Dialysate Sodium: Rationale for Evolution over Time

Oligo-anuric individuals receiving hemodialysis (HD) are dependent on the dialysis machine to regulate sodium and water balance. Interest in adjusting the dialysate sodium concentration to promote tolerance of the HD procedure dates back to the early years of dialysis therapy. Evolution of dialysis equipment technologies and clinical characteristics of the dialysis population have prompted clinicians to increase the dialysate sodium concentration over time. Higher dialysate sodium concentrations generally promote hemodynamic stabilization and reduce intradialytic symptoms but often do so at the expense of stimulating thirst and promoting volume expansion. The opposite may be true for lower dialysate sodium concentrations. Observational data suggest that the association between dialysate sodium and outcomes may differ by serum sodium levels, supporting the trend toward individualization of the dialysate sodium prescription. However, lack of randomized controlled clinical trial data, along with operational safety concerns related to individualized dialysate sodium prescriptions, have prevented expert consensus regarding the optimal approach to the dialysate sodium prescription

Dialysate sodium, serum sodium and mortality in maintenance hemodialysis

Abstract Background. Individuals with end-stage kidney disease appear to have stable pre-dialysis serum sodium concentrations over time, with lower values associating with increased mortality. Dialysate sodium concentrations have increased over many years in response to shorter treatments, but the relationship between serum sodium, dialysate sodium and outcomes in chronic hemodialysis patients has not yet been systematically examined. Methods. We studied a cohort of 2272 individuals receiving thrice-weekly hemodialysis treatment. Available data included demographics, laboratory and clinical measures, details of the dialysis prescription and 30-month follow-up. We examined the distribution of serum and dialysate sodium among subjects and compared mortality according to dialysate and serum sodium concentrations using Cox regression models. Results. Dialysate sodium concentration varied within and among dialysis centers. The pre-dialysis serum sodium concentration (mean 136.1 mmol/L) did not differ across dialysate sodium concentrations. There was evidence for effect modification for mortality according to differing serum sodium and dialysate sodium concentrations (P ¼ 0.05). For each 4 mmol/L increment in serum sodium, the hazard ratio for death was 0.72 [95% confidence interval (CI) 0.63-0.81] with lower dialysate sodium compared to 0.86 (95% CI 0.75-0.99) for higher dialysate sodium. Higher dialysate sodium concentration was associated with mortality at higher, but not lower, pre-dialysis serum sodium concentrations. Conclusions. The pre-dialysis serum sodium concentration appears to be unaffected by the dialysate sodium concentration. The relationship between serum and dialysate sodium and mortality appears to be variable. Further research is warranted to determine the biological mechanisms of these associations and to re-examine total body sodium handling in hemodialysis

C-Reactive protein and risk of ESRD: results from the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)

Background: To better understand a potential association of elevated C-reactive protein (CRP) level with progression of chronic kidney disease (CKD), we examined the relationship of CRP level with the development of end-stage renal disease (ESRD) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). Study Design Post hoc analysis of a randomized controlled trial. Setting & Participants: 4,038 patients with type 2 diabetes, CKD, and anemia in TREAT. Predictor: Baseline serum CRP concentrations. Outcomes: The primary outcome was development of ESRD; secondary outcomes included doubling of serum creatinine level, a composite of ESRD/serum creatinine doubling, and a composite of death or ESRD. Measurements: We fit unadjusted and adjusted Cox regression models to test the association of baseline CRP level with time to the development of the outcomes of interest. Results: Mean age of participants was 67 years, 43% were men, and 64% were white. Approximately half (48%) the patients had CRP levels > 3.0 mg/L; 668 patients developed ESRD, and 1,270 developed the composite outcome of death or ESRD. Compared with patients with baseline CRP levels ≤ 3.0 mg/L, those with moderately/markedly elevated CRP levels (≥6.9 mg/L; 24% of patients) had a higher adjusted risk for ESRD (HR, 1.32; 95% CI, 1.07-1.63) and the composite outcome of death or ESRD (HR, 1.41; 95% CI, 1.21-1.64). Although nonsignificant, similar trends were noted in competing-risk models. Limitations: Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Conclusions: Elevated baseline CRP levels are common in type 2 diabetic patients with anemia and CKD and are associated with the future development of ESRD and the composite of death or ESRD

Change in hemoglobin trajectory and darbepoetin dose approaching end-stage renal disease: data from the trial to reduce cardiovascular events with aranesp therapy trial

Background: The pathogenesis of chronic kidney disease associated anemia is multifactorial and includes decreased production of erythropoietin (EPO), iron deficiency, inflammation, and EPO resistance. To better understand the trajectory of these parameters, we described temporal trends in hemoglobin (Hb), ferritin, transferrin saturation, C-reactive protein (CRP), and darbepoetin dosing in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT). Methods: We performed a post hoc analysis of 4,038 participants in TREAT. Mixed effects linear regression models were used to determine the trajectory of parameters of interest prior to end-stage renal disease (ESRD). Likelihood ratio tests were used to determine the overall differences in biomarker values and differences in trajectories between those who did and did not develop ESRD. Results: Hb declined precipitously in the year prior to the development of ESRD (irrespective of treatment assignment), and was on average 1.15 g/dL (95% CI –1.26 to –1.04) lower in those who developed ESRD versus those who did not, at the time of ESRD/end of follow-up. Simultaneously, the mean darbepoetin dose and CRP concentration increased, while serum ferritin and transferrin saturations were >140 μg/L and 20%, respectively. Conclusions: Our analyses provide descriptive insights regarding the temporal changes of Hb, darbepoetin dose, and related parameters as ESRD approaches in participants of TREAT. Hb declined as much as 1–2 years prior to the development of ESRD, without biochemical evidence of iron deficiency. The most precipitous decline occurred in the months immediately prior to ESRD, despite administration of escalating doses of darbepoetin and in parallel with an increase in CRP

Effect of dapagliflozin on cause-specific mortality in patients with heart failure across the spectrum of ejection fraction

Importance: In 2 trials enrolling patients with heart failure (HF) across the spectrum of ejection fraction (EF), dapagliflozin has been shown to reduce the rate of the composite of worsening HF events or death from cardiovascular (CV) causes. Objective: To examine the effects of dapagliflozin on cause-specific CV and non-CV mortality across the spectrum of EF. Design, Setting, and Participants: This was a participant-level, pooled, prespecified secondary analysis of data from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure, or DAPA-HF trial (participant left ventricular EF [LVEF] ≤40%), and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure, or DELIVER trial (participant LVEF >40%), to assess the effects of randomized treatment on cause-specific mortality. The trials assigned adjacent populations of patients with chronic HF, New York Heart Association class II-IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The primary outcome for each study was a composite of worsening HF events (hospitalization or urgent heart failure visits) or CV death. Clinical outcomes, including all deaths, were adjudicated as to cause by clinical end points committees blinded to treatment assignment. Intervention: Dapagliflozin vs placebo. Main Outcomes and Measures: The mode of death in relation to baseline EF was examined, as well as the effect of randomized treatment on cause-specific death in Cox regression models. Relationships with continuous EF were modeled using Poisson regression. Results: Of 11 007 patients in the pooled data set, there were 1628 deaths during follow-up (mean [SD] age, 71.7 [10.3] years; 1139 male [70.0%]). Of those who died, 872 (53.5%) were ascribed to CV deaths, 487 (29.9%) to non-CV deaths, and 269 (16.5%) to undetermined causes. Of CV deaths, 289 (33.1%; this represented 17.8% of total deaths) were due to HF, 441 (50.6%; 27.1% of total deaths) were sudden, 69 (7.9%; 4.2% of total deaths) were due to stroke, 47 (5.4%; 2.9% of total deaths) to myocardial infarction, and 26 (3.0%; 1.6% of total deaths) were due to other CV causes. The proportion of non-CV deaths was higher in those with higher EF. In the pooled population, across the spectrum of EF, treatment with dapagliflozin was associated with lower rates of CV death (hazard ratio [HR], 0.86; 95% CI, 0.75-0.98; P = .02), principally due to lower rates of sudden death (HR, 0.84; 95% CI, 0.70-1.01; P = .07) and HF death (HR, 0.88; 95% CI, 0.70-1.11; P = .30), with little difference in rates of death from stroke or MI. Conclusions and Relevance: In a pooled analysis of patients with HF in the DAPA-HF and DELIVER randomized clinical trials, across the full spectrum of LVEF, dapagliflozin significantly reduced risks of CV death with contributions from lower rates of sudden death and death from progressive HF. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124, NCT0361921

Angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction

Background: In patients with heart failure, chronic kidney disease (CKD) is common and associated with a higher risk of renal events than in patients without CKD. We assessed the renal effects of angiotensin/neprilysin inhibition in patients with heart failure and preserved ejection fraction (HFpEF) enrolled in PARAGON-HF. Methods: In this randomized, double-blind, event-driven trial, we assigned 4,822 patients with HFpEF to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein we present the results of the pre-specified renal composite outcome (time to first occurrence of either: ≥50% reduction in eGFR, end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope. Results: At randomization, eGFR was 63±19 ml/min/1.73m2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio [HR], 0.50; 95%CI, 0.33 to 0.77; P=0.001). The treatment effect on the composite renal endpoint did not differ according to the baseline eGFR (<60 vs ≥ 60 ml/min/1.73 m2 (P-interaction=0.92). The decline in eGFR was less for sacubitril/valsartan compared with valsartan (-1.8 [95%CI, -2.0 to -1.6] vs. -2.4 [95%CI, -2.6 to - 2.2] ml/min/1.73m2/year). Conclusions: In patients with HFpEF, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, compared with valsartan

Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation

Background: Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. Methods and Findings: Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6–15.8, p = 1×10−7) and ME ARDS (OR 8.4, 95% CI 2.9–24.2, p = 9×10−5) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10−4) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. Conclusions: Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients. Please see later in the article for the Editors' Summar

Cardiovascular-kidney-metabolic overlap in heart failure with mildly reduced or preserved ejection fraction a trial-level analysis

No abstract available

Serum uric acid, influence of sacubitril/valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON-HF

Aims: To determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure with preserved ejection fraction (HFpEF), and whether sacubitril/valsartan reduces SUA and SUA‐related therapies. Methods and Results: We analyzed 4795 participants from PARAGON‐HF. We related baseline hyperuricemia (using assay definitions) to the primary outcome (CV death and total HF hospitalization). Between baseline and 4 months, we assessed the association between changes in SUA and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ‐OSS) and other cardiac biomarkers. We simultaneously adjusted for baseline and time‐updated SUA to determine whether lowering SUA was associated with clinical benefit. Average age was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricemia was associated with increased risk for the primary outcome (rate ratio 1.61, 95%CI 1.37, 1.90). The treatment effect of sacubitril/valsartan for the primary endpoint was not significantly modified by hyperuricemia (p‐interaction = 0.14). Sacubitril/valsartan reduced SUA −0.38 mg/dL (95%CI: −0.45, −0.31) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (−0.51 vs. ‐0.32 mg/dL) (p‐interaction = 0.031). Sacubitril/valsartan reduced the odds of initiating SUA‐related treatments by 32% during follow‐up (p &lt; 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ‐OSS and directly associated with high‐sensitivity Troponin T (p &lt; 0.05). Time‐updated SUA was a stronger predictor of adverse outcomes than baseline SUA. Conclusions: SUA independently predicted adverse outcomes in HFpEF. Sacubitril/valsartan reduced SUA and related therapy initiation compared to valsartan. Reducing SUA was associated with improved outcomes

Dapagliflozin in patients with heart failure and deterioration in renal function

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline recommended in the management of heart failure (HF). Although these therapies can be initiated even in patients with comorbid chronic kidney disease, some patients may face deterioration of kidney function over time. Objectives: In this study, the authors sought to examine the safety and efficacy of continuing SGLT2 inhibitors in HF when the estimated glomerular filtration rate (eGFR) falls below thresholds for initiation. Methods: Associations between a deterioration of eGFR to &lt;25 mL/min/1.73 m2, efficacy, and safety outcomes and treatment with dapagliflozin were evaluated in time-updated Cox proportional hazard models in a participant-level pooled analysis of the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. Results: Among 11,007 patients, 347 (3.2%) experienced a deterioration of eGFR to &lt;25 mL/min/1.73 m2 at least once in follow-up. These patients had a higher risk of the primary composite outcome (HR: 1.87; 95% CI: 1.48-2.35; P &lt; 0.001). The risk of the primary outcome was lower with dapagliflozin compared with placebo among patients who did (HR: 0.53; 95% CI: 0.33-0.83) as well as did not (HR: 0.78; 95% CI: 0.72-0.86) experience deterioration of eGFR to &lt;25 mL/min/1.73 m2 (Pinteraction = 0.17). The risk of safety outcomes, including drug discontinuation, was higher among patients with deterioration of eGFR to &lt;25 mL/min/1.73 m2; however, rates remained similar between treatment groups including among those who remained on study drug. Conclusions: Patients with deterioration of eGFR to &lt;25 mL/min/1.73 m2 had elevated risks of cardiovascular outcomes yet appeared to benefit from continuation of dapagliflozin with no excess in safety outcomes between treatment groups. The benefit-to-risk ratio may favor continuation of dapagliflozin treatment in patients with HF experiencing deterioration of kidney function. Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124; and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213