of 10g/dL. Based on current data, although ESAs may promote progression or worsen outcomes in some cancers, we lack data that ESAs increase the likelihood of developing new cancers in patients on dialysis or earlier stages of CKD.

KDOQI US Commentary on the 2017 ACC/AHA Hypertension Guideline.

Hypertension is a modifiable risk factor for cardiovascular morbidity and mortality and reduction of elevated blood pressure (BP) remains an important intervention for slowing kidney disease progression. Over the past decade, the most appropriate BP target for initiation and titration of BP-lowering medications has been an area of intense research and debate within the clinical community. In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) in conjunction with several other professional societies released new hypertension guidelines based on data from a systematic review of clinical trials and observational data. While many of the recommendations in the ACC/AHA hypertension guideline are relevant to nephrology practice, BP targets and management strategies for patients receiving dialysis are not discussed. This Kidney Disease Outcomes Quality Initiative (KDOQI) commentary focuses largely on recommendations from the ACC/AHA hypertension guidelines that are pertinent to individuals at risk of chronic kidney disease or with non-dialysis-dependent chronic kidney disease. This KDOQI commentary also includes a brief discussion of the consensus statement regarding hypertension diagnosis and management for adults receiving maintenance dialysis published by the European Renal and Cardiovascular Medicine Working Group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension. Overall, we support the vast majority of the ACC/AHA recommendations and highlight select areas in which best diagnosis and treatment options remain controversial.

Utility of positron emission tomography-computed tomography in patients with chronic lymphocytic leukemia following B-cell receptor pathway inhibitor therapy.

The utility of positron emission tomography-computed tomography (PET-CT) in distinguishing Richter's transformation versus chronic lymphocytic leukemia (CLL) progression after ibrutinib and/or idelalisib was assessed in a post hoc analysis of a phase II study of venetoclax. Patients underwent PET-CT at screening and were not enrolled/treated if Richter's transformation was confirmed pathologically. Of 167 patients screened, 57 met criteria for biopsy after PET-CT. Of 35 patients who underwent biopsy, eight had Richter's transformation, two had another malignancy, and 25 had CLL. A PET-CT maximum standardized uptake value (SUVmax) ≥10 had 71% sensitivity and 50% specificity for detecting Richter's transformation [Odds Ratio (OR): 2.5, 95%CI: 0.4-15; P=0.318]. Response rate to venetoclax was similar for screening SUVmax <10 versus ≥10 (65% vs. 62%) (n=127 enrolled), though median progression-free survival was longer at <10 months (24.7 vs. 15.4 months; P=0.0335). Six patients developed Richter's transformation on venetoclax, of whom two had screening biopsy demonstrating CLL (others did not have a biopsy) and five had screening SUVmax <10. We have defined the test characteristics for PET-CT to distinguish progression of CLL as compared to Richter's transformation when biopsied in patients treated with B-cell receptor signaling pathway inhibitors. Overall diminished sensitivity and specificity as compared to prior reports of patients treated with chemotherapy/chemoimmunotherapy suggest it has diminished ability to discriminate these two diagnoses using a SUVmax ≥10 cutoff. This cutoff did not identify venetoclax-treated patients with an inferior response but may be predictive of inferior progression-free survival. (Registered at clinicaltrials.gov identifier: 02141282).