Update on Hemodialysis-Induced Multiorgan Ischemia: Brains and Beyond.

Hemodialysis is a life-saving treatment for patients with kidney failure. However, patients requiring hemodialysis have a 10-20 times higher risk of cardiovascular morbidity and mortality than that of the general population. Patients encounter complications such as episodic intradialytic hypotension, abnormal perfusion to critical organs (heart, brain, liver, and kidney), and damage to vulnerable vascular beds. Recurrent conventional hemodialysis exposes patients to multiple episodes of circulatory stress, exacerbating and being aggravated by microvascular endothelial dysfunction. This promulgates progressive injury that leads to irreversible multiorgan injury and the well-documented higher incidence of cardiovascular disease and premature death. This review aims to examine the underlying pathophysiology of hemodialysis-related vascular injury and consider a range of therapeutic approaches to improving outcomes set within this evolved rubric.‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬.

Reassuring Data on the Cardiovascular Risk in Adults With X-linked Hypophosphatemia Receiving Conventional Therapy.

CONTEXT: X-linked hypophosphatemia (XLH) is a rare genetic disorder that results in increased plasma levels of fibroblast growth factor 23 (FGF23). Several studies have demonstrated a direct association between FGF23 and cardiovascular mortality in cohorts of patients with chronic renal failure. However, in patients with XLH, studies on the cardiovascular impact of the disease are rare, with contradictory results. OBJECTIVE: The aim was to assess whether the disease led to an increased cardiovascular risk. METHODS: We conducted a single-center retrospective observational study on a local cohort of adult patients with XLH. The primary endpoint was a composite endpoint of the frequency of left ventricular hypertrophy (LVH) or presence of high blood pressure. Our secondary objectives were to assess echocardiographic, pulse wave velocity, and central blood pressure data as other markers of CV health. Independently of this cohort, tissue sodium content with magnetic resonance imaging was studied in 2 patients with XLH before and after burosumab. RESULTS: Twenty-two patients were included. Median serum phosphate was 0.57 (0.47-0.72) mmol/L and FGF23 94 pg/L (58-2226). Median blood pressure was 124 (115-130)/68 (65-80) mm Hg, with only 9% of patients being hypertensive. A majority of patients (69%) had no LVH, only 1 had a left ventricular mass >100 g/m² and 25% of patients had left ventricular remodeling. Pulse wave velocity was normal in all patients. No differences in skin and muscle sodium content were observed before and after burosumab in the 2 patients who underwent sodium magnetic resonance imaging. CONCLUSION: We found no elevated risk of developing hypertension or LVH in patients with XLH.

A novel multiplex biomarker panel for profiling human acute and chronic kidney disease.

Acute and chronic kidney disease continues to confer significant morbidity and mortality in the clinical setting. Despite high prevalence of these conditions, few validated biomarkers exist to predict kidney dysfunction. In this study, we utilized a novel kidney multiplex panel to measure 21 proteins in plasma and urine to characterize the spectrum of biomarker profiles in kidney disease. Blood and urine samples were obtained from age-/sex-matched healthy control subjects (HC), critically-ill COVID-19 patients with acute kidney injury (AKI), and patients with chronic or end-stage kidney disease (CKD/ESKD). Biomarkers were measured with a kidney multiplex panel, and results analyzed with conventional statistics and machine learning. Correlations were examined between biomarkers and patient clinical and laboratory variables. Median AKI subject age was 65.5 (IQR 58.5-73.0) and median CKD/ESKD age was 65.0 (IQR 50.0-71.5). Of the CKD/ESKD patients, 76.1% were on hemodialysis, 14.3% of patients had kidney transplant, and 9.5% had CKD without kidney replacement therapy. In plasma, 19 proteins were significantly different in titer between the HC versus AKI versus CKD/ESKD groups, while NAG and RBP4 were unchanged. TIMP-1 (PPV 1.0, NPV 1.0), best distinguished AKI from HC, and TFF3 (PPV 0.99, NPV 0.89) best distinguished CKD/ESKD from HC. In urine, 18 proteins were significantly different between groups except Calbindin, Osteopontin and TIMP-1. Osteoactivin (PPV 0.95, NPV 0.95) best distinguished AKI from HC, and ß2-microglobulin (PPV 0.96, NPV 0.78) best distinguished CKD/ESKD from HC. A variety of correlations were noted between patient variables and either plasma or urine biomarkers. Using a novel kidney multiplex biomarker panel, together with conventional statistics and machine learning, we identified unique biomarker profiles in the plasma and urine of patients with AKI and CKD/ESKD. We demonstrated correlations between biomarker profiles and patient clinical variables. Our exploratory study provides biomarker data for future hypothesis driven research on kidney disease.

Non-invasive intradialytic percutaneous perfusion monitoring: a view to the heart through the skin.

Introduction: The life-sustaining treatment of hemodialysis (HD) induces recurrent and cumulative systemic circulatory stress resulting in cardiovascular injury. These recurrent insults compound preexisting cardiovascular sequalae leading to the development of myocardial injury and resulting in extremely high morbidity/mortality. This is largely a consequence of challenged microcirculatory flow within the myocardium (evidenced by detailed imaging-based studies). Currently, monitoring during HD is performed at the macrovascular level. Non-invasive monitoring of organ perfusion would allow the detection and therapeutic amelioration of this pathophysiological response to HD. Non-invasive percutaneous perfusion monitoring of the skin (using photoplethysmography-PPG) has been shown to be predictive of HD-induced myocardial stunning (a consequence of segmental ischemia). In this study, we extended these observations to include a dynamic assessment of skin perfusion during HD compared with directly measured myocardial perfusion during dialysis and cardiac contractile function. Methods: We evaluated the intradialytic microcirculatory response in 12 patients receiving conventional HD treatments using continuous percutaneous perfusion monitoring throughout HD. Cardiac echocardiography was performed prior to the initiation of HD, and again at peak-HD stress, to assess the development of regional wall motion abnormalities (RWMAs). Myocardial perfusion imaging was obtained at the same timepoints (pre-HD and peak-HD stress), utilizing intravenous administered contrast and a computerized tomography (CT)-based method. Intradialytic changes in pulse strength (derived from PPG) were compared with the development of HD-induced RWMAs (indicative of myocardial stunning) and changes in myocardial perfusion. Results: We found an association between the lowest pulse strength reduction (PPG) and the development of RWMAs (p = 0.03) and also with changes in global myocardial perfusion (CT) (p = 0.05). Ultrafiltration rate (mL/kg/hour) was a significant driver of HD-induced circulatory stress [(associated with the greatest pulse strength reduction (p = 0.01), a reduction in global myocardial perfusion (p = 0.001), and the development of RWMAs (p = 0.03)]. Discussion: Percutaneous perfusion monitoring using PPG is a useful method of assessing intradialytic hemodynamic stability and HD-induced circulatory stress. The information generated at the microcirculatory level of the skin is reflective of direct measures of myocardial perfusion and the development of HD-induced myocardial stunning. This approach for the detection and management of HD-induced cardiac injury warrants additional evaluation.

Recent Advances in Sodium Magnetic Resonance Imaging and Its Future Role in Kidney Disease.

Sodium imbalance is a hallmark of chronic kidney disease (CKD). Excess tissue sodium in CKD is associated with hypertension, inflammation, and cardiorenal disease. Sodium magnetic resonance imaging (23Na MRI) has been increasingly utilized in CKD clinical trials especially in the past few years. These studies have demonstrated the association of excess sodium tissue accumulation with declining renal function across whole CKD spectrum (early- to end-stage), biomarkers of systemic inflammation, and cardiovascular dysfunction. In this article, we review recent advances of 23Na MRI in CKD and discuss its future role with a focus on the skin, the heart, and the kidney itself.

Hemodialysis-Related Acute Brain Injury Demonstrated by Application of Intradialytic Magnetic Resonance Imaging and Spectroscopy.

SIGNIFICANCE STATEMENT: Hemodialysis (HD) results in reduced brain blood flow, and HD-related circulatory stress and regional ischemia are associated with brain injury over time. However, studies to date have not provided definitive direct evidence of acute brain injury during a HD treatment session. Using intradialytic magnetic resonance imaging (MRI) and spectroscopy to examine HD-associated changes in brain structure and neurochemistry, the authors found that multiple white (WM) tracts had diffusion imaging changes characteristic of cytotoxic edema, a consequence of ischemic insult and a precursor to fixed structural WM injury. Spectroscopy showed decreases in prefrontal N -acetyl aspartate (NAA) and choline concentrations consistent with energy deficit and perfusion anomaly. This suggests that one HD session can cause brain injury and that studies of interventions that mitigate this treatment's effects on the brain are warranted. BACKGROUND: Hemodialysis (HD) treatment-related hemodynamic stress results in recurrent ischemic injury to organs such as the heart and brain. Short-term reduction in brain blood flow and long-term white matter changes have been reported, but the basis of HD-induced brain injury is neither well-recognized nor understood, although progressive cognitive impairment is common. METHODS: We used neurocognitive assessments, intradialytic anatomical magnetic resonance imaging, diffusion tensor imaging, and proton magnetic resonance spectroscopy to examine the nature of acute HD-associated brain injury and associated changes in brain structure and neurochemistry relevant to ischemia. Data acquired before HD and during the last 60 minutes of HD (during maximal circulatory stress) were analyzed to assess the acute effects of HD on the brain. RESULTS: We studied 17 patients (mean age 63±13 years; 58.8% were male, 76.5% were White, 17.6% were Black, and 5.9% were of Indigenous ethnicity). We found intradialytic changes, including the development of multiple regions of white matter exhibiting increased fractional anisotropy with associated decreases in mean diffusivity and radial diffusivity-characteristic features of cytotoxic edema (with increase in global brain volumes). We also observed decreases in proton magnetic resonance spectroscopy-measured N -acetyl aspartate and choline concentrations during HD, indicative of regional ischemia. CONCLUSIONS: This study demonstrates for the first time that significant intradialytic changes in brain tissue volume, diffusion metrics, and brain metabolite concentrations consistent with ischemic injury occur in a single dialysis session. These findings raise the possibility that HD might have long-term neurological consequences. Further study is needed to establish an association between intradialytic magnetic resonance imaging findings of brain injury and cognitive impairment and to understand the chronic effects of HD-induced brain injury. CLINICAL TRIALS INFORMATION: NCT03342183 .

Effects of pediatric chronic kidney disease and its etiology on tissue sodium concentration: a pilot study.

BACKGROUND: Sodium-23 magnetic resonance imaging (23Na MRI) allows non-invasive assessment of tissue sodium concentration ([Na+]). Age and chronic kidney disease (CKD) are associated with increased tissue [Na+] in adults, but limited information is available pertaining to children and adolescents. We hypothesized that pediatric CKD is associated with altered tissue [Na+] compared to healthy controls. METHODS: This was a case-control exploratory study on healthy children and adults and pediatric CKD patients. Study participants underwent an investigational visit, blood/urine biochemistry, and leg 23Na MRI for tissue [Na+] quantification (whole leg, skin, soleus muscle). CKD was stratified by etiology and patients' tissue [Na+] was compared against healthy controls by computing individual Z-scores. An absolute Z-score > 1.96 was deemed to deviate significantly from the mean of healthy controls. Pearson correlation was used to compute the associations between tissue [Na+] and kidney function. RESULTS: A total of 36 pediatric participants (17 healthy, 19 CKD) and 19 healthy adults completed the study. Healthy adults had significantly higher tissue [Na+] compared with pediatric groups; conversely, no significant differences were found between healthy children/adolescents and CKD patients. Four patients with glomerular disease and one kidney transplant recipient due to atypical hemolytic-uremic syndrome had elevated whole-leg [Na+] Z-scores. Reduced whole-leg [Na+] Z-scores were found in two patients with tubular disorders (Fanconi syndrome, proximal-distal renal tubular acidosis). All tissue [Na+] measures were significantly associated with proteinuria and hypoalbuminemia. CONCLUSIONS: Depending on etiology, pediatric CKD was associated with either increased (glomerular disease) or reduced (tubular disorders) tissue [Na+] compared with healthy controls. A higher resolution version of the Graphical abstract is available as Supplementary information.

Initial evaluation of extracorporeal immunomodulatory therapy for the treatment of critically ill COVID-19 infected patients.

Severe COVID-19 infection results in significant immune dysregulation resulting from excessive recruitment and activation of neutrophils. The aim of this study was to confirm feasibility, initial safety and detect signal of efficacy of a non-propriety device delivered using an intermittent extra-corporeal system (LMOD) allowing leucocytes modulation in the setting of Severe COVID-19 infection. Twelve patients were recruited. Inclusion criteria were > 18 years age, confirmed COVID-19, acute respiratory distress syndrome requiring mechanical support and hypotension requiring vasopressor support. Primary end point was vasopressor requirements (expressed as epinephrine dose equivalents) and principle secondary endpoints related to safety, ability to deliver the therapy and markers of inflammation assessed over five days after treatment initiation. LMOD treatment appeared safe, defined by hemodynamic stability and no evidence of white cell number depletion from blood. We demonstrated a significant decrease in vasopressor doses (-37%, p = 0.02) in patients receiving LMOD therapy (despite these patients having to tolerate an additional extracorporeal intermittent therapy). Vasopressor requirements unchanged/increasing in control group (+ 10%, p = 0.48). Although much about the use of this therapy in the setting of severe COVID-19 infection remains to be defined (e.g. optimal dose and duration), this preliminary study supports the further evaluation of this novel extracorporeal approach.

Assessment of microcirculatory function during hemodialysis.

PURPOSE OF REVIEW: Patients with chronic kidney disease characteristically exhibit microcirculatory dysfunction, in combination with vascular damage. Hemodialysis superimposes additional circulatory stress to the microvasculature (repetitive ischemic insults/cumulative damage) resulting in high mortality. Intradialytic monitoring and hemodialysis delivery is currently limited to macrovascular/systemic assessment and detection of intradialytic systemic hypotension. Monitoring of the microcirculation has the potential to provide valuable information on hemodialysis-induced circulatory stress likely to result in end-organ ischemia (with/without systemic hypotension) generating an opportunity to intervene before tissue injury occurs. RECENT FINDINGS: Various noninvasive technologies have been used assessing the microcirculation in hemodialysis patients at rest. Some technologies have also been applied during hemodialysis studying the effects of treatment on the microcirculation. Despite the approach used, results are consistent. Hemodialysis patients have impaired microcirculations with treatment adding additional stress to inadequately regulated vascular beds. Utility/practicality/clinical relevance vary significantly between methodologies. SUMMARY: Intradialytic monitoring of the microcirculation can provide additional insights into a patient's individual response to treatment. However, this valuable perspective has not been adopted into clinical practice. A microcirculatory view could provide a window of opportunity to enable a precision medicine approach to treatment delivery improving current woefully poor subjective and objective clinical outcomes.

Outcomes and predictors of skin sodium concentration in dialysis patients.

Background: Sodium-23 magnetic resonance imaging (23Na MRI) allows the measurement of skin sodium concentration ([Na+]). In patients requiring dialysis, no data are available relating to the clinical outcomes associated with skin sodium accumulation or the determinants of increasing deposition. Methods: This was an exploratory, observational study of adult hemodialysis (HD) and peritoneal dialysis (PD) patients. Participants underwent skin [Na+] quantification with leg 23Na MRI at the study's beginning. Outcomes of interest were all-cause mortality and composite all-cause mortality plus major adverse cardiovascular events. Cumulative total and event-free survival were assessed using the Kaplan-Meier survival function after stratification into skin [Na+] quartiles. Cox proportional hazards regression was used to model the association between skin [Na+] and outcomes of interest. Multiple linear regression was used to model the predictors of skin [Na+]. Results: A total of 52 participants (42 HD and 10 PD) underwent the study procedures. The median follow-up was 529 days (interquartile range: 353-602). Increasing skin [Na+] quartiles were associated with significantly shorter overall and event-free survival (log-rank χ2(1) = 3.926, log-rank χ2(1) = 5.685; P for trend <0.05 in both instances). Skin [Na+] was associated with all-cause mortality {hazard ratio (HR) 4.013, [95% confidence interval (95% CI) 1.988-8.101]; P < 0.001} and composite events [HR 2.332 (95% CI 1.378-3.945); P < 0.01], independently of age, sex, serum [Na+] and albumin. In multiple regression models, dialysate [Na+], serum albumin and congestive heart failure were significantly associated with skin [Na+] in HD patients (R2 adj = 0.62). Conclusions: Higher skin [Na+] was associated with worse clinical outcomes in dialysis patients and may represent a direct therapeutic target.

Functional Sodium MRI Helps to Measure Corticomedullary Sodium Content in Normal and Diseased Human Kidneys.

Background To the knowledge of the authors, urinary osmolarity is the only tool currently available to assess kidney corticomedullary gradient (CMG). Comparisons between CMG and urinary osmolarity and the use of modalities such as sodium MRI to evaluate renal disease in humans are lacking. Purpose To investigate the ability of sodium MRI to measure CMG dynamics compared with urinary osmolarity after water load in healthy volunteers and CMG in participants with kidney disease. Materials and Methods A prospective study was conducted from July 2020 to January 2021 in fasting healthy volunteers undergoing water load and participants with chronic kidney disease (CKD) from cardiorenal syndrome included in a clinical trial. In both groups, CMG was estimated by measuring the medulla-to-cortex signal ratio from sodium MRI at 3.0 T. A custom-built two-loop (diameter, 18 cm) butterfly radiofrequency surface coil, tuned for sodium frequency (33.786 MHz), was used to acquire renal sodium images. Two independent observers measured all sodium MRI cortical and medullary values for each region of interest to compute the intraclass correlation coefficient. Pearson correlation was performed between urinary osmolarity and CMG. Results Five participants with CKD (mean age, 77 years ± 12 [standard deviation]; all men) and 10 healthy volunteers (mean age, 42 years ± 15; six men, four women) were evaluated. A reduction was observed between baseline and peak urinary dilution time for both mean medulla-to-cortex ratios (1.55 ± 0.11 to 1.31 ± 0.09, respectively; P < .001) and mean urinary osmolarity (756 mOsm/L ± 157 to 73 mOsm/L ± 14, respectively; P < .001) in healthy volunteers. Medulla-to-cortex and corresponding urinary osmolarity were correlated in both groups (r2 = 0.22; P < .001). Kidney sodium tissue content was successfully acquired in all five participants with CKD. The intraclass correlation coefficient measurement was 0.99 (P < .001). Conclusion Functional sodium MRI accurately depicted corticomedullary gradient (CMG) dynamic changes in healthy volunteers and demonstrated feasibility of CMG measurement in participants with reduced kidney function. Clinical trial registration no. NCT04170855. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Laustsen and Bøgh in this issue.

Impact of Expanded Hemodialysis Using Medium Cut-off Dialyzer on Quality of Life: Application of Dynamic Patient-Reported Outcome Measurement Tool.

RATIONALE & OBJECTIVE: Current hemodialysis (HD) treatments have limited ability to clear larger-molecular-weight uremic toxins. Retention is associated with increased symptom burden, low health-related quality of life (HRQoL), and high mortality. Improved clearance, using novel medium cut-off dialyzers, termed expanded HD (HDx), may be associated with improved subjective experience. We have previously developed a dynamic patient-reported outcome measure (PROM) instrument to allow iterative recording to better appreciate the overall burden of disease and assess the impact of therapy changes. STUDY DESIGN: Single-center interventional pilot study. SETTING & PARTICIPANTS: 28 patients established on maintenance HD, London, Ontario, Canada. INTERVENTION: Initial study consisting of 2-week observation (baseline-conventional high-flux HD) followed by 12 weeks of HDx. HRQoL was assessed using the dynamic PROM instrument thrice weekly (enabled in a dedicated app as the London Evaluation of Illness [LEVIL]). Extension phase; 2-week baseline with 24 weeks of HDx and 8-week washout. OUTCOMES: Principal aim was to establish whether HDx therapy was associated with improved HRQoL, evidence of dose-dependant response, and whether effects were durable over time, using LEVIL. RESULTS: Patients with lower LEVIL scores (<70/100) at baseline showed improvement in overall HRQoL after 8 weeks of therapy with similar carryover effect. General well-being, energy, and sleep quality were improved significantly as a consequence of HDx therapy. There were no detrimental effects of HDx detected in patients with higher baseline HRQoL. LIMITATIONS: Small nonrandomized sample size. The coronavirus disease 2019 pandemic interfered with the extension phase. CONCLUSIONS: Dynamic PROM assessment effectively identified patients with lower HRQoL and higher symptom burden, demonstrating durable time/dose-dependent improvements across a range of symptom domains. The use of this instrument may allow targeted selection of patients most likely to benefit from HDx therapy and assist in monitoring response and defining effect size and treatment duration to allow optimal design of further definitive randomized controlled trials of this newly introduced technology. FUNDING: Baxter Healthcare Canada. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03640858.

Tissue Sodium Storage in Patients With Heart Failure: A New Therapeutic Target?

BACKGROUND: Preclinical data suggest sodium deposited (without water) in tissues may lead to aberrant remodeling and systemic inflammation, independently of fluid overload in patients with heart failure (HF). Tissue salt storage can be measured noninvasively and quantitatively with 23Na-magnetic resonance imaging. We aimed to investigate the possibility that patients with HF complicated by renal dysfunction are subject to higher tissue sodium concentration exposure than patients with chronic kidney disease alone. METHODS: We conducted an exploratory study including 18 patients with HF, 34 hemodialysis patients (with no meaningful renal clearance of sodium), and 31 patients with chronic kidney disease, with glomerular filtration rate matched to the patients with HF. Every patient underwent 23Na-magnetic resonance imaging of the calf, to quantify tissue sodium and allow comparison among the 3 patient groups. RESULTS: There were no differences in age, sex, and body mass index between groups. Median (interquartile range) skin sodium content in HF (31 [23-37] mmol/L) was very high and indistinguishable from skin sodium content in hemodialysis patients (30 [22-35] mmol/L), P=0.6. Patients with HF exhibited significantly higher skin sodium content than matched estimated glomerular filtration rate chronic kidney disease patients (22 [19-26] mmol/L), P=0.005. Median muscle sodium content in patients with HF was significantly higher than in patients with chronic kidney disease, P=0.002. There was no relationship with estimated glomerular filtration rate in patients with HF. We report a significant correlation between skin sodium and urinary sodium (P=0.04) but no correlation with muscle sodium. Patients who were assessed as being volume depleted (sodium excretion fraction <1%) had lower skin sodium content than patients with sodium excretion fraction >1% (P=0.03). CONCLUSIONS: We have demonstrated that patients with HF characteristically have very high levels of skin sodium storage, comparable to well-characterized extreme levels seen in patients with end-stage kidney disease requiring hemodialysis. 23Na-magnetic resonance imaging may allow precision medicine in the management of this challenging group of patients with HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03004547.

MyTEMP: Statistical Analysis Plan of a Registry-Based, Cluster-Randomized Clinical Trial.

BACKGROUND: Major Outcomes with Personalized Dialysate TEMPerature (MyTEMP) is a 4-year cluster-randomized clinical trial comparing the effect of using a personalized, temperature-reduced dialysate protocol versus a dialysate temperature of 36.5°C on cardiovascular-related death and hospitalization. Randomization was performed at the level of the dialysis center ("the cluster"). OBJECTIVE: The objective is to outline the statistical analysis plan for the MyTEMP trial. DESIGN: MyTEMP is a pragmatic, 2-arm, parallel-group, registry-based, open-label, cluster-randomized trial. SETTING: A total of 84 dialysis centers in Ontario, Canada. PATIENTS: Approximately 13 500 patients will have received in-center hemodialysis at the 84 participating dialysis centers during the trial period (April 3, 2017, to March 1, 2021, with a maximum follow-up to March 31, 2021). METHODS: Patient identification, baseline characteristics, and study outcomes will be obtained primarily through Ontario administrative health care databases held at ICES. Covariate-constrained randomization was used to allocate the 84 dialysis centers (1:1) to the intervention group or the control group. Centers in the intervention group used a personalized, temperature-reduced dialysate protocol, and centers in the control group used a fixed dialysate temperature of 36.5°C. OUTCOMES: The primary outcome is a composite of cardiovascular-related death or major cardiovascular-related hospitalization (defined as a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke) recorded in administrative health care databases. The key secondary outcome is the mean drop in intradialytic systolic blood pressure, defined as the patients' predialysis systolic blood pressure minus their nadir systolic blood pressure during the dialysis treatment. Anonymized data on patients' predialysis and intradialytic systolic blood pressure were collected at monthly intervals from each dialysis center. ANALYSIS PLAN: The primary analysis will follow an intent-to-treat approach. The primary outcome will be analyzed at the patient level as the hazard ratio of time-to-first event, estimated from a subdistribution hazards model. Within-center correlation will be accounted for using a robust sandwich estimator. In the primary analysis, patients' observation time will end if they experience the primary outcome, emigrate from Ontario, or die of a noncardiovascular cause (which will be treated as a competing risk event). The between-group difference in the mean drop in intradialytic systolic blood pressure obtained during the dialysis sessions throughout the trial period will be analyzed at the center level using an unadjusted random-effects linear mixed model. TRIAL STATUS: The MyTEMP trial period is April 3, 2017, to March 31, 2021. We expect to analyze and report results by 2023 once the updated data are available at ICES. TRIAL REGISTRATION: MyTEMP is registered with the US National Institutes of Health at clincaltrials.gov (NCT02628366). STATISTICAL ANALYTIC PLAN: Version 1.1 June 15, 2021.

CONTEXTE: L'essai MyTEMP (Major Outcomes with Personalized Dialysate Temperature) est un essai clinique randomisé en grappes d'une durée de 4 ans comparant l'effet d'un protocole de dialysat personnalisé à température réduite par rapport au dialysat à 36,5 °C sur les hospitalisations et les décès dus à des problèmes cardiovasculaires. La répartition aléatoire des sujets a été effectuée au niveau du centre de dialyse (ci-après appelé « groupe ¼). OBJECTIFS: Exposer les grandes lignes du plan d'analyse statistique de l'essai MyTEMP. TYPE D'ÉTUDE: MyTEMP est un essai clinique pragmatique ouvert, à deux bras, en groupes parallèles, basé sur un registre, et randomisé en grappes. CADRE: L'essai est mené dans 84 centres de dialyse en Ontario (Canada). SUJETS: On estime qu'environ 13 500 patients auront reçu des soins d'hémodialyse dans les 84 centres de dialyse participants au cours de la période de l'essai (3 avril 2017 au 1er mars 2021; suivi maximal jusqu'au 31 mars 2021). MÉTHODOLOGIE: Les résultats et les données concernant l'identification des patients et leurs caractéristiques initiales seront principalement tirés des bases de données administratives du système de santé ontarien tenues par l'ICES. Une répartition aléatoire restreinte par les covariables a été employée pour classer les 84 centres de dialyse (1:1) dans le groupe d'intervention ou le groupe témoin. Le groupe d'intervention a utilisé un protocole personnalisé de dialysat à température réduite et le groupe témoin un dialysat à température fixe (36,5 °C). RÉSULTATS: Le principal critère d'évaluation est la combinaison d'un décès d'origine cardiovasculaire ou d'une hospitalisation majeure liée à la santé cardiovasculaire (définie comme une hospitalisation pour un infarctus du myocarde, une insuffisance cardiaque congestive ou un AVC ischémique) enregistrée dans les bases de données administratives du système de santé. Le principal critère d'évaluation secondaire est la baisse moyenne de la tension artérielle systolique intradialytique, laquelle est définie comme la tension artérielle systolique du patient avant la dialyse moins la tension artérielle systolique minimale pendant la dialyse. Les données anonymisées sur la tension artérielle systolique initiale et la tension artérielle systolique intradialytique des patients ont été colligées à intervalles mensuels dans chaque centre de dialyse. PLAN D'ANALYSE: L'analyse primaire adoptera une approche fondée sur l'intention de traiter. Le principal critère d'évaluation sera analysé au niveau du patient comme le risque relatif de survenue d'un premier événement, estimé à partir d'un modèle de risques de sous-distribution. La corrélation intracentre sera prise en compte à l'aide d'un robuste estimateur sandwich. Dans l'analyse primaire, le temps d'observation des patients prendra fin s'ils présentent le principal critère d'évaluation, s'ils déménagent hors de l'Ontario ou s'ils décèdent d'une cause non cardiovasculaire (qui sera traitée comme un événement à risque concurrentiel). La différence entre les groupes quant à la baisse moyenne de la tension artérielle systolique intradialytique, obtenue pendant les séances de dialyse tout au long de l'essai, sera analysée au niveau du centre avec un modèle linéaire mixte à effets aléatoires non corrigé. STATUT DE L'ESSAI: L'essai MyTEMP couvre la période du 3 avril 2017 au 31 mars 2021. Nous comptons analyser et rendre compte des résultats d'ici 2023, dès que les données mises à jour seront disponibles à l'ICES. ENREGISTREMENT DE L'ESSAI: MyTEMP est enregistré auprès du National Institute of Health des États-Unis sur clincaltrials.gov (NCT02628366).

Therapeutic Hypothermia Reduces Peritoneal Dialysis Induced Myocardial Blood Flow Heterogeneity and Arrhythmia.

Background: Moderate therapeutic hypothermia (TH) is a well-recognized cardio-protective strategy. The instillation of fluid into the peritoneum provides an opportunity to deliver moderate hypothermia as primary prevention against cardiovascular events. We aimed to to investigate both cardiac perfusion consequences (overall blood flow and detailed assessment of perfusion heterogeneity) and subsequently simulate the associated arrhythmic risk for patients undergoing peritoneal dialysis (PD) induced TH. Methods: Patients underwent high resolution myocardial perfusion scanning using high resolution 256 slice CT scanning, at rest and with adenosine stress. The first visit using the patient's usual PD regimen, on the second visit the same regime was utilized but with cooled peritoneal dialysate at 32°C. Myocardial blood flow (MBF) was quantified from generated perfusion maps, reconstructed in 3D. MBF heterogeneity was assessed by fractal dimension (FD) measurement on the 3D left ventricular reconstruction. Arrhythmogenicity was quantified from a sophisticated computational simulation using a multi-scale human 3D ventricle wedge electrophysiological computational model. Results: We studied 7 PD patients, mean age of 60 ± 7 and mean vintage dialysis of 23.6 ± 17.6 months. There were no significant different in overall segmental MBF between normothermic condition (NT) and TH. MBF heterogeneity was significantly decreased (-14%, p = 0.03) at rest and after stress (-14%, p = 0.03) when cooling was applied. Computational simulation showed that TH allowed a normalization of action potential, QT duration and T wave. Conclusion: TH-PD results in moderate hypothermia leading to a reduction in perfusion heterogeneity and simulated risk of non-terminating malignant ventricular arrhythmias.

Hemodialysis Patients Have Impaired Cerebrovascular Reactivity to CO2 Compared to Chronic Kidney Disease Patients and Healthy Controls: A Pilot Study.

INTRODUCTION: Recurrent hemodialysis (HD)-induced ischemia has emerged as a mechanism responsible for cognitive impairment in HD patients. Impairment of cerebrovascular function in HD patients may render the brain vulnerable to HD-induced ischemic injury. Cerebrovascular reactivity to CO2 (CVR) is a noninvasive marker of cerebrovascular function. Whether CVR is impaired in HD patients is unknown. In this study, we compared CVR between healthy participants, HD patients, and chronic kidney disease (CKD) patients not yet requiring dialysis. METHODS: This was a single-center prospective observational study carried out at Kidney Clinical Research Unit in London, Canada. We used carefully controlled hypercapnia to interrogate brain vasomotor control. Transcranial Doppler was combined with 10-mm Hg step changes in CO2 from baseline to hypercapnia (intervention) and back to baseline (recovery) to assess CVR in 8 HD, 10 CKD, and 17 heathy participants. RESULTS: HD patients had lower CVR than CKD or healthy participants during both intervention and recovery (P < 0.0001). There were no differences in CVR between healthy and CKD participants during either intervention (P = 0.88) or recovery (P = 0.99). The impaired CVR in HD patients was independent of CO2-induced changes in blood pressure, heart rate, cardiac output, or dialysis vintage. In the CKD group, CVR was not associated with the estimated glomerular filtration rate. CONCLUSIONS: Our study shows that HD patients have impaired CVR relative to CKD and healthy participants. This renders HD patients vulnerable to ischemic injury during circulatory stress of dialysis and may contribute to the pathogenesis of cognitive impairment.

Exploring the Link Between Hepatic Perfusion and Endotoxemia in Hemodialysis.

INTRODUCTION: The liver receives gut-derived endotoxin via the portal vein, clearing it before it enters systemic circulation. Hemodialysis negatively impacts the perfusion and function of multiple organs systems. Dialysate cooling reduces hemodialysis-induced circulatory stress and protects organs from ischemic injury. This study examined how hemodialysis disrupts liver hemodynamics and function, its effect on endotoxemia, and the potential protective effect of dialysate cooling. METHODS: Fifteen patients were randomized to receive either standard (36.5°C dialysate temperature) or cooled (35.0°C) hemodialysis first in a two-visit crossover trial. We applied computed tomography (CT) liver perfusion imaging to patients before, 3 hours into and after each hemodialysis session. We measured hepatic perfusion and perfusion heterogeneity. Hepatic function was measured by indocyanine green (ICG) clearance. Endotoxin levels in blood throughout dialysis were also measured. RESULTS: During hemodialysis, overall liver perfusion did not significantly change, but portal vein perfusion trended towards increasing (P = 0.14) and perfusion heterogeneity significantly increased (P = 0.038). In addition, ICG clearance decreased significantly during hemodialysis (P = 0.016), and endotoxin levels trended towards increasing during hemodialysis (P = 0.15) and increased significantly after hemodialysis (P = 0.037). Applying dialysate cooling trended towards abrogating these changes but did not reach statistical significance compared to standard hemodialysis. CONCLUSION: Hemodialysis redistributes liver perfusion, attenuates hepatic function, and results in endotoxemia. Higher endotoxin levels in end-stage renal disease (ESRD) patients may result from the combination of decreased hepatic clearance function and increasing fraction of liver perfusion coming from toxin-laden portal vein during hemodialysis. The protective potential of dialysate cooling should be explored further in future research studies.