Uremic pruritus in patients on hemodialysis is associated with depression, lower quality of life, and mortality. We studied the prevalence, awareness, and treatment of pruritus to assess how well ...this important condition is currently managed internationally.
Data from 35,452 patients on hemodialysis in up to 17 countries from the Dialysis Outcomes and Practice Patterns Study were analyzed to describe pruritus prevalence from 1996 to 2015. Data from 6256 patients and 268 medical directors in 17 countries in 2012-2015 were analyzed to describe predictors, effects, medical directors' awareness, and treatment of pruritus.
Patients very much or extremely bothered by itching declined from 28% in 1996 to 18% in 2015. In 2012-2015, among patients nearly always or always bothered by itching, pruritus had a major effect on work and social life; 18% used no treatment for pruritus, and 17% did not report itching to health care staff. In total, 69% of medical directors underestimated the prevalence of pruritus in their unit. Managing high serum phosphorus and low Kt/V was ranked as the most important intervention, but no relationship was found between these factors and pruritus; 57% of medical directors used oral antihistamines for first-line chronic treatment of pruritus. Gabapentin was used by 45% as first-, second-, or third-line treatment. Nalfurafine was only used in Japan.
The prevalence of pruritus in people on hemodialysis is decreasing but remains underestimated. Large numbers of patients on hemodialysis with severe pruritus do not receive treatment. There is wide variation in the use of unlicensed medications for the treatment of pruritus. These data provide a benchmark for initiatives to improve the management of uremic pruritus.
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Intravenous (IV) iron is required for optimal management of anemia in the majority of hemodialysis (HD) patients. While IV iron prescription has increased over time, the best dosing strategy is ...unknown and any effect of IV iron on survival is unclear. Here we used adjusted Cox regression to analyze associations between IV iron dose and clinical outcomes in 32,435 HD patients in 12 countries from 2002 to 2011 in the Dialysis Outcomes and Practice Patterns Study. The primary exposure was total prescribed IV iron dose over the first 4 months in the study, expressed as an average dose/month. Compared with 100–199mg/month (the most common dose range), case-mix-adjusted mortality was similar for the 0, 1–99, and 200–299mg/month categories but significantly higher for the 300–399mg/month (HR of 1.13, 95% CI of 1.00–1.27) and 400mg/month or more (HR of 1.18, 95% CI of 1.07–1.30) groups. Convergent validity was proved by an instrumental variable analysis, using HD facility as the instrument, and by an analysis expressing IV iron dose/kg body weight. Associations with cause-specific mortality (cardiovascular, infectious, and other) were generally similar to those for all-cause mortality. The hospitalization risk was elevated among patients receiving 300mg/month or more compared with 100–199mg/month (HR of 1.12, 95% CI of 1.07–1.18). In light of these associations, a well-powered clinical trial to evaluate the safety of different IV iron-dosing strategies in HD patients is urgently needed.
64
Cu and
123
I are attracting attention in taking up their role in the development and practical use of PSMA-targeting radiopharmaceuticals. The development of urea-based small molecule PSMA ligands ...labeled
64
Cu and
123
I has been progressing steadily with the challenge of obtaining optimal performance as PSMA-targeting radiopharmaceutical for prostate cancer. In this review, the authors provide an overview of recent research projects and future directions for the production of cyclotron-based medical radioisotopes
64
Cu and
123
I, and their application in the development of urea-based small molecule PSMA ligands labeled
64
Cu and
123
I as radiopharmaceuticals for prostate cancer.
Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel ...N-N-(S)-1,3-dicarboxypropylcarbamoyl-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine ε-nitrogen atom, a dipeptide including two phenylalanine residues in the L-configuration as the peptide fragment of the linker, and 3- or 4-(tributylstannyl)benzoic acid as a prosthetic group in their structures for radiolabeling. The standard compounds 127IPSMA-m-IB and 127IPSMA-p-IB for comparative and characterization studies were first synthesized using two alternative synthetic approaches. An important advantage of the alternative synthetic approach, in which the prosthetic group (NHS-activated esters of compounds) is first conjugated with the polypeptide sequence followed by replacement of the Sn(Bu)3 group with radioiodine, is that the radionuclide is introduced in the final step of synthesis, thereby minimizing operating time with iodine-123 during the radiolabeling process. The obtained DCL urea-based PSMA inhibitors were radiolabeled with iodine-123. The radiolabeling optimization results showed that the radiochemical yield of 123IPSMA-p-IB was higher than that of 123IPSMA-m-IB, which were 74.9 ± 1.0% and 49.4 ± 1.2%, respectively. The radiochemical purity of 123IPSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of 123IPSMA-p-IB demonstrated a considerable affinity and specific binding to PC-3 PIP (PSMA-expressing cells) in vitro. The in vivo biodistribution of this new radioligand 123IPSMA-p-IB showed less accumulation than 177LuLu-PSMA-617 in several normal organs (liver, kidney, and bone). These results warrant further preclinical development, including toxicology evaluation and experiments in tumor-bearing mice.
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Missed hemodialysis (HD) treatments not due to hospitalization have been associated with poor clinical outcomes and related in part to treatment nonadherence. Using data from the ...Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 5 (2012-2015), we report findings from an international investigation of missed treatments among patients prescribed thrice-weekly HD.
Prospective observational study.
8,501 patients participating in DOPPS, on HD therapy for more than 120 days, from 20 countries. Longitudinal and cross-sectional analyses were performed based on the 4,493 patients from countries in which 4-month missed treatment risk was > 5%.
The main predictor of patient outcomes was 1 or more missed treatments in the 4 months before DOPPS phase 5 enrollment; predictors of missed treatments included country, patient characteristics, and clinical factors.
Mortality, hospitalization, laboratory measures, patient-reported outcomes, and 4-month missed treatment risk.
Outcomes were assessed using Cox proportional hazards, logistic, and linear regression, adjusting for case-mix and country.
The 4-month missed treatment risk varied more than 50-fold across all 20 DOPPS countries, ranging from < 1% in Italy and Japan to 24% in the United States. Missed treatments were more likely with younger age, less time on dialysis therapy, shorter HD treatment time, lower Kt/V, longer travel time to HD centers, and more symptoms of depression. Missed treatments were positively associated with all-cause mortality (HR, 1.68; 95% CI, 1.37-2.05), cardiovascular mortality, sudden death/cardiac arrest, hospitalization, serum phosphorus level > 5.5mg/dL, parathyroid hormone level > 300pg/mL, hemoglobin level < 10g/dL, higher kidney disease burden, and worse general and mental health.
Possible residual confounding; temporal ambiguity in the cross-sectional analyses.
In the countries with a 4-month missed treatment risk > 5%, HD patients were more likely to die, be hospitalized, and have poorer patient-reported outcomes and laboratory measures when 1 or more missed treatments occurred in a 4-month period. The large variation in missed treatments across 20 nations suggests that their occurrence is potentially modifiable, especially in the United States and other countries in which missed treatment risk is high.
Benefits and risks of antithrombotic agents remain unclear in the hemodialysis population. To help clarify this we determined variation in antithrombotic agent use, rates of major bleeding events, ...and factors predictive of stroke and bleeding in 48,144 patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases I–IV. Antithrombotic agents including oral anticoagulants (OACs), aspirin (ASA), and anti-platelet agents (APAs) were recorded along with comorbidities at study entry, and clinical events including hospitalization due to bleeding were then collected every 4 months. There was wide variation in OAC (0.3–18%), APA (3–25%), and ASA use (8–36%), and major bleeding rates (0.05–0.22 events/year) among countries. All-cause mortality, cardiovascular mortality, and bleeding events requiring hospitalization were elevated in patients prescribed OACs across adjusted models. The CHADS2 score predicted the risk of stroke in atrial fibrillation patients. Gastrointestinal bleeding in the past 12 months was highly predictive of major bleeding events; for patients with previous gastrointestinal bleeding, the rate of bleeding exceeded the rate of stroke by at least twofold across all categories of CHADS2 score, including patients at high stroke risk. Appropriate risk stratification and a cautious approach should be considered before OAC use in the dialysis population.
Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel ...N-N-(S)-1,3-dicarboxypropylcarbamoyl-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine ε-nitrogen atom, a dipeptide including two phenylalanine residues in the L-configuration as the peptide fragment of the linker, and 3- or 4-(tributylstannyl)benzoic acid as a prosthetic group in their structures for radiolabeling. The standard compounds sup.127IPSMA-m-IB and sup.127IPSMA-p-IB for comparative and characterization studies were first synthesized using two alternative synthetic approaches. An important advantage of the alternative synthetic approach, in which the prosthetic group (NHS-activated esters of compounds) is first conjugated with the polypeptide sequence followed by replacement of the Sn(Bu)sub.3 group with radioiodine, is that the radionuclide is introduced in the final step of synthesis, thereby minimizing operating time with iodine-123 during the radiolabeling process. The obtained DCL urea-based PSMA inhibitors were radiolabeled with iodine-123. The radiolabeling optimization results showed that the radiochemical yield of sup.123IPSMA-p-IB was higher than that of sup.123IPSMA-m-IB, which were 74.9 ± 1.0% and 49.4 ± 1.2%, respectively. The radiochemical purity of sup.123IPSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of sup.123IPSMA-p-IB demonstrated a considerable affinity and specific binding to PC-3 PIP (PSMA-expressing cells) in vitro. The in vivo biodistribution of this new radioligand sup.123IPSMA-p-IB showed less accumulation than sup.177LuLu-PSMA-617 in several normal organs (liver, kidney, and bone). These results warrant further preclinical development, including toxicology evaluation and experiments in tumor-bearing mice.
The epithelial cell adhesion molecule (EpCAM) is intensively overexpressed in 40–60% of prostate cancer (PCa) cases and can be used as a target for the delivery of drugs and toxins. The designed ...ankyrin repeat protein (DARPin) Ec1 has a high affinity to EpCAM (68 pM) and a small size (18 kDa). Radiolabeled Ec1 might be used as a companion diagnostic for the selection of PCa patients for therapy. The study aimed to investigate the influence of radiolabel position (N- or C-terminal) and composition on the targeting and imaging properties of Ec1. Two variants, having an N- or C-terminal cysteine, were produced, site-specifically conjugated to a DOTA chelator and labeled with cobalt-57, gallium-68 or indium-111. Site-specific radioiodination was performed using ((4-hydroxyphenyl)-ethyl)maleimide (HPEM). Biodistribution of eight radiolabeled Ec1-probes was measured in nude mice bearing PCa DU145 xenografts. In all cases, positioning of a label at the C-terminus provided the best tumor-to-organ ratios. The non-residualizing 125II-HPEM label provided the highest tumor-to-muscle and tumor-to-bone ratios and is more suitable for EpCAM imaging in early-stage PCa. Among the radiometals, indium-111 provided the highest tumor-to-blood, tumor-to-lung and tumor-to-liver ratios and could be used at late-stage PCa. In conclusion, label position and composition are important for the DARPin Ec1.
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.
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.
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.
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.
Anemia management protocols in hemodialysis (HD) units differ conspicuously regarding optimal intravenous (IV) iron dosing; consequently, patients receive markedly different cumulative exposures to ...IV iron and erythropoiesis-stimulating agents (ESAs). Complementary to IV iron safety studies, our goal was to gain insight into optimal IV iron dosing by estimating the effects of IV iron doses on Hgb, TSAT, ferritin, and ESA dose in common clinical practice.
9,471 HD patients (11 countries, 2009-2011) in the DOPPS, a prospective cohort study, were analyzed. Associations of IV iron dose (3-month average, categorized as 0, <300, ≥300 mg/month) with 3-month change in Hgb, TSAT, ferritin, and ESA dose were evaluated using adjusted GEE models.
Relative change: Monotonically positive associations between IV iron dose and Hgb, TSAT, and ferritin change, and inverse associations with ESA dose change, were observed across multiple strata of prior Hgb, TSAT, and ferritin levels. Absolute change: TSAT, ferritin, and ESA dose changes were nearest zero with IV iron <300 mg/month, rather than 0 mg/month or ≥300 mg/month by maintenance or replacement dosing. Findings were robust to numerous sensitivity analyses.
Though residual confounding cannot be ruled out in this observational study, findings suggest that IV iron dosing <300 mg/month, as commonly seen with maintenance dosing of 100-200 mg/month, may be a more effective approach to support Hgb than the higher IV iron doses (300-400 mg/month) often given in many European and North American hemodialysis clinics. Alongside studies supporting the safety of IV iron in 100-200 mg/month dose range, these findings help guide the rational dosing of IV iron in anemia management protocols for everyday hemodialysis practice.
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