Physician Compliance With a Computerized Clinical Decision Support System for Anemia Management of Patients With End-stage Kidney Disease on Hemodialysis: Retrospective Electronic Health Record Observational Study.

BACKGROUND: Previous studies on clinical decision support systems (CDSSs) for the management of renal anemia in patients with end-stage kidney disease undergoing hemodialysis have previously focused solely on the effects of the CDSS. However, the role of physician compliance in the efficacy of the CDSS remains ill-defined. OBJECTIVE: We aimed to investigate whether physician compliance was an intermediate variable between the CDSS and the management outcomes of renal anemia. METHODS: We extracted the electronic health records of patients with end-stage kidney disease on hemodialysis at the Far Eastern Memorial Hospital Hemodialysis Center (FEMHHC) from 2016 to 2020. FEMHHC implemented a rule-based CDSS for the management of renal anemia in 2019. We compared the clinical outcomes of renal anemia between the pre- and post-CDSS periods using random intercept models. Hemoglobin levels of 10 to 12 g/dL were defined as the on-target range. Physician compliance was defined as the concordance of adjustments of the erythropoietin-stimulating agent (ESA) between the CDSS recommendations and the actual physician prescriptions. RESULTS: We included 717 eligible patients on hemodialysis (mean age 62.9, SD 11.6 years; male n=430, 59.9%) with a total of 36,091 hemoglobin measurements (average hemoglobin and on-target rate were 11.1, SD 1.4, g/dL and 59.9%, respectively). The on-target rate decreased from 61.3% (pre-CDSS) to 56.2% (post-CDSS) owing to a high hemoglobin percentage of >12 g/dL (pre: 21.5%; post: 29%). The failure rate (hemoglobin <10 g/dL) decreased from 17.2% (pre-CDSS) to 14.8% (post-CDSS). The average weekly ESA use of 5848 (SD 4211) units per week did not differ between phases. The overall concordance between CDSS recommendations and physician prescriptions was 62.3%. The CDSS concordance increased from 56.2% to 78.6%. In the adjusted random intercept model, the post-CDSS phase showed increased hemoglobin by 0.17 (95% CI 0.14-0.21) g/dL, weekly ESA by 264 (95% CI 158-371) units per week, and 3.4-fold (95% CI 3.1-3.6) increased concordance rate. However, the on-target rate (29%; odds ratio 0.71, 95% CI 0.66-0.75) and failure rate (16%; odds ratio 0.84, 95% CI 0.76-0.92) were reduced. After additional adjustments for concordance in the full models, increased hemoglobin and decreased on-target rate tended toward attenuation (from 0.17 to 0.13 g/dL and 0.71 to 0.73 g/dL, respectively). Increased ESA and decreased failure rate were completely mediated by physician compliance (from 264 to 50 units and 0.84 to 0.97, respectively). CONCLUSIONS: Our results confirmed that physician compliance was a complete intermediate factor accounting for the efficacy of the CDSS. The CDSS reduced failure rates of anemia management through physician compliance. Our study highlights the importance of optimizing physician compliance in the design and implementation of CDSSs to improve patient outcomes.

Extremely Low Dose of Erythropoiesis-Stimulating Agent May Be Associated with Increased Mortality in Hemodialysis Patients.

INTRODUCTION: Although high-dose erythropoiesis-stimulating agent (ESA) has been shown to increase mortality risk and adverse cardiovascular events in hemodialysis patients, the safety of extremely low-dose ESA is unclear. METHODS: We retrospectively analyzed the association between ESA dose and mortality in the monthly dosing range of 0-43,000 U of equivalent epoetin alfa in 304 Taiwan hemodialysis patients by using Cox proportional hazard model and cubic spline model. RESULTS: Compared with mean monthly ESA dose of 15,000-25,000 U (mean ± standard deviation 20,609 ± 2,662 U), monthly ESA dose of less than 15,000 U (mean ± standard deviation 7,413 ± 4,510 U) is associated with increased mortality. Monthly ESA dose of 25,001-43,000 U (mean ± standard deviation 31,160 ± 4,304 U) is not associated with higher mortality risk than monthly ESA dose of 15,000-25,000 U. The results were consistent in Cox proportional hazard models and cubic spline models. Subgroup analyses showed no significant heterogeneities among prespecified subgroups. CONCLUSIONS: Extremely low dose of ESA in hemodialysis patients may be associated with increased mortality risk. Future studies are warranted to prove this association.

Adverse events following the first, second and third doses of a COVID-19 vaccine in hemodialysis patients.

BACKGROUND: This study aimed to identify adverse events following the first three doses of COVID-19 vaccines in hemodialysis (HD) patients. Risk factors associated with postvaccination adverse events were explored. METHODS: Postvaccination adverse events in 438 HD patients who received 3 doses of COVID-19 vaccines were prospectively assessed. The adverse events among three doses were compared using generalized linear mixed models. Factors associated with adverse events were assessed with multivariate analyses. RESULTS: The vast majority of participants received Oxford/AstraZeneca ChAdOx1 as their first two doses and Moderna mRNA-1273 as their third dose. Overall, 79%, 50% and 84% of the participants experienced at least one adverse event after their first, second, and third doses, respectively. These adverse events were mostly minor, short-lived and less than 5% reported daily activities being affected. Compared with the first dose, the second dose caused a lower rate of adverse events. Compared with the first dose, the third dose elicited a higher rate of injection site reactions and a lower rate of systemic reactions. Multivariate analyses showed that every 10-year increase of age (odds ratio 0.67, 95% confidence intervals 0.57-0.79) was associated with decreased risk of adverse events, while female sex (2.82, 1.90-4.18) and arteriovenous fistula (1.73, 1.05-2.84) were associated with increased risk of adverse events. Compared with Oxford/AstraZeneca ChAdOx1, Moderna mRNA-1273 was associated with an increased risk of injection site reactions. CONCLUSIONS: COVID-19 vaccination was well tolerated in HD patients. Age, sex, dialysis vascular access and vaccine types were associated with postvaccination adverse events.

Humoral antibody response to the first dose of the ChAdOx1 nCoV-19 vaccine in Asian patients undergoing hemodialysis.

BACKGROUND AND OBJECTIVES: The immunogenicity of vaccines is known to be attenuated in patients with end-stage kidney disease due to uremia. Patients on dialysis were excluded from coronavirus disease 2019 (COVID-19) vaccine trials; thus, the effectiveness of vaccines for this population is unclear. The aim of this study was to explore whether Asian dialysis patients can effectively produce an immune response after being vaccinated with the first dose of the ChAdOx1 nCoV-19 vaccine. DESIGN SETTING, PARTICIPANTS, AND MEASUREMENTS: In this prospective cohort study, we included Asian hemodialysis patients who received the ChAdOx1 nCoV-19 vaccine. At 3 weeks after the first dose of vaccination, we assessed the humoral immune response by measuring anti-SARS-CoV-2 S antibody titers. The primary outcome was the seropositive rate following vaccination, defined as an antibody titer greater than or equal to 0.8 U/ml. Factors associated with seropositivity were explored in multivariate logistic regression analyses. RESULTS: In total, 434 participants were included. The mean age was 64 years, the mean dialysis vintage was 6 years, and 61% of the participants were men. At a mean time of 22 days from vaccination, 56% of the participants were seropositive. The vast majority (88%) had low antibody titers (< 15 U/ml). The multivariate logistic regression analyses showed that older age (every increase of 10 years, odds ratio [OR] 0.80, 95% CI 0.65-0.98, p = 0.03) was negatively associated with seropositivity and that higher Kt/V (every increase of 0.1, OR 1.14, 95% CI 1.01-1.28, p = 0.03) and higher serum albumin level (every increase of 0.1 g/dl, OR 1.09, 95% CI 1.02-1.18, p = 0.02) were positively associated with seropositivity. CONCLUSIONS: In Asian hemodialysis patients, the seropositive rate was low, and most had low antibody titers after the first dose of the ChAdOx1 nCoV-19 vaccine. Younger age, better dialysis adequacy, and higher albumin levels were associated with seropositivity.

Alternative Complement Pathway Is Activated and Associated with Galactose-Deficient IgA1 Antibody in IgA Nephropathy Patients.

Background: Galactose-deficient IgA1 (Gd-IgA1) and alternative complement pathway activation are considered to be involved in the pathogenesis of IgA nephropathy (IgAN). Nevertheless, the relationships between alternative pathway activation and disease activity or Gd-IgA1 level remains unclear. Methods: Ninety-eight biopsy-diagnosed IgAN, twenty-five primary focal segmental sclerosis (FSGS) patients and forty-two healthy individuals were recruited in this study. Among them, fifty IgAN patients received immunosuppression. Follow-up blood samples at 1 and 3~6 months after immunosuppression were collected. Plasma levels of complement C5a, factor Ba and Gd-IgA1 were measured and analyzed. Immunostaining for complement was performed in twenty-five IgAN and FSGS patients. Results: At baseline, IgAN patients had higher levels of plasma C5a, factor Ba and Gd-IgA1 than control subjects. Gd-IgA1 levels positively correlated with plasma C5a and factor Ba. In addition, levels of factor Ba and Gd-IgA1 were positively associated with proteinuria and negatively associated with renal function. Immunostaining revealed positive staining for factor Bb and C3c in glomeruli in IgAN patients, but not in FSGS patients. At baseline, patients receiving immunosuppression had more severe proteinuria and higher factor Ba. After 6 months, eGFR declined and proteinuria persisted in patients without immunosuppression. In contrast, patients who received immunosuppression exhibited decreased plasma levels of C5a, factor Ba, and Gd-IgA1 as early as 1 month after treatment. Proteinuria decreased and renal function also remained stable 6 months after immunosuppression. Conclusions: Our results indicate a close relationship between alternative complement pathway activation, Gd-IgA1 concentration and clinical severity of IgAN. Level of complement factor B may be a potential marker for disease activity and therapeutic target in IgAN patients.

Emergence of T cell immunosenescence in diabetic chronic kidney disease.

BACKGROUND: Type 2 diabetes is an important challenge given the worldwide epidemic and is the most important cause of end-stage renal disease (ESRD) in developed countries. It is known that patients with ESRD and advanced renal failure suffer from immunosenescence and premature T cell aging, but whether such changes develop in patients with less severe chronic kidney disease (CKD) is unclear. METHOD: 523 adult patients with type 2 diabetes were recruited for this study. Demographic data and clinical information were obtained from medical chart review. Immunosenescence, or aging of the immune system was assessed by staining freshly-obtained peripheral blood with immunophenotyping panels and analyzing cells using multicolor flow cytometry. RESULT: Consistent with previously observed in the general population, both T and monocyte immunosenescence in diabetic patients positively correlate with age. When compared to diabetic patients with preserved renal function (estimated glomerular filtration rate > 60 ml/min), patients with impaired renal function exhibit a significant decrease of total CD3+ and CD4+ T cells, but not CD8+ T cell and monocyte numbers. Immunosenescence was observed in patients with CKD stage 3 and in patients with more severe renal failure, especially of CD8+ T cells. However, immunosenescence was not associated with level of proteinuria level or glucose control. In age, sex and glucose level-adjusted regression models, stage 3 CKD patients exhibited significantly elevated percentages of CD28-, CD127-, and CD57+ cells among CD8+ T cells when compared to patients with preserved renal function. In contrast, no change was detected in monocyte subpopulations as renal function declined. In addition, higher body mass index (BMI) is associated with enhanced immunosenescence irrespective of CKD status. CONCLUSION: The extent of immunosenescence is not significantly associated with proteinuria or glucose control in type 2 diabetic patients. T cells, especially the CD8+ subsets, exhibit aggravated characteristics of immunosenescence during renal function decline as early as stage 3 CKD. In addition, inflammation increases since stage 3 CKD and higher BMI drives the accumulation of CD8+CD57+ T cells. Our study indicates that therapeutic approaches such as weight loss may be used to prevent the emergence of immunosenescence in diabetes before stage 3 CKD.

Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Cardiovascular Disease Risk in End-Stage Renal Disease.

Plasma leucine-Rich α-2-glycoprotein 1 (LRG1) is an innovative biomarker for inflammation and angiogenesis. Many adverse pathophysiological changes including inflammation, atherosclerosis, and premature mortality is associated with End-stage renal disease (ESRD). However, whether levels of plasma LRG1 correlate with the co-morbidities of ESRD patients is unknown. Plasma LRG1 and high-sensitivity C-reactive protein (hsCRP) were analyzed by ELISA in 169 hemodialysis patients from the Immunity in ESRD (iESRD) study. Patient demographics and comorbidities at the time of enrollment were recorded. Peripheral blood monocyte and T cell subsets were assessed by multicolor flow cytometry. In the univariate analysis, a higher level of LRG1 was associated with the presence of cardiovascular disease (CVD) and peripheral arterial occlusive disease (PAOD). In multivariate logistic regression models, higher LRG1 tertile was significantly associated with PAOD (odds ratio = 3.49) and CVD (odds ratio = 1.65), but not with coronary artery disease, history of myocardial infarction, or stroke after adjusting for gender, diabetes, hemoglobin, albumin, calcium-phosphate product, and level of hsCRP. In addition, the level of LRG1 had a positive correlation with IL-6, hsCRP, and also more advanced T cell differentiation. The association suggests that LRG1 participates in the progression of atherosclerosis by inducing inflammation. Therefore, the role of LRG1 in coexisting inflammatory response should be further investigated in the pathogenesis of cardiovascular morbidity and mortality in patients with ESRD.

A comprehensive characterization of aggravated aging-related changes in T lymphocytes and monocytes in end-stage renal disease: the iESRD study.

BACKGROUND: Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of the immune system. Nevertheless, the etiology and impact of these changes in ESRD patients remain unknown. RESULTS: Compared to healthy individuals, ESRD patients exhibit accelerated immunosenescence in both T cell and monocyte compartments, characterized by a dramatic reduction in naïve CD4+ and CD8+ T cell numbers but increase in CD8+ TEMRA cell and proinflammatory monocyte numbers. Notably, within ESRD patients, aging-related immune changes positively correlated not only with increasing age but also with longer dialysis vintage. In multivariable-adjusted logistic regression models, the combination of high terminally differentiated CD8+ T cell level and high intermediate monocyte level, as a composite predictive immunophenotype, was independently associated with prevalent coronary artery disease as well as cardiovascular disease, after adjustment for age, sex, systemic inflammation and presence of diabetes. Levels of terminally differentiated CD8+ T cells also positively correlated with the level of uremic toxin p-cresyl sulfate. CONCLUSIONS: Aging-associated adaptive and innate immune changes are aggravated in ESRD and are associated with cardiovascular diseases. For the first time, our study demonstrates the potential link between immunosenescence in ESRD and duration of exposure to the uremic milieu.

Anti-cytomegalovirus IgG antibody titer is positively associated with advanced T cell differentiation and coronary artery disease in end-stage renal disease.

BACKGROUND: Accumulating evidence indicates that persistent human cytomegalovirus (HCMV) infection is associated with several health-related adverse outcomes including atherosclerosis and premature mortality in individuals with normal renal function. Patients with end-stage renal disease (ESRD) exhibit impaired immune function and thus may face higher risk of HCMV-related adverse outcomes. Whether the level of anti-HCMV immune response may be associated with the prognosis of hemodialysis patients is unknown. RESULTS: Among 412 of the immunity in ESRD study (iESRD study) participants, 408 were HCMV seropositive and were analyzed. Compared to 57 healthy individuals, ESRD patients had higher levels of anti-HCMV IgG. In a multivariate-adjusted logistic regression model, the log level of anti-HCMV IgG was independently associated with prevalent coronary artery disease (OR = 1.93, 95% CI = 1.2~ 3.2, p = 0.01) after adjusting for age, sex, hemoglobin, diabetes, calcium phosphate product and high sensitivity C-reactive protein. Levels of anti-HCMV IgG also positively correlated with both the percentage and absolute number of terminally differentiated CD8+ and CD4+ CD45RA+ CCR7- TEMRA cells, indicating that immunosenescence may participate in the development of coronary artery disease. CONCLUSION: This is the first study showing that the magnitude of anti-HCMV humoral immune response positively correlates with T cell immunosenescence and coronary artery disease in ESRD patients. The impact of persistent HCMV infection should be further investigated in this special patient population.

Urinary π-glutathione S-transferase Predicts Advanced Acute Kidney Injury Following Cardiovascular Surgery.

Urinary biomarkers augment the diagnosis of acute kidney injury (AKI), with AKI after cardiovascular surgeries being a prototype of prognosis scenario. Glutathione S-transferases (GST) were evaluated as biomarkers of AKI. Urine samples were collected in 141 cardiovascular surgical patients and analyzed for urinary alpha-(α-) and pi-(π-) GSTs. The outcomes of advanced AKI (KDIGO stage 2, 3) and all-cause in-patient mortality, as composite outcome, were recorded. Areas under the receiver operator characteristic (ROC) curves and multivariate generalized additive model (GAM) were applied to predict outcomes. Thirty-eight (26.9%) patients had AKI, while 12 (8.5%) were with advanced AKI. Urinary π-GST differentiated patients with/without advanced AKI or composite outcome after surgery (p < 0.05 by generalized estimating equation). Urinary π-GST predicted advanced AKI at 3 hrs post-surgery (p = 0.033) and composite outcome (p = 0.009), while the corresponding ROC curve had AUC of 0.784 and 0.783. Using GAM, the cutoff value of 14.7 µg/L for π-GST showed the best performance to predict composite outcome. The addition of π-GST to the SOFA score improved risk stratification (total net reclassification index = 0.47). Thus, urinary π-GST levels predict advanced AKI or hospital mortality after cardiovascular surgery and improve in SOFA outcome assessment specific to AKI.

A case of anaphylactic shock induced by FX60 polysulfone hemodialyzer but not F6-HPS polysulfone hemodialyzer.

A 75-year-old woman was admitted for dyspnea and fever. She underwent emergent dialysis smoothly under F6-HPS polysulfone hemodialyzer. With two subsequent hemodialysis sessions, severe anaphylactic reaction with cardiopulmonary resuscitation occurred under FX60 polysulfone dialyzer. Further dialysis sessions by F6-HPS polysulfone dialyzer were uneventful. This rare case demonstrated that dialyzer reaction may be markedly different even with the same material and the same manufacturer.