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.

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.

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.

Cognitive Impairment Early After Initiating Maintenance Hemodialysis: A Cross Sectional Study.

Background: Abnormalities in cognitive function are almost universal in patients receiving hemodialysis (HD) and are associated with worse quality of life, impaired decision making, increased healthcare utilization and mortality. While cognitive impairment in the HD population is increasingly recognized, it is unclear how quickly it develops after starting HD. Methods: This was a cross-sectional study of a cohort of low dialysis vintage HD patients (<12 months). We used the validated Cambridge Brain Science (CBS) battery of web-based tests to evaluate cognition compared to age- and sex matched controls across three cognitive domains: verbal processing, reasoning and short-term memory. Results: Forty-nine HD patients were included in this study; 43 completed the full battery of tests. The average scores for HD patients were consistently below the age and sex-matched controls. Fifty-five percent of HD patients had cognitive impairment in verbal skills, 43% in reasoning and 18% in short-term memory. Conclusions: There is a high prevalence of CI evident early after starting HD, with the largest deficits seen in reasoning and verbal processing. These deficits may be attributable to the HD treatment itself. Further studies are needed to characterize the natural history of CI in this patient population and to test interventions aimed at preventing or slowing its progression.

Erratum to: Relapsing Minimal Change Disease Superimposed on Late-Onset p.N215S Fabry Nephropathy.

[This corrects the article DOI: 10.1093/ckj/sfab148.].

Relapsing minimal change disease superimposed on late-onset p.N215S Fabry nephropathy.

We present the case of a 76-year-old man with late-onset Fabry disease caused by the p.N215S missense mutation, with Fabry cardiomyopathy and nephropathy. In this case, the diagnosis of Fabry disease was incidental and followed minimal change disease (MCD) onset, with nephrotic syndrome and acute kidney injury requiring renal replacement therapy. Fabry nephropathy associated with the p.N215S mutation is becoming increasingly recognized among older patients. The importance of electron microscopy is herein highlighted and histological features common to Fabry nephropathy and MCD are discussed, along with the challenges associated with the diagnosis and clinical management.

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.

Pruritus: Is there a grain of salty truth?

Hemodialysis patients characteristically suffer from a range of unpleasant symptoms. Uremic pruritus effects close to half of the chronic kidney disease population, reducing quality of life and associated with increased mortality. Its pathophysiology though is poorly understood; currently deployed therapeutic approaches are ineffective. Excessive levels of skin and soft tissue sodium accumulate in dialysis patients, producing a range of biological consequences, including inflammation. We report an index case of a hemodialysis patient with debilitating pruritus and extreme levels of tissue sodium, measured with Sodium-23 magnetic resonance imaging. Both the tissue sodium loading and pruritus responded fully to initiation of expanded hemodialysis therapy with a recently introduced medium cutoff dialysis membrane-based dialyzer.

Tissue sodium concentrations in chronic kidney disease and dialysis patients by lower leg sodium-23 magnetic resonance imaging.

BACKGROUND: Sodium-23 magnetic resonance imaging (23Na MRI) allows direct measurement of tissue sodium concentrations. Current knowledge of skin, muscle and bone sodium concentrations in chronic kidney disease (CKD) and renal replacement therapy patients is limited. In this study we measured the tissue sodium concentrations in CKD, hemodialysis (HD) and peritoneal dialysis (PD) patients with 23Na MRI of the lower leg and explored their correlations with established clinical biomarkers. METHODS: Ten healthy controls, 12 CKD Stages 3-5, 13 HD and 10 PD patients underwent proton and 23Na MRI of the leg. The skin, soleus and tibia were segmented manually and tissue sodium concentrations were measured. Plasma and serum samples were collected from each subject and analyzed for routine clinical biomarkers. Tissue sodium concentrations were compared between groups and correlations with blood-based biomarkers were explored. RESULTS: Tissue sodium concentrations in the skin, soleus and tibia were higher in HD and PD patients compared with controls. Serum albumin showed a strong, negative correlation with soleus sodium concentrations in HD patients (r = -0.81, P < 0.01). Estimated glomerular filtration rate showed a negative correlation with tissue sodium concentrations (soleus: r = -0.58, P < 0.01; tibia: r = -0.53, P = 0.01) in merged control-CKD patients. Hemoglobin was negatively correlated with tissue sodium concentrations in CKD (soleus: r = -0.65, P = 0.02; tibia: r = -0.73, P < 0.01) and HD (skin: r = -0.60, P = 0.04; tibia: r = -0.76, P < 0.01). CONCLUSION: Tissue sodium concentrations, measured by 23Na MRI, increase in HD and PD patients and may be associated with adverse metabolic effects in CKD and dialysis.

Intradialytic exercise preconditioning: an exploratory study on the effect on myocardial stunning.

BACKGROUND: Exercise preconditioning provides immediate protection against cardiac ischemia in clinical/preclinical studies in subjects without chronic kidney disease. In individuals requiring renal replacement therapy, hemodialysis (HD) results in significant circulatory stress, causing acute ischemia with resultant recurrent and cumulative cardiac injury (myocardial stunning). Intradialytic exercise (IDE) has been utilized to improve functional status in individuals receiving HD. The objective of this study was to explore the role of IDE as a preconditioning intervention and assess its effect on HD-induced myocardial stunning. METHODS: We performed a single-center cross-sectional exploratory study in adults on chronic HD participating in a clinical IDE program. HD-induced cardiac stunning was evaluated over two HD sessions within the same week: a control visit (no exercise) and an exposure visit (usual intradialytic cycling). Echocardiography was performed at the same three time points for each visit. Longitudinal strain values for 12 left ventricular segments were generated using speckle-tracking software to assess the presence of HD-induced regional wall motion abnormalities (RWMAs), defined as a ≥20% reduction in strain; two or more RWMAs represent myocardial stunning. RESULTS: A total of 19 patients were analyzed (mean age 57.2 ± 11.8 years, median dialysis vintage 3.8 years). The mean number of RWMAs during the control visit was 4.5 ± 2.6, falling to 3.6 ± 2.7 when incorporating IDE (a reduction of -0.95 ± 2.9; P = 0.17). At peak HD stress, the mean number of RWMAs was 5.8 ± 2.7 in the control visit versus 4.0 ± 1.8 during the exposure visit (a reduction of -1.8 ± 2.8; P = 0.01). CONCLUSION: We demonstrated for the first time that IDE is associated with a significant reduction in HD-induced acute cardiac injury.