Publications by authors named "Bruce Robinson"

618 Publications

Routinely measured cardiac troponin I and N-terminal pro-B-type natriuretic peptide as predictors of mortality in haemodialysis patients.

ESC Heart Fail 2022 Jan 13. Epub 2022 Jan 13.

Fukuoka Renal Clinic, Fukuoka, Japan.

Aims: Cardiac troponin (cTn) and B-type natriuretic peptide (BNP) are elevated in haemodialysis (HD) patients, and this elevation is associated with HD-induced myocardial stunning/myocardial strain. However, studies using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS) have shown that these cardiac biomarkers are measured in <2% of HD patients in real-world practice. This study aimed to examine whether routinely measured N-terminal pro-BNP (NT-proBNP) and cTnI (contemporary assay) are more appropriate than clinical models for reclassifying the risk of HD patients who have the highest risk of death.

Methods And Results: Pre-dialysis levels of cTnI and NT-proBNP at study enrolment were measured in 1152 HD patients (Japan DOPPS Phase 5). The patients were prospectively followed for 3 years. Cox regression was used to test the associations of cardiac biomarkers with all-cause mortality, adjusting for potential confounders. Subgroup analyses were performed to assess potential effect modification of clinical characteristics, such as age, systolic blood pressure, HD vintage, diabetes mellitus, coronary artery disease, and a history of congestive heart failure. At baseline, 337 (29%) patients had elevated cTnI (99th percentile of a healthy population: >0.04 ng/mL) with a median (inter-quartile range) level of 0.020 (0.005-0.041) ng/mL, and 1140 (99%) patients had elevated NT-proBNP (cut-off for heart failure: >125 pg/mL) with a median level of 3658 (1689-9356) pg/mL. There were 167 deaths during a median follow-up of 2.8 (2.2-2.8) years. Higher levels of both cardiac biomarkers were incrementally associated with mortality after adjustment for potential confounders. Even after adjustment for alternative cardiac biomarkers, the overall P value for the association was <0.01 for both biomarkers. However, the prognostic significance of NT-proBNP was moderately diminished when cTnI was added to the model. The hazard ratios of mortality for cTnI > 0.04 ng/mL (vs. cTnI < 0.006 ng/mL) and NT-proBNP > 8000 pg/mL (vs. NT-proBNP < 2000 pg/mL) were 2.56 (95% confidence interval: 1.37-4.81) and 1.90 (95% confidence interval: 0.95-3.79), respectively. Subgroup analyses showed that the associations of both cardiac biomarkers with mortality were generally consistent between stratified groups.

Conclusions: Routinely measured NT-proBNP and cTnI levels are strongly associated with mortality among prevalent HD patients. These associations remain robust, even after adjustment for alternative biomarkers, suggesting that cTnI and NT-proBNP have identical prognostic significance and may reflect different pathological aspects of cardiac abnormalities.
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http://dx.doi.org/10.1002/ehf2.13784DOI Listing
January 2022

Barriers to conservative care from patients' and nephrologists' perspectives: The CKD-REIN Study.

Nephrol Dial Transplant 2022 Jan 13. Epub 2022 Jan 13.

Service de Néphrologie, CHRU de Nancy, Vandoeuvre-lès-Nancy, France.

Background: Conservative care is increasingly considered an alternative to kidney replacement therapy for kidney failure management, mostly among the elderly. We investigated its status and the barriers to its implementation from patients' and providers' perspectives.

Methods: We analyzed data from 1204 patients with advanced CKD (eGFR < 30 mL/min/1.73 m2) enrolled at 40 nationally representative nephrology clinics (2013-2016) who completed a self-administered questionnaire about the information they received and their preferred treatment option, including conservative care, if their kidneys failed. Nephrologists (N = 137) also reported data about their clinics' resources and practices regarding conservative care.

Results: All participating facilities reported they were routinely able to offer conservative care, but only 37% had written protocols and only 5% a person or team primarily responsible for it. Overall 6% of patients were estimated to use conservative care. Among nephrologists, 82% reported they were fairly or extremely comfortable discussing conservative care, but only 28% usually or always offered this option for older (>75 years) patients approaching kidney failure. They used various terminology for this care, conservative management and non-dialysis care mentioned most often. Among patients, 5% of those >75 years reported receiving information about this option, and 2% preferring it.

Conclusions: Although reported by nephrologists to be widely available and easily discussed, conservative care is only occasionally offered to older patients, most of whom report they were not informed of this option. The lack of a person or team responsible for conservative care and unclear information appear to be key barriers to its implementation.
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http://dx.doi.org/10.1093/ndt/gfac009DOI Listing
January 2022

Thrombocytopenia predicts mortality in Chinese hemodialysis patients- an analysis of the China DOPPS.

BMC Nephrol 2022 Jan 3;23(1):11. Epub 2022 Jan 3.

Department of Nephrology, Peking University People's Hospital, Unit 10C in Ward Building; 11 Xizhimennan Street, Xicheng District, Beijing, 100044, China.

Background: Hemodialysis (HD) patients have a higher mortality rate compared with general population. Our previous study revealed that platelet counts might be a potential risk factor. The role of platelets in HD patients has rarely been studied. The aim of this study is to examine if there is an association of thrombocytopenia (TP) with elevated risk of all-cause mortality and cardiovascular (CV) death in Chinese HD patients.

Methods: Data from a prospective cohort study, China Dialysis Outcomes and Practice Patterns Study (DOPPS) 5, were analyzed. Demographic data, comorbidities, platelet counts and other lab data, and death records which extracted from the medical record were analyzed. TP was defined as the platelet count below the lower normal limit (< 100*10/L). Associations between platelet counts and all-cause and CV mortality were evaluated using Cox regression models. Stepwise multivariate logistic regression was used to identify the independent associated factors, and subgroup analyses were also carried out.

Results: Of 1369 patients, 11.2% (154) had TP at enrollment. The all-cause mortality rates were 26.0% vs. 13.3% (p < 0.001) in patients with and without TP. TP was associated with higher all-cause mortality after adjusted for covariates (HR:1.73,95%CI:1.11,2.71), but was not associated with CV death after fully adjusted (HR:1.71,95%CI:0.88,3.33). Multivariate logistic regression showed that urine output < 200 ml/day, cerebrovascular disease, hepatitis (B or C), and white blood cells were independent impact factors (P < 0.05). Subgroup analysis found that the effect of TP on all-cause mortality was more prominent in patients with diabetes or hypertension, who on dialysis thrice a week, with lower ALB (< 4 g/dl) or higher hemoglobin, and patients without congestive heart failure, cerebrovascular disease, or hepatitis (P < 0.05).

Conclusion: In Chinese HD patients, TP is associated with higher risk of all-cause mortality, but not cardiovascular mortality. Platelet counts may be a useful prognostic marker for clinical outcomes among HD patients, though additional study is needed.
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http://dx.doi.org/10.1186/s12882-021-02579-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722075PMC
January 2022

Why we still need drugs for COVID-19 and can't just rely on vaccines.

Respirology 2021 Dec 30. Epub 2021 Dec 30.

Perth USAsia Centre, The University of Western Australia, Perth, Western Australia, Australia.

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http://dx.doi.org/10.1111/resp.14199DOI Listing
December 2021

The global impact of the Coronavirus 2019 pandemic on in-centre haemodialysis services: an International Society of Nephrology -Dialysis Outcomes Practice Patterns Study survey.

Kidney Int Rep 2021 Dec 13. Epub 2021 Dec 13.

Population Health Sciences, Bristol Medical School, University of Bristol, United Kingdom.

Introduction: To assess the impact of the COVID-19 pandemic impact on haemodialysis centres, The Dialysis Outcomes and Practice Patterns Study and International Society of Nephrology (ISN) collaborated on a web-survey of centres.

Methods: A combined approach of random sampling and open invitation was used between March 2020 and March 2021. Responses were obtained from 412 centres in 78 countries and all 10 ISN regions.

Results: In 8 regions, rates of SARS-CoV-2 infection were <20% in most centres, but in North East Asia and Newly Independent States and Russia rates were ≥20% and ≥30%, respectively. Mortality was ≥10% in most centres in 8 regions, though lower in North America and Caribbean and North East Asia. Diagnostic testing was not available in 33%, 37%, and 61% of centres in Latin America, Africa, and East and Central Europe, respectively. Surgical masks were widely available, but severe shortages of particulate-air filter masks were reported in Latin America (18%) and Africa (30%). Rates of infection in staff ranged from 0% in 90% of centres in North East Asia to ≥50% in 63% of centres in the Middle East and 68% of centres in Newly Independent States and Russia. In most centres <10% of staff died, but in Africa and South Asia 2% and 6% of centres reported ≥50% mortality, respectively.

Conclusion: There has been wide global variation in SARS-CoV-2 infection rates amongst haemodialysis patients and staff, PPE availability, and testing, and the ways in which services have been redesigned in response to the pandemic.
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http://dx.doi.org/10.1016/j.ekir.2021.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684834PMC
December 2021

Changes in practice patterns in Japan from before to after JSDT 2013 guidelines on hemodialysis prescriptions: results from the JDOPPS.

BMC Nephrol 2021 Oct 14;22(1):339. Epub 2021 Oct 14.

Arbor Research Collaborative for Health, Ann Arbor, USA.

Background: The Japanese Society for Dialysis Therapy (JSDT) published in 2013 inaugural hemodialysis (HD) guidelines. Specific targets include 1.4 for single-pool Kt/V (spKt/V) with a minimum dose of 1.2, minimum dialysis session length of 4 hours, minimum blood flow rate (BFR) of 200 mL/min, fluid removal rate no more than 15 mL/kg/hr, and hemodiafiltration (HDF) therapy for certain identified symptoms. We evaluated the effect of these guidelines on actual practice in the years spanning 2005 - 2018.

Methods: Analyses were carried out to describe trends in the above HD prescription practices from December 2005 to April 2013 (before guideline publication) to August 2018 based on prevalent patient cross-sections from approximately 60 randomly selected HD facilities participating in the Japan Dialysis Outcomes and Practice Patterns Study.

Results: From April 2006 to August 2017 continual rises occurred in mean spKt/V (from 1.35 to 1.49), and percent of patients having spKt/V>1.2 (71% to 85%). Mean BFR increased with time from 198.3 mL/min (April 2006) to 218.4 mL/min (August 2017) , along with percent of patients with BFR >200 ml/min (65% to 85%). HDF use increased slightly from 6% (April 2006 and August 2009) to 8% by April 2013, but increased greatly thereafter to 23% by August 2017. In contrast, mean HD treatment time showed little change from 2006-2017, whereas mean UFR declined from 11.3 in 2006 to 8.4 mL/Kg/hour in 2017.

Conclusions: From 2006 - 2018 Japanese HD patients experienced marked improvement in reaching the spKt/V target specified by the 2013 JSDT guidelines. This may have been due to moderate increase in mean BFR even though mean HD session length did not change much. In addition, HDF use increased dramatically in this time period. Other HD delivery changes during this time, such as increased use of super high flux dialyzers, also merit study. While we cannot definitively conclude a causal relationship between the publication of the guidelines and the subsequent practice changes in Japan, those changes moved practice closer to the recommendations of the guidelines.
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http://dx.doi.org/10.1186/s12882-021-02543-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518149PMC
October 2021

Design and synthesis of chromophores with enhanced electro-optic activities in both bulk and plasmonic-organic hybrid devices.

Mater Horiz 2022 Jan 4;9(1):261-270. Epub 2022 Jan 4.

Department of Chemistry, University of Washington, Seattle, WA 98195, USA.

This study demonstrates enhancement of in-device electro-optic activity a series of theory-inspired organic electro-optic (OEO) chromophores based on strong (diarylamino)phenyl electron donating moieties. These chromophores are tuned to minimize trade-offs between molecular hyperpolarizability and optical loss. Hyper-Rayleigh scattering (HRS) measurements demonstrate that these chromophores, herein described as BAH, show >2-fold improvement in standard chromophores such as JRD1, and approach that of the recent BTP and BAY chromophore families. Electric field poled bulk devices of neat and binary BAH chromophores exhibited significantly enhanced EO coefficients () and poling efficiencies (/) compared with state-of-the-art chromophores such as JRD1. The neat BAH13 devices with charge blocking layers produced very large poling efficiencies of 11.6 ± 0.7 nm V and maximum value of 1100 ± 100 pm V at 1310 nm on hafnium dioxide (HfO). These results were comparable to that of our recently reported BAY1 but with much lower loss (extinction coefficient, ), and greatly exceeding that of other previously reported OEO compounds. 3 : 1 BAH-FD : BAH13 blends showed a poling efficiency of 6.7 ± 0.3 nm V and an even greater reduction in . 1 : 1 BAH-BB : BAH13 showed a higher poling efficiency of 8.4 ± 0.3 nm V, which is approximately a 2.5-fold enhancement in poling efficiency JRD1. Neat BAH13 was evaluated in plasmonic-organic hybrid (POH) Mach-Zehnder modulators with a phase shifter length of 10 μm and slot widths of 80 and 105 nm. In-device BAH13 achieved a maximum of 208 pm V at 1550 nm, which is ∼1.7 times higher than JRD1 under equivalent conditions.
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http://dx.doi.org/10.1039/d1mh01206aDOI Listing
January 2022

Blood flow rate: An independent risk factor of mortality in Chinese hemodialysis patients.

Semin Dial 2021 Sep 22. Epub 2021 Sep 22.

Department of Nephrology, Peking University People's Hospital, Beijing, China.

Background: Studies suggested the association between blood flow rate (BFR) and mortality might be beyond dialysis adequacy. This study aimed to explore if BFR is an independent predictor of clinical outcomes in Chinese hemodialysis (HD) patients.

Methods: This study included data from patients in China Dialysis Outcomes and Practice Patterns Study (DOPPS) Phase 5. Patients with a record of BFR were included, and demographic data, comorbidities, hospitalization, and death records were collected. Associations between BFR and all-cause mortality and hospitalization were analyzed using Cox regression models.

Results: One thousand four hundred twelve (98.9%) patients were included. Most patients were with BFR < 300 ml/min. After full adjustment, each 10-ml/min increase of BFR was associated with a 6.4% decrease in all-cause mortality risk (HR: 0.936, 95% CI: 0.880-0.996) but not first hospitalization (HR: 0.987, 95% CI: 0.949-1.027). The impact of BFR on mortality may be more prominent in patients who were male gender, nondiabetic, albumin < 4.0 g/dl, and hemoglobin ≥ 9.0 g/dl.

Conclusion: Increased BFR is independently associated with a lower risk of all-cause mortality within the range of BFR 200-300 ml/min. And this effect is more pronounced in patients who were male gender, nondiabetic, albumin < 4.0 g/dl, and hemoglobin ≥ 9.0 g/dl.
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http://dx.doi.org/10.1111/sdi.13023DOI Listing
September 2021

Electro-Optic Activity in Excess of 1000 pm V Achieved via Theory-Guided Organic Chromophore Design.

Adv Mater 2021 Nov 20;33(45):e2104174. Epub 2021 Sep 20.

Department of Chemistry, University of Washington, Box 351700, Seattle, WA, 98195, USA.

High performance organic electro-optic (OEO) materials enable ultrahigh bandwidth, small footprint, and extremely low drive voltage in silicon-organic hybrid and plasmonic-organic hybrid photonic devices. However, practical OEO materials under device-relevant conditions are generally limited to performance of ≈300 pm V (10× the EO response of lithium niobate). By means of theory-guided design, a new series of OEO chromophores is demonstrated, based on strong bis(4-dialkylaminophenyl)phenylamino electron donating groups, capable of EO coefficients (r ) in excess of 1000 pm V . Density functional theory modeling and hyper-Rayleigh scattering measurements are performed and confirm the large improvement in hyperpolarizability due to the stronger donor. The EO performance of the exemplar chromophore in the series, BAY1, is evaluated neat and at various concentrations in polymer host and shows a nearly linear increase in r and poling efficiency (r /E , E is poling field) with increasing chromophore concentration. 25 wt% BAY1/polymer composite shows a higher poling efficiency (3.9 ± 0.1 nm V ) than state-of-the-art neat chromophores. Using a high-ε charge blocking layer with BAY1, a record-high r (1100 ± 100 pm V ) and poling efficiency (17.8 ± 0.8 nm V ) at 1310 nm are achieved. This is the first reported OEO material with electro-optic response larger than thin-film barium titanate.
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http://dx.doi.org/10.1002/adma.202104174DOI Listing
November 2021

Change in Practice of Radioactive Iodine Administration in Differentiated Thyroid Cancer: A Single-Centre Experience.

Eur Thyroid J 2021 Jul 25;10(5):408-415. Epub 2021 May 25.

Department of Endocrinology, Royal North Shore Hospital, Sydney, New South Wales, Australia.

Objective: Our study aimed to analyse temporal trends in radioactive iodine (RAI) treatment for thyroid cancer over the past decade; to analyse key factors associated with clinical decisions in RAI dosing; and to confirm lower activities of RAI for low-risk patients were not associated with an increased risk of recurrence.

Methods: Retrospective analysis of 1,323 patients who received RAI at a quaternary centre in Australia between 2008 and 2018 was performed. Prospectively collected data included age, gender, histology, and American Joint Committee on Cancer stage (7th ed). American Thyroid Association risk was calculated retrospectively.

Results: The median activities of RAI administered to low-risk patients decreased from 3.85 GBq (104 mCi) in 2008-2016 to 2.0 GBq (54 mCi) in 2017-2018. The principal driver of this change was an increased use of 1 GBq (27 mCi) from 1.3% of prescriptions in 2008-2011 to 18.5% in 2017-2018. In patients assigned as low risk per ATA stratification, lower activities of 1 GBq or 2 GBq (27 mCi or 54 mCi) were not associated with an increased risk of recurrence. In patients assigned to intermediate- or high-risk categories who received RAI as adjuvant therapy, there was no difference in risk of recurrence between 4 GBq (108 mCi) and 6 GBq (162 mCi).

Conclusions: Our data demonstrate an evolution of RAI activities consistent with translation of ATA guidelines into clinical practice. Use of lower RAI activities was not associated with an increase in recurrence in low-risk thyroid cancer patients. Our data also suggest lower RAI activities may be as efficacious for adjuvant therapy in intermediate- and high-risk patients.
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http://dx.doi.org/10.1159/000516358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406251PMC
July 2021

Patient-Reported Outcomes with Selpercatinib Among Patients with RET Fusion-Positive Non-Small Cell Lung Cancer in the Phase I/II LIBRETTO-001 Trial.

Oncologist 2021 Sep 15. Epub 2021 Sep 15.

University of California at San Francisco, San Francisco, California, USA.

Background: LIBRETTO-001 is an ongoing, global, open-label, phase I/II study of selpercatinib in patients with advanced or metastatic solid tumors. We report interim patient-reported outcomes in patients with RET fusion-positive non-small cell lung cancer (NSCLC).

Patients And Methods: Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) version 3.0 at baseline (cycle 1, day 1), approximately every other 28-day cycle until cycle 13, and every 12 weeks thereafter. Data were evaluated through cycle 13 as few patients had reached later time points. A change of ≥10 points from baseline in domain scores was considered clinically meaningful.

Results: Among 253 selpercatinib-treated patients, 239 were categorized into subgroups by prior therapy: treatment-naïve (n = 39), one prior line of therapy (n = 64), or two or more prior lines of therapy (n = 136). The QLQ-C30 was completed by >85% of patients at each time point. Most patients overall and in each subgroup maintained or improved in all health-related quality of life (HRQoL) domains during treatment. The percentage of patients who experienced clinically meaningful improvements ranged from 61.1% to 66.7% for global health status, 33.3% to 61.1% for dyspnea, and 46.2% to 63.0% for pain. The 61.1% of patients with improved dyspnea had two or more prior lines of therapy; median time to first improvement was 3.4 months. At the first postbaseline evaluation (cycle 3), 45.9% of all patients reported a ≥ 10-point reduction in pain.

Conclusion: In this interim analysis, the majority of patients with RET fusion-positive NSCLC remained stable or improved on all QLQ-C30 subscales at each study visit, demonstrating favorable HRQoL as measured by the QLQ-C30 during treatment with selpercatinib.

Implications For Practice: Patients with non-small cell lung cancer (NSCLC) generally experience greater symptom burden and lower health-related quality of life (HRQoL) as the disease progresses. In a phase I/II trial, improvements in HRQoL were observed in over 60% of patients with advanced RET fusion-positive NSCLC who received selpercatinib, a highly selective RET inhibitor. More than one third of patients reported a reduction in dyspnea during study participation, and nearly half reported a reduction in pain by the first follow-up assessment.
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http://dx.doi.org/10.1002/onco.13976DOI Listing
September 2021

Patient-Reported Outcomes with Selpercatinib Treatment Among Patients with RET-Mutant Medullary Thyroid Cancer in the Phase I/II LIBRETTO-001 Trial.

Oncologist 2021 Sep 13. Epub 2021 Sep 13.

The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Medullary thyroid cancer (MTC) standard of care includes multikinase inhibitors (MKIs), which can exacerbate disease-related diarrhea, primarily because of non-RET kinase inhibition. We report diarrhea and other patient-reported outcomes (PROs) with selpercatinib, a highly selective RET inhibitor, among patients with RET-mutant MTC in the ongoing, phase I/II LIBRETTO-001 trial.

Materials And Methods: Instrument completion time points were baseline (cycle 1, day 1) and approximately every other 28-day cycle until cycle 13 (every 12 weeks thereafter) for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, and baseline, weekly during cycle 1, and day 1 of every cycle for the modified Systemic Therapy-Induced Diarrhea Assessment Tool (mSTIDAT). A ≥ 10-point change from baseline in domain score was considered clinically meaningful. PROs were summarized through cycle 13 in all patients and by subgroups with or without prior exposure to MKIs vandetanib and/or cabozantinib (V/C).

Results: Among the overall MTC population (n = 226), 88 (39%) and 124 (55%) patients comprised the V/C-naïve and previous V/C subgroups, respectively. Compliance was >85% for both instruments at each time point. Most patients maintained/improved in all health-related quality of life (HRQoL) subscales throughout treatment. Improvements in diarrhea were clinically meaningful in 43.5% of patients overall and in 36.8% and 51.3% of V/C-naïve and previous V/C subgroups, respectively. At baseline, 80.4% of all patients reported diarrhea on mSTIDAT. The percentage of patients who reported diarrhea was reduced to less than half of all patients (range: 33.3%-48.3%) after cycle 2.

Conclusion: These interim results demonstrate that patients with RET-mutant MTC improved/remained stable on all domains of HRQoL during treatment with selpercatinib. Future analyses will be conducted as the data mature.

Implications For Practice: Patients with metastatic medullary thyroid cancer (MTC) frequently experience disease-related diarrhea that can significantly impair daily living. Standards of care for the treatment of MTC include RET-targeted therapies as well as multikinase inhibitors (MKIs). Over 40% of patients with RET-mutant MTC who received selpercatinib, a highly selective RET inhibitor, reported clinical meaningful improvements in diarrhea in a phase I/II study. Patient-reported diarrhea improved in 36.8% of patients who had no previous treatment with MKIs and in 51.3% of patients who had previous treatment with MKIs. The percentage of patients who reported diarrhea prior to selpercatinib initiation (80.4%) was reduced to less than half (range: 33.3%-48.3%) after cycle 2 of selpercatinib treatment.
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http://dx.doi.org/10.1002/onco.13977DOI Listing
September 2021

Prescription of Direct Oral Anticoagulants to Patients With Moderate-to-Advanced CKD: Too Little or Just Right?

Kidney Int Rep 2021 Sep 12;6(9):2496-2500. Epub 2021 Jun 12.

Clinical Epidemiology Team, CESP (Centre de recherche en Epidémiologie et Santé des Populations), Université Paris-Saclay, UVSQ, Inserm, Villejuif, France.

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http://dx.doi.org/10.1016/j.ekir.2021.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418947PMC
September 2021

New Insights into Acute-on-Chronic Kidney Disease in Nephrology Patients: The CKD-REIN Study.

Nephrol Dial Transplant 2021 Sep 2. Epub 2021 Sep 2.

Paris-Saclay University, Versailles Saint Quentin University, Inserm, Clinical Epidemiology Team, CESP, Centre for Research in Epidemiology and Population Health, F-94807 Villejuif, France.

Background: Acute-on-chronic kidney disease (ACKD) is poorly understood and often overlooked. We studied its incidence, circumstances, determinants, and outcomes in patients with CKD.

Methods: We used the Kidney Disease Improving Global Outcomes criteria to identify all-stage acute kidney injury (AKI) events in 3033 nephrology outpatients with CKD stage 3-5 participating in the CKD-REIN cohort study (2013-2020), and cause-specific Cox models to estimate hazard ratios (HR, 95% confidence intervals [CI]) of AKI-associated risk factors.

Results: At baseline, 22% of the patients (mean age 67 years, 65% men, mean eGFR 32 ml/min/1.73m2) had a history of AKI. Over a 3-year follow-up, 443 had at least one AKI event: 27% were stage 2 or 3, and 11% required dialysis; 74% involved hospitalization including 47% acquired as hospital inpatients; a third were not reported in hospital discharge reports. Incidence rates were 10.1 and 4.8 per 100 person-years in patients with and without an AKI history, respectively. In 2375 patients without this history, male sex, diabetes, cardiovascular disease, cirrhosis, several drugs, low eGFR, and serum albumin levels were significantly associated with a higher risk of AKI, as were low birth weight (<2500 g) (adjusted HR, 1.98; 95%CI, 1.35 to 2.91) and hemoglobin level (HR 1.21; 1.12 to 1.32 per 1 g/dl decrease). Within one year, only 63% of the patients had recovered their previous kidney function, 13.7% had started kidney replacement therapy, and 12.7% had died.

Conclusions: The study highlights the high rate of hospital-acquired AKI events in patients with CKD, and their underreporting at hospital discharge. It also reveals low birth weight and anemia as possible new risk factors in CKD patients.
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http://dx.doi.org/10.1093/ndt/gfab249DOI Listing
September 2021

Physical functioning in patients with chronic kidney disease stage G3b-5 in Japan: The reach-J CKD cohort study.

Nephrology (Carlton) 2021 Dec 17;26(12):981-987. Epub 2021 Aug 17.

Department of Nephrology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

Aim: Chronic kidney disease (CKD) is an important public health problem. Recently, CKD has been found to be associated with poor physical functioning in community-dwelling elderly individuals. However, the physical functioning of non-dialysis (ND) patients with advanced CKD treated by nephrologists is unknown.

Methods: Patients with ND-CKD stage G3b-5 who participated in a nationwide Reach-J CKD cohort study were included in this study. Physical functioning and physical activity were assessed by the Katz Index, Lawton-Body instrumental activities of daily living (IADL) scale, and Rapid Assessment of Physical Activity questionnaire of the international CKD Outcomes and Practice Patterns Study (CKDopps) questionnaires. Dichotomies between good and poor physical functioning and physical activity scores were explored.

Results: Among 1628 patients, 84.3% had good physical functioning. Poor physical functioning was more common with older age (p < .001), higher CKD stage (p < .05), and comorbid conditions such as diabetes (p < .001), cardiovascular disease (p < .05), cerebrovascular disease (p < .001), and cancer (non-skin) (p < .05). Forty percent of the patients were inactive. Physical inactivity was more common with older age (p < .001) and higher CKD stage (p < .001).

Conclusion: A minority, but sizeable proportion of patients with advanced CKD treated by nephrologists in Japan have some disability in ADLs/IADLs. Nephrologists need to routinely assess the physical functioning and physical activity of patients with advanced CKD to provide individualized guidance and comprehensive support to these patients for their daily life.
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http://dx.doi.org/10.1111/nep.13955DOI Listing
December 2021

Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies.

Proc Natl Acad Sci U S A 2021 07;118(30)

Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;

Neoantigen-specific T cells are strongly implicated as being critical for effective immune checkpoint blockade treatment (ICB) (e.g., anti-PD-1 and anti-CTLA-4) and are being targeted for vaccination-based therapies. However, ICB treatments show uneven responses between patients, and neoantigen vaccination efficiency has yet to be established. Here, we characterize neoantigen-specific CD8 T cells in a tumor that is resistant to ICB and neoantigen vaccination. Leveraging the use of mass cytometry combined with multiplex major histocompatibility complex (MHC) class I tetramer staining, we screened and identified tumor neoantigen-specific CD8 T cells in the Lewis Lung carcinoma (LLC) tumor model (mRiok1). We observed an expansion of mRiok1-specific CD8 tumor-infiltrating lymphocytes (TILs) after ICB targeting PD-1 or CTLA-4 with no sign of tumor regression. The expanded neoantigen-specific CD8 TILs remained phenotypically and functionally exhausted but displayed cytotoxic characteristics. When combining both ICB treatments, mRiok1-specific CD8 TILs showed a stem-like phenotype and a higher capacity to produce cytokines, but tumors did not show signs of regression. Furthermore, combining both ICB treatments with neoantigen vaccination did not induce tumor regression either despite neoantigen-specific CD8 TIL expansion. Overall, this work provides a model for studying neoantigens in an immunotherapy nonresponder model. We showed that a robust neoantigen-specific T-cell response in the LLC tumor model could fail in tumor response to ICB, which will have important implications in designing future immunotherapeutic strategies.
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http://dx.doi.org/10.1073/pnas.2025570118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325261PMC
July 2021

Etelcalcetide Utilization, Dosing Titration, and Chronic Kidney Disease-Mineral and Bone Disease (CKD-MBD) Marker Responses in US Hemodialysis Patients.

Am J Kidney Dis 2021 Jul 15. Epub 2021 Jul 15.

Arbor Research Collaborative for Health, Ann Arbor, Michigan.

Rationale & Objective: Clinical trial data have demonstrated the efficacy of etelcalcetide for reducing parathyroid hormone (PTH) levels in hemodialysis (HD) patients. We provide a real-world summary of etelcalcetide utilization, dosing, effectiveness, and discontinuation since its US introduction in April 2017.

Study Design: New-user design within prospective cohort.

Setting & Participants: 2,596 new users of etelcalcetide from April 2017 through August 2019 in a national sample of adult maintenance HD patients in the US Dialysis Outcomes and Practice Patterns Study (DOPPS).

Predictors: Baseline PTH, prior cinacalcet use, initial etelcalcetide dose.

Outcome: Trajectories of etelcalcetide dose, chronic kidney disease-mineral and bone disease (CKD-MBD) medications, and levels of PTH, serum calcium, and phosphorus in the 12 months after etelcalcetide initiation.

Analytical Approach: Cumulative incidence methods for etelcalcetide discontinuation and linear generalized estimating equations for trajectory analyses.

Results: By August 2019, etelcalcetide prescriptions increased to 6% of HD patients from their first use in April 2017. Starting etelcalcetide dose was 15 mg/wk in 70% of patients and 7.5 mg/wk in 27% of patients; 49% of new users were prescribed cinacalcet in the prior 3 months. Etelcalcetide discontinuation was 9%, 17%, and 27% by 3, 6, and 12 months after initiation. One year after etelcalcetide initiation, mean PTH levels declined by 40%, from 948 to 566 pg/mL, and the proportion of patients with PTH within target (150-599 pg/mL) increased from 33% to 64% overall, from 0 to 60% among patients with baseline PTH ≥ 600 pg/mL, and from 30% to 63% among patients with prior cinacalcet use. The proportion of patients with serum phosphorus > 5.5 mg/dL decreased from 55% to 45%, while the prevalence of albumin-corrected serum calcium < 7.5 mg/dL remained at 1%-2%. There were increases in use of active vitamin D (from 77% to 87%) and calcium-based phosphate binders (from 41% to 50%) in the 12 months after etelcalcetide initiation.

Limitations: Data are unavailable for provider dosing protocols, dose holds, or reasons for discontinuation.

Conclusions: In the 12 months after etelcalcetide initiation, patients had large and sustained reductions in PTH levels. These results support the utility of etelcalcetide as an effective therapy to achieve the KDIGO-recommended guidelines for CKD-MBD markers in HD patients.
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http://dx.doi.org/10.1053/j.ajkd.2021.05.020DOI Listing
July 2021

Serum Biomarkers of Iron Stores Are Associated with Increased Risk of All-Cause Mortality and Cardiovascular Events in Nondialysis CKD Patients, with or without Anemia.

J Am Soc Nephrol 2021 08 8;32(8):2020-2030. Epub 2021 Jul 8.

Arbor Research Collaborative for Health, Ann Arbor, Michigan.

Background: Approximately 30%-45% of patients with nondialysis CKD have iron deficiency. Iron therapy in CKD has focused primarily on supporting erythropoiesis. In patients with or without anemia, there has not been a comprehensive approach to estimating the association between serum biomarkers of iron stores, and mortality and cardiovascular event risks.

Methods: The study included 5145 patients from Brazil, France, the United States, and Germany enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study, with first available transferrin saturation (TSAT) and ferritin levels as exposure variables. We used Cox models to estimate hazard ratios (HRs) for all-cause mortality and major adverse cardiovascular events (MACE), with progressive adjustment for potentially confounding variables. We also used linear spline models to further evaluate functional forms of the exposure-outcome associations.

Results: Compared with patients with a TSAT of 26%-35%, those with a TSAT ≤15% had the highest adjusted risks for all-cause mortality and MACE. Spline analysis found the lowest risk at TSAT 40% for all-cause mortality and MACE. Risk of all-cause mortality, but not MACE, was also elevated at TSAT ≥46%. Effect estimates were similar after adjustment for hemoglobin. For ferritin, no directional associations were apparent, except for elevated all-cause mortality at ferritin ≥300 ng/ml.

Conclusions: Iron deficiency, as captured by TSAT, is associated with higher risk of all-cause mortality and MACE in patients with nondialysis CKD, with or without anemia. Interventional studies evaluating the effect on clinical outcomes of iron supplementation and therapies for alternative targets are needed to better inform strategies for administering exogenous iron.
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http://dx.doi.org/10.1681/ASN.2020101531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455257PMC
August 2021

Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Oncol 2021 08 5;22(8):1126-1138. Epub 2021 Jul 5.

Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: Patients with radioiodine-refractory differentiated thyroid cancer (DTC) previously treated with vascular endothelial growth factor receptor (VEGFR)-targeted therapy have aggressive disease and no available standard of care. The aim of this study was to evaluate the tyrosine kinase inhibitor cabozantinib in this patient population.

Methods: In this global, randomised, double-blind, placebo-controlled, phase 3 trial, patients aged 16 years and older with radioiodine-refractory DTC (papillary or follicular and their variants) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to oral cabozantinib (60 mg once daily) or matching placebo, stratified by previous lenvatinib treatment and age. The randomisation scheme used stratified permuted blocks of block size six and an interactive voice-web response system; both patients and investigators were masked to study treatment. Patients must have received previous lenvatinib or sorafenib and progressed during or after treatment with up to two VEGFR tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib on disease progression confirmed by blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (confirmed response per Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) in the first 100 randomly assigned patients (objective response rate intention-to-treat [OITT] population) and progression-free survival (time to earlier of disease progression per RECIST version 1.1 or death) in all patients (intention-to-treat [ITT] population), both assessed by BIRC. This report presents the primary objective response rate analysis and a concurrent preplanned interim progression-free survival analysis. The study is registered with ClinicalTrials.gov, NCT03690388, and is no longer enrolling patients.

Findings: Between Feb 27, 2019, and Aug 18, 2020, 227 patients were assessed for eligibility, of whom 187 were enrolled from 164 clinics in 25 countries and randomly assigned to cabozantinib (n=125) or placebo (n=62). At data cutoff (Aug 19, 2020) for the primary objective response rate and interim progression-free survival analyses, median follow-up was 6·2 months (IQR 3·4-9·2) for the ITT population and 8·9 months (7·1-10·5) for the OITT population. An objective response in the OITT population was achieved in ten (15%; 99% CI 5·8-29·3) of 67 patients in the cabozantinib group versus 0 (0%; 0-14·8) of 33 in the placebo (p=0·028) but did not meet the prespecified significance level (α=0·01). At interim analysis, the primary endpoint of progression-free survival was met in the ITT population; cabozantinib showed significant improvement in progression-free survival over placebo: median not reached (96% CI 5·7-not estimable [NE]) versus 1·9 months (1·8-3·6); hazard ratio 0·22 (96% CI 0·13-0·36; p<0·0001). Grade 3 or 4 adverse events occurred in 71 (57%) of 125 patients receiving cabozantinib and 16 (26%) of 62 receiving placebo, the most frequent of which were palmar-plantar erythrodysaesthesia (13 [10%] vs 0), hypertension (11 [9%] vs 2 [3%]), and fatigue (ten [8%] vs 0). Serious treatment-related adverse events occurred in 20 (16%) of 125 patients in the cabozantinib group and one (2%) of 62 in the placebo group. There were no treatment-related deaths.

Interpretation: Our results show that cabozantinib significantly prolongs progression-free survival and might provide a new treatment option for patients with radioiodine-refractory DTC who have no available standard of care.

Funding: Exelixis.
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http://dx.doi.org/10.1016/S1470-2045(21)00332-6DOI Listing
August 2021

Hyperkalemia excursions are associated with an increased risk of mortality and hospitalizations in hemodialysis patients.

Clin Kidney J 2021 Jul 14;14(7):1760-1769. Epub 2020 Dec 14.

Arbor Research Collaborative for Health, Ann Arbor, MI, USA.

Background: Hyperkalemia is common among hemodialysis (HD) patients and has been associated with adverse clinical outcomes. Previous studies considered a single serum potassium (K) measurement or time-averaged values, but serum K excursions out of the target range may be more reflective of true hyperkalemia events. We assessed whether hyperkalemia excursions lead to an elevated risk of adverse clinical outcomes.

Methods: Using data from 21 countries in Phases 4-6 (2009-18) of the Dialysis Outcomes and Practice Patterns Study (DOPPS), we investigated the associations between peak serum K level, measured monthly predialysis, over a 4-month period ('peak K') and clinical outcomes over the subsequent 4 months using Cox regression, adjusted for potential confounders.

Results: The analysis included 62 070 patients contributing a median of 3 (interquartile range 2-6) 4-month periods. The prevalence of hyperkalemia based on peak K was 58% for >5.0, 30% for >5.5 and 12% for >6.0 mEq/L. The all-cause mortality hazard ratio for peak K (reference ≤5.0 mEq/L) was 1.15 [95% confidence interval (CI) 1.09, 1.21] for 5.1-5.5 mEq/L, 1.19 (1.12, 1.26) for 5.6-6.0 mEq/L and 1.33 (1.23, 1.43) for >6.0 mEq/L. Results were qualitatively consistent when analyzing hospitalizations and a cardiovascular composite outcome.

Conclusions: Among HD patients, we identified a lower K threshold (peak K 5.1-5.5 mEq/L) than previously reported for increased risk of hospitalization and mortality, with the implication that a greater proportion (>50%) of the HD population may be at risk. A reassessment of hyperkalemia severity ranges is needed, as well as an exploration of new strategies for effective management of chronic hyperkalemia.
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http://dx.doi.org/10.1093/ckj/sfaa208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243282PMC
July 2021

A genome-wide association study suggests correlations of common genetic variants with peritoneal solute transfer rates in patients with kidney failure receiving peritoneal dialysis.

Kidney Int 2021 11 29;100(5):1101-1111. Epub 2021 Jun 29.

School of Medicine, Faculty of Medicine and Health Sciences, Keele University, Keele, UK.

Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD. Heritability of PSTR was estimated using genomic-restricted maximum-likelihood analysis, and the association of PSTR with a genome-wide polygenic risk score was also tested. The mean four-hour dialysate/plasma creatinine ratio in participants was 0.70. In 2212 participants of European ancestry, no signal reached genome-wide significance but 23 single nucleotide variants at four loci demonstrated suggestive associations with PSTR. Meta-analysis of ancestry-stratified regressions in 2850 participants revealed five single-nucleotide variants at four loci with suggestive correlations with PSTR. Association across ancestry strata was consistent for rs28644184 at the KDM2B locus. The estimated heritability of PSTR was 19%, and a permuted model polygenic risk score was significantly associated with PSTR. Thus, this genome-wide association study of patients receiving peritoneal dialysis bolsters evidence for a genetic contribution to inter-individual variability in PSTR.
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http://dx.doi.org/10.1016/j.kint.2021.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545920PMC
November 2021

Secondary hyperparathyroidism, weight loss, and longer term mortality in haemodialysis patients: results from the DOPPS.

J Cachexia Sarcopenia Muscle 2021 08 1;12(4):855-865. Epub 2021 Jun 1.

Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan.

Background: Wasting is a common complication of kidney failure that leads to weight loss and poor outcomes. Recent experimental data identified parathyroid hormone (PTH) as a driver of adipose tissue browning and wasting, but little is known about the relations among secondary hyperparathyroidism, weight loss, and risk of mortality in dialysis patients.

Methods: We included 42,319 chronic in-centre haemodialysis patients from the Dialysis Outcomes and Practice Patterns Study phases 2-6 (2002-2018). Linear mixed models were used to estimate the association between baseline PTH and percent weight change over 12 months, adjusting for country, demographics, comorbidities, and labs. Accelerated failure time models were used to assess 12 month weight loss as a mediator between baseline high PTH and mortality after 12 months.

Results: Baseline PTH was inversely associated with 12 month weight change: 12 month weight loss >5% was observed in 21%, 18%, 18%, 17%, 15%, and 14% of patients for PTH ≥600 pg/mL, 450-600, 300-450, 150-300, 50-150, and <50 pg/mL, respectively. In adjusted analyses, 12 month weight change compared with PTH 150-299 pg/mL was -0.60%, -0.12%, -0.10%, +0.15%, and +0.35% for PTH ≥600, 450-600, 300-450, 50-150, and <50 pg/mL, respectively. This relationship was robust regardless of recent hospitalization and was more pronounced in persons with preserved appetite. During follow-up after the 12 month weight measure [median, 1.0 (interquartile range, 0.6-1.7) years; 6125 deaths], patients with baseline PTH ≥600 pg/mL had 11% [95% confidence interval (CI), 9-13%] shorter lifespan, and 18% (95% CI, 14-23%) of this effect was mediated through weight loss ≥2.5%.

Conclusions: Secondary hyperparathyroidism may be a novel mechanism of wasting, corroborating experimental data, and, among chronic dialysis patients, this pathway may be a mediator between elevated PTH levels and mortality. Future research should determine whether PTH-lowering therapy can limit weight loss and improve longer term dialysis outcomes.
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http://dx.doi.org/10.1002/jcsm.12722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350219PMC
August 2021

Multimodality Treatment Improves Locoregional Control, Progression-Free and Overall Survival in Patients with Anaplastic Thyroid Cancer: A Retrospective Cohort Study Comparing Oncological Outcomes and Morbidity between Multimodality Treatment and Limited Treatment.

Ann Surg Oncol 2021 Nov 25;28(12):7520-7530. Epub 2021 May 25.

University of Sydney Endocrine Surgical Unit, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, Australia.

Background: Patients with anaplastic thyroid cancer (ATC) have poor overall survival, and the optimal management approach remains unclear. The aim of this study is to evaluate our experience with multimodality (MMT) versus limited treatment (LT) for ATC.

Patients And Methods: A cohort study of patients with ATC managed in a tertiary referral center was undertaken. The outcomes of MMT were compared with those of LT. The primary outcome measures were locoregional control and progression-free and overall survival. Secondary outcome measures were treatment-related complications and factors associated with improved survival.

Results: In total, 59 patients (35 females) with a median age of 73 years (range 39-99 years) and ATC stage IVA (n = 2), IVB (n = 28), or IVC (n = 29) were included. LT was utilized in 25 patients (42%), and 34 cases had MMT. MMT patients had a longer time of locoregional control (18.5 versus 1.9 months; p < 0.001), progression-free survival (3.5 versus 1.2 months; p < 0.001), and overall survival (6.9 versus 2.0 months; p < 0.001) when compared with LT. For patients with stage IVC ATC, locoregional control (p = 0.03), progression-free survival (p < 0.001), and overall survival (p < 0.001) were superior in the MMT cohort compared with LT. MMT had more treatment-related complications than LT (p < 0.001). An Eastern Cooperative Oncology Group performance status < 2 (HR 0.30; p = 0.001) and MMT (HR 0.35; p = 0.008) were associated with improved overall survival.

Conclusion: MMT is likely to improve locoregional control, progression-free survival, and overall survival in selected ATC patients including stage IVC tumors but comes with a greater complication risk.
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http://dx.doi.org/10.1245/s10434-021-10146-3DOI Listing
November 2021

Worldwide Early Impact of COVID-19 on Dialysis Patients and Staff and Lessons Learned: A DOPPS Roundtable Discussion.

Kidney Med 2021 Jul-Aug;3(4):619-634. Epub 2021 May 14.

Arbor Research Collaborative for Health, Ann Arbor, MI.

As the worst global pandemic of the past century, coronavirus disease 2019 (COVID-19) has had a disproportionate effect on maintenance dialysis patients and their health care providers. At a virtual roundtable on June 12, 2020, Dialysis Outcomes and Practice Patterns Study (DOPPS) investigators from 15 countries in Asia, Europe, and the Americas described and compared the effects of COVID-19 on dialysis care, with recent updates added. Most striking is the huge difference in risk to dialysis patients and staff across the world. Per-population cases and deaths among dialysis patients vary more than 100-fold across participating countries, mirroring burden in the general population. International data indicate that the case-fatality ratio remains at 10% to 30% among dialysis patients, confirming the gravity of infection, and that cases are much more common among in-center than home dialysis patients. This latter finding merits urgent study because in-center patients often have greater community exposure, and in-center transmission may be uncommon under optimal protocols. Greater telemedicine use is a welcome change here to stay, and our community needs to improve emergency planning and protect dialysis staff from the next pandemic. Finally, the pandemic's challenges have prompted widespread partnering and innovation in kidney care and research that must be sustained after this global health crisis.
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http://dx.doi.org/10.1016/j.xkme.2021.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120787PMC
May 2021

Mortality, hospitalization and transfer to haemodialysis and hybrid therapy, in Japanese peritoneal dialysis patients.

Perit Dial Int 2021 May 18:8968608211016127. Epub 2021 May 18.

Kawashima Hospital, Tokushima, Japan.

Background And Objectives: Survival of peritoneal dialysis (PD) patients in Japan is high, but few reports exist on cause-specific mortality, transfer to haemodialysis (HD) or hybrid dialysis and hospitalisation risks. We aimed to identify reasons for transfer to HD, hybrid dialysis and hospitalisation in the Japan Peritoneal Dialysis and Outcomes Practice Patterns Study.

Methods: This observational study included 808 adult PD patients across 31 facilities in Japan in 2014-2017. Information on all-cause and cause-specific mortality and hospitalisation and permanent transfer to HD and PD/HD hybrid therapy were prospectively collected and rates calculated.

Results: Median follow-up time was 1.66 years where 162 patients transferred to HD, 79 transferred to hybrid dialysis and 74 patients died. All-cause and cardiovascular disease (CVD)-related mortality rates were 5.1 and 1.7 deaths/100 patient-years, respectively. Rates of transfer to HD and hybrid therapy were 11.2 and 5.5 transfers/100 patient-years, respectively. Among HD transfers, 40% were due to infection (including peritonitis), while 20% were due to inadequate solute/water clearance. Eighty-one percent of hybrid dialysis transfers were due to inadequate solute/water clearance. All--cause, peritonitis-related and CVD-related hospitalisation rates were 120.4, 21.1 and 15.6/100 patient-years, respectively. Median hospital length of stay was 19 days.

Conclusions: Mortality, hospitalisation and transfer to HD/hybrid dialysis rates are relatively low in Japan compared to many other countries with hybrid transfers, accounting for one-third of dialysis transfers from PD. Further study is needed to explain the high inter-facility variation in hospitalisation rates and how to further reduce hospitalisation rates for Japanese PD patients.
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http://dx.doi.org/10.1177/08968608211016127DOI Listing
May 2021

Open-Label, Single-Arm, Multicenter, Phase II Trial of Lenvatinib for the Treatment of Patients With Anaplastic Thyroid Cancer.

J Clin Oncol 2021 07 7;39(21):2359-2366. Epub 2021 May 7.

The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Anaplastic thyroid cancer (ATC), an aggressive malignancy, is associated with a poor prognosis and an unmet need for effective treatment, especially for patients without mutations or or fusions. Lenvatinib is US Food and Drug Administration-approved for radioiodine-refractory differentiated thyroid cancer and has previously demonstrated activity in a small study of patients with ATC (n = 17). We aimed to further evaluate lenvatinib in ATC.

Methods: This open-label, multicenter, international, phase II study enrolled patients with ATC, who had ≥ 1 measurable target lesion, to receive lenvatinib 24 mg once daily. The primary end points were objective response rate (ORR) by investigator assessment per RECIST v1.1 and safety. Responses were confirmed ≥ 4 weeks after the initial response. Additional end points included progression-free survival and overall survival (OS).

Results: The study was halted for futility as the minimum ORR threshold of 15% was not met upon interim analysis. The interim analysis set included the first 20 patients. The full analysis set includes all 34 enrolled and treated patients. In the full analysis set, one patient achieved a partial response (ORR, 2.9%; 95% CI, 0.1 to 15.3). More than half of the evaluable patients experienced tumor shrinkage; three patients experienced a > 30% tumor reduction. The median progression-free survival was 2.6 months (95% CI, 1.4 to 2.8); the median overall survival was 3.2 months (95% CI, 2.8 to 8.2). The most common treatment-related adverse events (AEs) were hypertension (56%), decreased appetite (29%), fatigue (29%), and stomatitis (29%). No major treatment-related bleeding events or grade 5 treatment-related AEs occurred.

Conclusion: The safety profile of lenvatinib in ATC was manageable, and many AEs were attributable to the progression of ATC. The results suggest that lenvatinib monotherapy may not be an effective treatment for ATC; further investigation may be warranted.
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http://dx.doi.org/10.1200/JCO.20.03093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280094PMC
July 2021

Beta-2 microglobulin and all-cause mortality in the era of high-flux hemodialysis: results from the Dialysis Outcomes and Practice Patterns Study.

Clin Kidney J 2021 May 27;14(5):1436-1442. Epub 2020 Oct 27.

Division of Nephrology, Michael's Hospital, University of Toronto, Toronto, ON, Canada.

Background: Beta-2 microglobulin (β2M) accumulates in hemodialysis (HD) patients, but its consequences are controversial, particularly in the current era of high-flux dialyzers. High-flux HD treatment improves β2M removal, yet β2M and other middle molecules may still contribute to adverse events. We investigated patient factors associated with serum β2M, evaluated trends in β2M levels and in hospitalizations due to dialysis-related amyloidosis (DRA), and estimated the effect of β2M on mortality.

Methods: We studied European and Japanese participants in the Dialysis Outcomes and Practice Patterns Study. Analysis of DRA-related hospitalizations spanned 1998-2018 ( = 23 976), and analysis of β2M and mortality in centers routinely measuring β2M spanned 2011-18 ( = 5332). We evaluated time trends with linear and Poisson regression and mortality with Cox regression.

Results: Median β2M changed nonsignificantly from 2.71 to 2.65 mg/dL during 2011-18 (P = 0.87). Highest β2M tertile patients (>2.9 mg/dL) had longer dialysis vintage, higher C-reactive protein and lower urine volume than lowest tertile patients (≤2.3 mg/dL). DRA-related hospitalization rates [95% confidence interval (CI)] decreased from 1998 to 2018 from 3.10 (2.55-3.76) to 0.23 (0.13-0.42) per 100 patient-years. Compared with the lowest β2M tertile, adjusted mortality hazard ratios (95% CI) were 1.16 (0.94-1.43) and 1.38 (1.13-1.69) for the middle and highest tertiles. Mortality risk increased monotonically with β2M modeled continuously, with no indication of a threshold.

Conclusions: DRA-related hospitalizations decreased over 10-fold from 1998 to 2018. Serum β2M remains positively associated with mortality, even in the current high-flux HD era.
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http://dx.doi.org/10.1093/ckj/sfaa155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087125PMC
May 2021

Association of Local Unit Sampling and Microbiology Laboratory Culture Practices With the Ability to Identify Causative Pathogens in Peritoneal Dialysis-Associated Peritonitis in Thailand.

Kidney Int Rep 2021 Apr 2;6(4):1118-1129. Epub 2021 Feb 2.

St. Michael's Hospital, Toronto, Ontario, Canada.

Introduction: This describes variations in facility peritoneal dialysis (PD) effluent (PDE) culture techniques and local microbiology laboratory practices, competencies, and quality assurance associated with peritonitis, with a specific emphasis on factors associated with culture-negative peritonitis (CNP).

Methods: Peritonitis data were prospectively collected from 22 Thai PD centers between May 2016 and October 2017 as part of the Peritoneal Dialysis Outcomes and Practice Patterns Study. The first cloudy PD bags from PD participants with suspected peritonitis were sent to local and central laboratories for comparison of pathogen identification. The associations between these characteristics and CNP were evaluated.

Results: CNP was significantly more frequent in local laboratories (38%) compared with paired PDE samples sent to the central laboratory (12%,  < 0.05). Marked variations were observed in PD center practices, particularly with respect to specimen collection and processing, which often deviated from International Society for Peritoneal Dialysis Guideline recommendations, and laboratory capacities, capabilities, and certification. Lower rates of CNP were associated with PD nurse specimen collection, centrifugation of PDE, immediate transfer of samples to the laboratory, larger hospital size, larger PD unit size, availability of an on-site nephrologist, higher laboratory capacity, and laboratory ability to perform aerobic cultures, undertake standard operating procedures in antimicrobial susceptibilities, and obtain local accreditation.

Conclusion: There were large variations in PD center and laboratory capacities, capabilities, and practices, which in turn were associated with the likelihood of culturing and correctly identifying organisms responsible for causing PD-associated peritonitis. Deviations in practice from International Society for Peritoneal Dialysis guideline recommendations were associated with higher CNP rates.
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http://dx.doi.org/10.1016/j.ekir.2021.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071630PMC
April 2021
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