Pruritus in Hemodialysis Patients: Longitudinal Associations With Clinical and Patient-Reported Outcomes.

RATIONALE & OBJECTIVE: Cross-sectional studies have reported an association of chronic kidney disease-associated pruritus (CKD-aP) with adverse clinical events and patient-reported outcomes (PROs). We studied the longitudinal associations between changes in CKD-aP and clinical outcomes among patients receiving maintenance hemodialysis. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 7,976 hemodialysis recipients across 21 countries in phases 4-6 (2009-2018) of the Dialysis Outcomes and Practice Patterns Study (DOPPS) who had 2 CKD-aP assessments approximately 12 months apart. EXPOSURES: Exposure status was based on the assessment of pruritis initially and again approximately 1 year later. Four groups were identified, including those with moderate or more severe pruritis only at the initial assessment (resolved), only at the second assessment (incident), at neither assessment (absent), or at both assessments (persistent). OUTCOMES: Laboratory values and PROs ascertained at the initial assessment of pruritis and 1 year later. ANALYTICAL APPROACH: Linear mixed model to investigate changes in laboratory values and PROs over the 1-year study period across the 4 exposure groups. RESULTS: 51% of patients had moderate to severe CKD-aP symptoms at either assessment (22% at both). The prevalences of depression, restless sleep, and feeling drained increased over the study period (+13%,+10%, and+14%, respectively) among patients with incident pruritus and decreased (-5%, -8%, and -12%, respectively) among patients with resolved pruritus. Minimal changes in PROs over time were observed for the absent and persistent groups. Changes over time in laboratory values (phosphorus, Kt/V) were not detected for either of these groups. Compared with patients with absent CKD-aP, the adjusted HRs for patients with persistent CKD-aP were 1.29 (95% CI, 1.09-1.53) for all-cause mortality, 1.17 (1.07-1.28) for all-cause hospitalization, and 1.48 (1.26-1.74) for cardiovascular events. LIMITATIONS: No interim evaluation of CKD-aP symptoms between the 2 assessments; potential selection bias from patients who died or were otherwise lost to follow-up before the second assessment. CONCLUSIONS: CKD-aP symptoms are chronic, and these findings highlight the potential value of repeated assessment of this symptom using standardized approaches. Future research should systematically investigate potential causes of CKD-aP and options for its effective treatment. PLAIN-LANGUAGE SUMMARY: Previous research has studied itching and its consequences in hemodialysis recipients only at a single time point. We surveyed 7,976 patients receiving maintenance hemodialysis to assess itching over a period of 1 year. We found that, among those experiencing itching at the initial assessment, more than half had persistent symptoms 1 year later. Those in whom itching developed during follow-up were more likely to experience depression, poor sleep, long recovery times after dialysis, and feeling faint or drained. These patients also rated their quality of life as poorer than those who did not experience itching. These findings emphasize the potential value of clinical detection of itching and the pursuit of effective treatments for patients receiving dialysis experiencing these symptoms.

Outcome and effect of vaccination in SARS-CoV-2 Omicron infection in hemodialysis patients: a cohort study.

BACKGROUND: Hemodialysis patients are at high risk of Covid-19, though vaccination has significant efficacy in preventing and reducing the severity of infection. Little information is available on disease severity and vaccine efficacy since the dissemination of the Omicron variant. METHODS: In a multi-center study, during a period of the epidemic driven by the Omicron variant, all hemodialysis patients positive for SARS-CoV-2 were identified. Outcomes were analyzed according to predictor variables including vaccination status. Risk of infection was analyzed using a Cox proportional hazards model. RESULTS: SARS-CoV-2 infection was identified in 1126 patients including 200 (18%) unvaccinated, 56 (5%) post first dose, 433 (38%) post second dose, and 437 (39%) at least 7 days beyond their third dose. The majority of patients had a mild course but 160 (14%) were hospitalized and 28 (2%) died. In regression models adjusted for age and comorbidity, two-dose vaccination was associated with a 39% (95%CI: 2%-62%) reduction in admissions, but third doses provided additional protection, with a 51% (95%CI: 25%-69%) further reduction in admissions. Among 1265 patients at risk at the start of the observation period, SARS-CoV-2 infection was observed in 211 (17%). Two-dose vaccination was associated with a 41% (95%CI: 3%-64%) reduction in the incidence of infection, with no clear additional effect provided by third doses. CONCLUSIONS: These data demonstrate lower incidence of SARS-CoV-2 infection after vaccination in dialysis patients during an Omicron dominant period of the epidemic. Among those developing infection, severe illness was less common with prior vaccination, particularly after third vaccine doses.

The effect of intravenous iron supplementation on exercise capacity in iron-deficient but not anaemic patients with chronic kidney disease: study design and baseline data for a multicentre prospective double-blind randomised controlled trial.

BACKGROUND: Many people living with chronic kidney disease (CKD) are iron deficient, even though they may not be anaemic. The Iron and Muscle study aims to evaluate whether iron supplementation reduces symptoms of fatigue, improves muscle metabolism, and leads to enhanced exercise capacity and physical function. We report here the trial design and baseline characteristics. METHODS: This is a prospective, double-blind multicentre randomised controlled trial (RCT) including 75 non-dialysis stage 3-4 CKD patients with iron deficiency but without anaemia. Patients were randomly (1:1) assigned to either: i) intravenous iron therapy, or ii) placebo, with concurrent recruitment of eight CKD non-iron deficient participants and six healthy volunteers. The primary outcome of the study is the six-minute walk test (6MWT) distance between baseline and four-weeks. An additional exercise training programme for patients in both groups was initiated and completed between 4 and 12 weeks, to determine the effect of iron repletion compared to placebo treatment in the context of patients undertaking an exercise programme. Additional secondary outcomes include fatigue, physical function, muscle strength, muscle metabolism, quality of life, resting blood pressure, clinical chemistry, safety and harms associated with the iron therapy intervention and the exercise training intervention, and hospitalisations. All outcomes were conducted at baseline, 4, and 12 weeks, with a nested qualitative study, to investigate the experience of living with iron deficiency and intervention acceptability. The cohort have been recruited and baseline assessments undertaken. RESULTS: Seventy-five individuals were recruited. 44% of the randomised cohort were male, the mean (SD) age was 58 (14) years, and 56% were White. Body mass index was 31 (7) kg/m2; serum ferritin was 59 (45) µg/L, transferrin saturation was 22 (10) %, and haemoglobin was 125 (12) g/L at randomisation for the whole group. Estimated glomerular filtration rate was 35 (12) mL/min/1.73 m2 and the baseline 6MWT distance was 429 (174) m. CONCLUSION: The results from this study will address a substantial knowledge gap in the effects of intravenous iron therapy, and offer potential clinical treatment options, to improve exercise capacity, physical function, fatigue, and muscle metabolism, for non-dialysis patients with CKD who are iron-deficient but not anaemic. It will also offer insight into the potential novel effects of an 8-week exercise training programme. TRIAL REGISTRATION: EudraCT: 2018-000,144-25 Registered 28/01/2019.

One size does not fit all: understanding individual living kidney donor risk.

Living donor kidney transplantation is the optimal treatment for end-stage kidney disease (ESKD) but confers a risk upon the donor, both in the short term and many years after donation. While perioperative mortality is low and longevity does not appear to be adversely affected, there are small increases in the risk of other important morbidities. The overall risk of ESKD among donors is low but appears to be three- to five-fold higher than among healthy non-donors, and this relative risk is even higher among donors of African ancestry. For these individuals, apolipoprotein L1 genotyping may be helpful. Kidney donors also have an increased risk of developing hypertension post-donation and a modestly increased risk of developing gout. Living kidney donation also increases the risk of gestational hypertension and preeclampsia while not affecting other important pregnancy outcomes. As our understanding of donor risk grows, it is important to counsel prospective donors according to their individual risk and so obtain better informed donor consent. As knowledge advances, it is also important that all clinicians who manage kidney transplant candidates have an up to date understanding of donor risk to inform shared decision making.

C3a modulates IL-1ß secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation.

Interleukin-1ß (IL-1ß) is a proinflammatory cytokine and a therapeutic target in several chronic autoimmune states. Monocytes and macrophages are the major sources of IL-1ß. IL-1ß production by these cells requires Toll-like receptor (TLR) and adenosine triphosphate (ATP)-mediated P2X purinoceptor 7 (P2X7) signals, which together activate the inflammasome. However, how TLR signals and ATP availability are regulated during monocyte activation is unclear and the involvement of another danger signal system has been proposed. Here, we demonstrate that both lipopolysaccharide (LPS) and the anaphylatoxin C3a are needed for IL-1ß production in human macrophages and dendritic cells, while in monocytes, C3a enhanced the secretion of LPS-induced IL-1ß. C3a and LPS-stimulated monocytes increased T helper 17 (Th17) cell induction in vitro, and human rejecting, but not nonrejecting, kidney transplant biopsies were characterized by local generation of C3a and monocyte and Th17 cell infiltration. Mechanistically, C3a drives IL-1ß production in monocytes by controlling the release of intracellular ATP into the extracellular space via regulation of as-yet unidentified ATP-releasing channels in an extracellular signal-regulated kinase 1/2-dependent fashion. These data define a novel function for complement in inflammasome activation in monocytes and suggest that C3aR-mediated signaling is a vital component of the IL-1ß-Th17 axis.

Mannan-binding lectin-associated serine protease 2 is critical for the development of renal ischemia reperfusion injury and mediates tissue injury in the absence of complement C4.

Mannan-binding lectin-associated serine protease 2 (MASP-2) has been described as the essential enzyme for the lectin pathway (LP) of complement activation. Since there is strong published evidence indicating that complement activation via the LP critically contributes to ischemia reperfusion (IR) injury, we assessed the effect of MASP-2 deficiency in an isogenic mouse model of renal transplantation. The experimental transplantation model used included nephrectomy of the remaining native kidney at d 5 post-transplantation. While wild-type (WT) kidneys grafted into WT recipients (n=7) developed acute renal failure (control group), WT grafts transplanted into MASP-2-deficient recipients (n=7) showed significantly better kidney function, less C3 deposition, and less IR injury. In the absence of donor or recipient complement C4 (n=7), the WT to WT phenotype was preserved, indicating that the MASP-2-mediated damage was independent of C4 activation. This C4-bypass MASP-2 activity was confirmed in mice deficient for both MASP-2 and C4 (n=7), where the protection from postoperative acute renal failure was no greater than in mice with MASP-2 deficiency alone. Our study highlights the role of LP activation in renal IR injury and indicates that injury occurs through MASP-2-dependent activation events independent of C4.

Control of innate immunological mechanisms as a route to drug minimization.

PURPOSE OF REVIEW: Much research in transplantation focuses on treatments for rejection and induction of tolerance. Recent evidence has shown that initial inflammation induced by innate immune effectors after transplantation has a key role in modulating adaptive immune responses that cause organ rejection. Here, we describe the role of the innate immune system, particularly the complement activation pathways, and how they influence adaptive immune responses post-transplantation and current strategies, which are under development to block these innate pathways. RECENT FINDINGS: Anaphylatoxins and their respective receptors are proving to be important in T-cell-mediated immunity and make attractive targets for therapies designed to promote tolerance in solid organ transplantation. Additionally, regulators of complement activation are currently being tested in clinical trials, with improvements in drug delivery. SUMMARY: Preventing ischaemia-reperfusion injury in transplanted organs significantly reduces immune activation and promotes graft survival. Research into the mechanisms of complement activation in both native organ ischaemia and transplantation models detail emerging roles for complement intermediates that can serve as targets for intervention, with the aim of reducing early post-transplant inflammation, reducing the intensity of immunosuppressive regimens, leading to prolonged graft survival.

Impact of Electronic Health Record Use on Cognitive Load and Burnout Among Clinicians: Narrative Review.

The cognitive load theory suggests that completing a task relies on the interplay between sensory input, working memory, and long-term memory. Cognitive overload occurs when the working memory's limited capacity is exceeded due to excessive information processing. In health care, clinicians face increasing cognitive load as the complexity of patient care has risen, leading to potential burnout. Electronic health records (EHRs) have become a common feature in modern health care, offering improved access to data and the ability to provide better patient care. They have been added to the electronic ecosystem alongside emails and other resources, such as guidelines and literature searches. Concerns have arisen in recent years that despite many benefits, the use of EHRs may lead to cognitive overload, which can impact the performance and well-being of clinicians. We aimed to review the impact of EHR use on cognitive load and how it correlates with physician burnout. Additionally, we wanted to identify potential strategies recommended in the literature that could be implemented to decrease the cognitive burden associated with the use of EHRs, with the goal of reducing clinician burnout. Using a comprehensive literature review on the topic, we have explored the link between EHR use, cognitive load, and burnout among health care professionals. We have also noted key factors that can help reduce EHR-related cognitive load, which may help reduce clinician burnout. The research findings suggest that inadequate efforts to present large amounts of clinical data to users in a manner that allows the user to control the cognitive burden in the EHR and the complexity of the user interfaces, thus adding more "work" to tasks, can lead to cognitive overload and burnout; this calls for strategies to mitigate these effects. Several factors, such as the presentation of information in the EHR, the specialty, the health care setting, and the time spent completing documentation and navigating systems, can contribute to this excess cognitive load and result in burnout. Potential strategies to mitigate this might include improving user interfaces, streamlining information, and reducing documentation burden requirements for clinicians. New technologies may facilitate these strategies. The review highlights the importance of addressing cognitive overload as one of the unintended consequences of EHR adoption and potential strategies for mitigation, identifying gaps in the current literature that require further exploration.

Evaluating the effect of a digital health intervention to enhance physical activity in people with chronic kidney disease (Kidney BEAM): a multicentre, randomised controlled trial in the UK.

BACKGROUND: Remote digital health interventions to enhance physical activity provide a potential solution to improve the sedentary behaviour, physical inactivity, and poor health-related quality of life that are typical of chronic conditions, particularly for people with chronic kidney disease. However, there is a need for high-quality evidence to support implementation in clinical practice. The Kidney BEAM trial evaluated the clinical effect of a 12-week physical activity digital health intervention on health-related quality of life. METHODS: In a single-blind, randomised controlled trial conducted at 11 centres in the UK, adult participants (aged ≥18 years) with chronic kidney disease were recruited and randomly assigned (1:1) to the Kidney BEAM physical activity digital health intervention or a waiting list control group. Randomisation was performed with a web-based system, in randomly permuted blocks of six. Outcome assessors were masked to treatment allocation. The primary outcome was the difference in the Kidney Disease Quality of Life Short Form version 1.3 Mental Component Summary (KDQoL-SF1.3 MCS) between baseline and 12 weeks. The trial was powered to detect a clinically meaningful difference of 3 arbitrary units (AU) in KDQoL-SF1.3 MCS. Outcomes were analysed by an intention-to-treat approach using an analysis of covariance model, with baseline measures and age as covariates. The trial was registered with ClinicalTrials.gov, NCT04872933. FINDINGS: Between May 6, 2021, and Oct 30, 2022, 1102 individuals were assessed for eligibility, of whom 340 participants were enrolled and randomly assigned to the Kidney BEAM intervention group (n=173) or the waiting list control group (n=167). 268 participants completed the trial (112 in the Kidney BEAM group and 156 in the waiting list control group). All 340 randomly assigned participants were included in the intention-to treat population. At 12 weeks, there was a significant improvement in KDQoL-SF.13 MCS score in the Kidney BEAM group (from mean 44·6 AU [SD 10·8] at baseline to 47·0 AU [10·6] at 12 weeks) compared with the waiting list control group (from 46·1 AU [10·5] to 45·0 AU [10·1]; between-group difference of 3·1 AU [95% CI 1·8-4·4]; p<0·0001). INTERPRETATION: The Kidney BEAM physical activity platform is an efficacious digital health intervention to improve mental health-related quality of life in patients with chronic kidney disease. These findings could facilitate the incorporation of remote digital health interventions into clinical practice and offer a potential intervention worthy of investigation in other chronic conditions. FUNDING: Kidney Research UK.

The development and internal pilot trial of a digital physical activity and emotional well-being intervention (Kidney BEAM) for people with chronic kidney disease.

This trial assessed the feasibility and acceptability of Kidney BEAM, a physical activity and emotional well-being self-management digital health intervention (DHI) for people with chronic kidney disease (CKD), which offers live and on-demand physical activity sessions, educational blogs and videos, and peer support. In this mixed-methods, multicentre randomised waitlist-controlled internal pilot, adults with established CKD were recruited from five NHS hospitals and randomised 1:1 to Kidney BEAM or waitlist control. Feasibility outcomes were based upon a priori progression criteria. Acceptability was primarily explored via individual semi-structured interviews (n = 15). Of 763 individuals screened, n = 519 (68%, 95% CI 65 to 71%) were eligible. Of those eligible, n = 303 (58%, 95% CI 54-63%) did not respond to an invitation to participate by the end of the pilot period. Of the 216 responders, 50 (23%, 95% CI 18-29%) consented. Of the 42 randomised, n = 22 (10 (45%) male; 49 ± 16 years; 14 (64%) White British) were allocated to Kidney BEAM and n = 20 (12 (55%) male; 56 ± 11 years; 15 (68%) White British) to the waitlist control group. Overall, n = 15 (30%, 95% CI 18-45%) withdrew during the pilot phase. Participants completed a median of 14 (IQR 5-21) sessions. At baseline, 90-100% of outcome data (patient reported outcome measures and a remotely conducted physical function test) were completed and 62-83% completed at 12 weeks follow-up. Interview data revealed that remote trial procedures were acceptable. Participants' reported that Kidney BEAM increased their opportunity and motivation to be physically active, however, lack of time remained an ongoing barrier to engagement with the DHI. An randomised controlled trial of Kidney BEAM is feasible and acceptable, with adaptations to increase recruitment, retention and engagement.Trial registration NCT04872933. Date of first registration 05/05/2021.

The use of eculizumab in renal transplantation.

The complement system plays a vital role in mediating disease processes within renal allografts. Eculizumab is a humanized monoclonal antibody that targets complement protein C5, inhibiting cleavage into C5a and C5b, and therefore preventing formation of the membrane attack complex (MAC). It has been used primarily within renal transplantation to treat atypical hemolytic-uremic syndrome (aHUS) and antibody-mediated rejection (AMR) post-transplant, and also as prophylaxis in transplants at high risk for these conditions. Eculizumab appears to be effective in protecting renal allografts when post-transplant aHUS or AMR occur, although the published cases report relatively short follow-up. It is unclear how long treatment should continue (a particularly important issue given the expense of the drug), or whether eculizumab contributes to the development of accommodation in humans. When used for prophylaxis, eculizumab also appears to be effective. Some highly sensitized patients have developed either acute AMR or features of chronic AMR despite administration of the drug - this suggests that complement activation is not the only mechanism responsible for AMR. All patients should receive vaccination against Neisseria meningitidis prior to receiving eculizumab. Clinical trials, predominantly in antibody-incompatible renal transplantation, are ongoing to determine the optimal use of C5 inhibition.

Targeting complement at the time of transplantation.

Complement activation occurs in at least two phases when an organ is transplanted into a naive recipient: during reperfusion with recipient blood particularly when the donor organ has undergone a significant period of ischaemia and then during acute rejection once the recipient immune system has recognised the donor tissue as non-self. Both of these reactions are most obvious in the extravascular compartment of the transplanted organ and involve local synthesis of some of the key complement components as well as loss of controls that limit the activation of the pivotal component C3. In contrast, sensitised individuals with pre-existing circulating antibodies have an immediate reaction against the transplant organ that is also complement dependent but is enacted in the intravascular space. All three types of injury (ischaemia-reperfusion, acute rejection, hyperacute rejection) have a critical effect on transplant outcome. Here we discuss therapeutic strategies that are designed to overcome the impact of these factors at the start of transplantation with the aim of improving long-term transplant outcomes. These include the concept of treating the donor organ with modified therapeutic regulators that are engineered to be retained by the donor organ after transplantation and prevent inflammatory injury during the critical early period. By targeting the donor organ with anchored therapeutic proteins, the systemic functions of complement including host defence remain intact. The control of complement activation during the first stages of transplantation, including the possibility that this will reduce the capacity of the graft for stimulating the adaptive immune system, offers an important prospect for increasing the longevity of the transplant and offsetting demand on the limited supply of donor organs. It also provides a model in which the benefits and indications for localised therapy to maximise therapeutic efficiency and minimise the systemic disturbance may be instructive in other complement-related disorders.

A Randomized Trial of Intravenous Iron Supplementation and Exercise on Exercise Capacity in Iron-Deficient Nonanemic Patients With CKD.

Introduction: Patients with chronic kidney disease (CKD) are often iron deficient, even when not anemic. This trial evaluated whether iron supplementation enhances exercise capacity of nonanemic patients with CKD who have iron-deficiency. Methods: Prospective, multicenter double-blind randomized controlled trial of nondialysis patients with CKD and iron-deficiency but without anemia (Hemoglobin [Hb] >110 g/l). Patients were assigned 1:1 to intravenous (IV) iron therapy, or placebo. An 8-week exercise program commenced at week 4. The primary outcome was the mean between-group difference in 6-minute walk test (6MWT) at 4 weeks. Secondary outcomes included 6MWT at 12 weeks, transferrin saturation (TSAT), serum ferritin (SF), Hb, renal function, muscle strength, functional capacity, quality of life, and adverse events at baseline, 4 weeks, and at 12 weeks. Mean between-group differences were analyzed using analysis of covariance models. Results: Among 75 randomized patients, mean (SD) age for iron therapy (n = 37) versus placebo (n = 38) was 54 (16) versus 61 (12) years; estimated glomerular filtration rate (eGFR) (34 [12] vs. 35 [11] ml/min per 1.73 m2], TSAT (23 [12] vs. 21 [6])%; SF (57 [64] vs. 62 [33]) µg/l; Hb (122.4 [9.2] vs. 127 [13.2] g/l); 6MWT (384 [95] vs. 469 [142] meters) at baseline, respectively. No significant mean between-group difference was observed in 6MWT distance at 4 weeks. There were significant increases in SF and TSAT at 4 and 12 weeks (P < 0.02), and Hb at 12 weeks (P = 0.009). There were no between-group differences in other secondary outcomes and no adverse events attributable to iron therapy. Conclusion: This trial did not demonstrate beneficial effects of IV iron therapy on exercise capacity at 4 weeks. A larger study is needed to confirm if IV iron is beneficial in nondialysis patients with CKD who are iron-deficient.

The Feasibility and User-Experience of a Digital Health Intervention Designed to Prevent Weight Gain in New Kidney Transplant Recipients-The ExeRTiOn2 Trial.

Half of kidney transplant recipients (KTRs) gain more than 5% of their body weight in the first year following transplantation. KTRs have requested support with physical activity (PA) and weight gain prevention, but there is no routine care offered. There are few high-quality studies investigating the clinical value of diet, PA or combined interventions to prevent weight gain. The development and evaluation of theoretically informed complex-interventions to mitigate weight gain are warranted. The aims of this mixed-methods randomized controlled trial (RCT) were to explore the feasibility, acceptability and user-experience of a digital healthcare intervention (DHI) designed to prevent post-transplant weight gain, in preparation for a large multi-center trial. New KTRs (<3 months) with access to an internet compatible device were recruited from a London transplant center. The usual care (UC) group received standard dietary and PA advice. The intervention group (IG) received access to a 12-week DHI designed to prevent post-transplant weight gain. Primary feasibility outcomes included screening, recruitment, retention, adherence, safety and hospitalizations and engagement and experience with the DHI. Secondary outcomes (anthropometrics, bioimpedance, arterial stiffness, 6-minute walk distance and questionnaires) were measured at baseline, 3- and 12-months. 38 KTRs were screened, of which 32 (84.2%) were eligible, and of those 20 (62.5%) consented, with 17 participants (85%) completing baseline assessment (Median 49 years, 58.8% male, Median 62 days post-transplant). Participants were randomized using a computer-generated list (n = 9 IG, n = 8 UC). Retention at 12-months was 13 (76.4%) (n = 6 IG, n = 7 UC). All a priori progression criteria were achieved. There were no associated adverse events. Reflexive thematic analysis revealed four themes regarding trial participation and experience whilst using the DHI. Halting recruitment due to COVID-19 resulted in the recruitment of 40% of the target sample size. Mixed-methods data provided important insights for future trial design. A definitive RCT is warranted and welcomed by KTRs. Clinical Trial Registration: www.clinicalTrials.gov, identifier: NCT03996551.

Hypertension and cardiovascular risk factor management in a multi-ethnic cohort of adults with CKD: a cross sectional study in general practice.

BACKGROUND: Hypertension, especially if poorly controlled, is a key determinant of chronic kidney disease (CKD) development and progression to end stage renal disease (ESRD). AIM: To assess hypertension and risk factor management, and determinants of systolic blood pressure control in individuals with CKD and hypertension. DESIGN AND SETTING: Cross-sectional survey using primary care electronic health records from 47/49 general practice clinics in South London. METHODS: Known effective interventions, management of hypertension and cardiovascular disease (CVD) risk in patients with CKD Stages 3-5 were investigated. Multivariable logistic regression analysis examined the association of demographic factors, comorbidities, deprivation, and CKD coding, with systolic blood pressure control status as outcome. Individuals with diabetes were excluded. RESULTS: Adults with CKD Stages 3-5 and hypertension represented 4131/286,162 (1.4%) of the total population; 1984 (48%) of these individuals had undiagnosed CKD without a recorded CKD clinical code. Hypertension was undiagnosed in 25% of the total Lambeth population, and in patients with CKD without diagnosed hypertension, 23.0% had systolic blood pressure > 140 mmHg compared with 39.8% hypertensives, p < 0.001. Multivariable logistic regression revealed that factors associated with improved systolic blood pressure control in CKD included diastolic blood pressure control, serious mental illness, history of cardiovascular co-morbidities, CKD diagnostic coding, and age < 60 years. African ethnicity and obesity were associated with poorer systolic blood pressure control. CONCLUSION: We found both underdiagnosed CKD and underdiagnosed hypertension in patients with CKD. The poor systolic blood pressure control in older age groups ≥ 60 years and in Black African or obese individuals is clinically important as these groups are at increased risk of mortality for cardiovascular diseases.

Utility of a Single Itch-Related Question and the Skindex-10 Questionnaire for Assessing Pruritus and Predicting Health-Related Quality of Life in Patients Receiving Hemodialysis.

Rationale & Objective: Chronic kidney disease-associated pruritus has been linked with poorer mental and physical health-related quality of life (HR-QOL) in patients receiving hemodialysis. We used the Skindex-10 questionnaire and a single itch-related question to evaluate their prediction of HR-QOL. Study Design: Prospective, international cohort. Setting & Participants: We analyzed data from 4,940 patients receiving hemodialysis from 17 countries enrolled in phase 5 (2013) of the Dialysis Outcomes and Practice Patterns Study. Predictors: The responses to the 10 questions of Skindex-10 (0-6 scale) pertaining to itchiness in the past week were summed to create a summary score (range, 0-60). Concurrently, a single question from the Kidney Disease Quality of Life 36-item survey asked "during the past 4 weeks, to what extent were you bothered by itchy skin?" with 5 responses, ranging from "not at all" to "extremely" bothered. Outcomes: Physical component summary (PCS) and mental component summary (MCS) scores of HR-QOL. Analytical Approach: We used separate linear regression models to evaluate the predictive power, based on R2 values, for 3 models: 1 for each predictor and 1 with both predictors. Results: The correlation between the single itch-related question and the Skindex-10 score was 0.72. A 10-point higher Skindex-10 score was associated with a 1.2-point lower PCS score (95% CI, -1.4 to -0.9) and a 1.5-point lower MCS score (95% CI, -1.7 to -1.3) . The R2 value for PCS was 0.065 when the single question was used and only 0.033 when Skindex-10 was used as the predictor; the R2 value for MCS was 0.056 for the single question versus 0.052 for Skindex-10. Limitations: Measurement bias and translation issues in the questionnaires. Conclusions: The single question about the extent to which the patients were bothered by itchy skin was highly correlated with the Skindex-10 score and at least as predictive of key HR-QOL measures. In daily clinical practice, using 1 simple question about the extent to which patients are bothered by itchy skin can be a feasible and efficient method for the routine assessment of pruritus.

Severity of COVID-19 after Vaccination among Hemodialysis Patients: An Observational Cohort Study.

BACKGROUND AND OBJECTIVES: Patients receiving hemodialysis are at high risk from coronavirus disease 2019 (COVID-19) and demonstrate impaired immune responses to vaccines. There have been several descriptions of their immunologic responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, but few studies have described the clinical efficacy of vaccination in patients on hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a multicenter observational study of the London hemodialysis population undergoing surveillance PCR testing during the period of vaccine rollout with BNT162b2 and AZD1222, all of those positive for SARS-CoV-2 were identified. Clinical outcomes were analyzed according to predictor variables, including vaccination status, using a mixed effects logistic regression model. Risk of infection was analyzed in a subgroup of the base population using a Cox proportional hazards model with vaccination status as a time-varying covariate. RESULTS: SARS-CoV-2 infection was identified in 1323 patients of different ethnicities (Asian/other, 30%; Black, 38%; and White, 32%), including 1047 (79%) unvaccinated, 86 (7%) after first-dose vaccination, and 190 (14%) after second-dose vaccination. The majority of patients had a mild course; however, 515 (39%) were hospitalized, and 172 (13%) died. Older age, diabetes, and immune suppression were associated with greater illness severity. In regression models adjusted for age, comorbidity, and time period, prior two-dose vaccination was associated with a 75% (95% confidence interval, 56 to 86) lower risk of admission and 88% (95% confidence interval, 70 to 95) fewer deaths compared with unvaccinated patients. No loss of protection was seen in patients over 65 years or with increasing time since vaccination, and no difference was seen between vaccine types. CONCLUSIONS: These data demonstrate a substantially lower risk of severe COVID-19 after vaccination in patients on dialysis who become infected with SARS-CoV-2.

Dendritic cell function in allostimulation is modulated by C5aR signaling.

Regulation of T cell immunity by C5a has been suggested from recent studies. However, the underlying mechanisms, particularly the involved cells and biochemical basis, are not well defined. In this study, the direct modulation of dendritic cell (DC) activation and its function in T cell stimulation by C5a-C5aR interaction and the involved signaling pathways were investigated. We show that DCs from C5aR(-/-) mice and normal DCs treated with C5aR antagonist have less-activated phenotype characterized with increased IL-10 and decreased IL-12p70 production in response to LPS stimulation, lowered surface expression of MHC class II, B7.2, and consequently have reduced capacity to stimulate allospecific T cells. Conversely, C5a stimulation up-regulates DC activation and its function in allostimulation. Furthermore, stimulation of C5aR mediates the inhibition of cAMP production and protein kinase A activity and is involved in activation of PI3K/AKT and NF-kappaB signaling in DCs. These results demonstrate that C5a acts directly on C5aR expressed on DCs resulting in the cell activation and subsequently enhances its capacity for allospecific T cell stimulation. It also suggests that NF-kappaB signaling induced by down-regulation of cAMP/ protein kinase A pathway and up-regulation of PI3K/AKT pathway following C5a stimulation may contribute to up-regulation of DC function.

Risk of COVID-19 Disease, Dialysis Unit Attributes, and Infection Control Strategy among London In-Center Hemodialysis Patients.

BACKGROUND AND OBJECTIVES: Patients receiving in-center hemodialysis treatment face unique challenges during the coronavirus disease 2019 (COVID-19) pandemic, specifically the need to attend for treatment that prevents self-isolation. Dialysis unit attributes and isolation strategies that might reduce dialysis center COVID-19 infection rates have not been previously examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We explored the role of variables, including community disease burden, dialysis unit attributes (size and layout), and infection control strategies, on rates of COVID-19 among patients receiving in-center hemodialysis in London, United Kingdom, between March 2, 2020 and May 31, 2020. The two outcomes were defined as (1) a positive test for infection or admission with suspected COVID-19 and (2) admission to the hospital with suspected infection. Associations were examined using a discrete time multilevel time-to-event analysis. RESULTS: Data on 5755 patients dialyzing in 51 units were analyzed; 990 (17%) tested positive and 465 (8%) were admitted with suspected COVID-19 between March 2 and May 31, 2020. Outcomes were associated with age, diabetes, local community COVID-19 rates, and dialysis unit size. A greater number of available side rooms and the introduction of mask policies for asymptomatic patients were inversely associated with outcomes. No association was seen with sex, ethnicity, or deprivation indices, nor with any of the different isolation strategies. CONCLUSIONS: Rates of COVID-19 in the in-center hemodialysis population relate to individual factors, underlying community transmission, unit size, and layout.