Oral Sodium Bicarbonate and Bone Turnover in CKD: A Secondary Analysis of the BASE Pilot Trial.

SIGNIFICANCE STATEMENT: In CKD, metabolic acidosis is commonly treated with alkali in the hope that it will improve bone health. In a post hoc analysis of the Bicarbonate Administration to Stabilize eGFR Pilot Trial, we investigated whether sodium bicarbonate affects serum levels of bone turnover markers and other hormones related to bone health in individuals with CKD who have normal to slightly reduced total CO2 (20-28 mEq/L). Sodium bicarbonate increased serum levels of α-klotho but had no significant effect on other bone health markers, including intact fibroblast growth factor-23 (iFGF-23), intact parathyroid hormone (iPTH), and bone-specific alkaline phosphatase (B-SAP). Further study is needed to determine the effect of bicarbonate administration on clinical aspects of bone health. BACKGROUND: Treatment with alkali has been hypothesized to improve bone health in CKD by mitigating adverse effects of acid on bone mineral. We investigated the effect of treatment with sodium bicarbonate on bone turnover markers and other factors related to bone metabolism in CKD. METHODS: This is a post hoc analysis of the Bicarbonate Administration to Stabilize eGFR Pilot Trial in which 194 individuals with CKD and serum total CO2 20-28 mEq/L were randomly assigned to placebo or one of two doses of sodium bicarbonate (0.5 or 0.8 mEq/kg lean body weight per day) for 28 weeks. The following serum measurements were performed at baseline, week 12, and week 28: B-SAP, c-telopeptide, procollagen type I intact N-terminal propeptide, iPTH, iFGF-23, soluble klotho, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and tartrate-resistant acid phosphatase 5b. The difference (sodium bicarbonate versus placebo) in mean change of each bone biomarker from baseline was determined using linear mixed models. RESULTS: One hundred sixty-eight participants submitted samples for post hoc investigations. Mean eGFR was 37±10 ml/min per 1.73 m2 and mean total CO2 was 24±3 mEq/L at baseline. Sodium bicarbonate induced a dose-dependent increase in soluble klotho levels compared with placebo. There was no significant effect of treatment with either dose of sodium bicarbonate on any of the other bone biomarkers, including iFGF-23, iPTH, and B-SAP. Effects on bone biomarkers were similar in those with baseline serum total CO2 <24 mEq/L compared with those with total CO2 ≥24 mEq/L. CONCLUSIONS: In this pilot trial of individuals with CKD and total CO2 20-28 mEq/L, sodium bicarbonate treatment increased serum klotho levels but did not affect other bone health markers over 28 weeks. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT02521181.

Iron deficiency in pulmonary vascular disease: pathophysiological and clinical implications.

AIMS: Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear. METHODS AND RESULTS: Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P > 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) <21% did. Compared to those with TSAT ≥21%, patients with TSAT <21% demonstrated lower peakVO2 [absolute difference: -1.89 (-2.73 to -1.04) mL/kg/min], 6-min walk test distance [absolute difference: -34 (-51 to -17) m], and SF-36 physical component score [absolute difference: -2.5 (-1.3 to -3.8)] after adjusting for age, sex, and hemoglobin (all P < 0.001). Patients with a TSAT <21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation <21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13-2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide. CONCLUSION: The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT <21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes.

The Predialysis Serum Sodium Level Modifies the Effect of Hemodialysis Frequency on Left-Ventricular Mass: The Frequent Hemodialysis Network Trials.

INTRODUCTION: The Frequent Hemodialysis Network (FHN) Daily and Nocturnal trials aimed to compare the effects of hemodialysis (HD) given 6 versus 3 times per week. More frequent in-center HD significantly reduced left-ventricular mass (LVM), with more pronounced effects in patients with low urine volumes. In this study, we aimed to explore another potential effect modifier: the predialysis serum sodium (SNa) and related proxies of plasma tonicity. METHODS: Using data from the FHN Daily and Nocturnal Trials, we compared the effects of frequent HD on LVM among patients stratified by SNa, dialysate-to-predialysis serum-sodium gradient (GNa), systolic and diastolic blood pressure, time-integrated sodium-adjusted fluid load (TIFL), and extracellular fluid volume estimated by bioelectrical impedance analysis. RESULTS: In 197 enrolled subjects in the FHN Daily Trial, the treatment effect of frequent HD on ∆LVM was modified by SNa. When the FHN Daily Trial participants are divided into lower and higher predialysis SNa groups (less and greater than 138 mEq/L), the LVM reduction in the lower group was substantially higher (-28.0 [95% CI -40.5 to -15.4] g) than in the higher predialysis SNa group (-2.0 [95% CI -15.5 to 11.5] g). Accounting for GNa, TIFL also showed more pronounced effects among patients with higher GNa or higher TIFL. Results in the Nocturnal Trial were similar in direction and magnitude but did not reach statistical significance. DISCUSSION/CONCLUSION: In the FHN Daily Trial, the favorable effects of frequent HD on left-ventricular hypertrophy were more pronounced among patients with lower predialysis SNa and higher GNa and TIFL. Whether these metrics can be used to identify patients most likely to benefit from frequent HD or other dialytic or nondialytic interventions remains to be determined. Prospective, adequately powered studies studying the effect of GNa reduction on mortality and hospitalization are needed.

A Randomized Trial Comparing the Safety, Adherence, and Pharmacodynamics Profiles of Two Doses of Sodium Bicarbonate in CKD: the BASE Pilot Trial.

BACKGROUND: Oral sodium bicarbonate (NaHCO3) may preserve kidney function in CKD, even if initiated when serum bicarbonate concentration is normal. Adequately powered trials testing this hypothesis have not been conducted, partly because the best dose for testing is unknown. METHODS: This multicenter pilot trial assessed the safety, tolerability, adherence, and pharmacodynamics of two doses of NaHCO3 over 28 weeks in adults with eGFR 20-44 or 45-59 ml/min per 1.73 m2 with urinary albumin/creatinine (ACR) ≥50 mg/g and serum bicarbonate 20-28 meq/L. We randomly assigned 194 participants from ten clinical sites to receive higher-dose (HD-NaHCO3; 0.8 meq/kg of lean body wt per day; n=90) or lower-dose (LD-NaHCO3; 0.5 meq/kg of lean body wt per day; n=52) NaHCO3 or matching placebo (n=52). The dose was adjusted depending on side effects. The prescribed dose at week 28 was the primary outcome; a dose was considered acceptable for a full-scale trial if ≥67% of participants were on full-dose and ≥80% were on ≥25% of the per-protocol dose. RESULTS: Mean±SD baseline eGFR was 36±9 ml/min per 1.73 m2, serum bicarbonate was 24±2 meq/L, and median (IQR) ACR was 181 (25-745) mg/g. Both doses were well tolerated without significant changes in BP, weight, or serum potassium. The proportions of adverse events and hospitalizations were similar across the groups. Consequently, 87% in HD-NaHCO3, 96% in LD-NaHCO3, and 87% in placebo were on full dose at week 28; and 91% in HD-NaHCO3, 98% in LD-NaHCO3, and 92% in placebo were on ≥25% of the per-protocol dose. Mean urinary ammonium excretion was 25% lower and serum bicarbonate concentration was 1.3 meq/L higher in HD-NaHCO3 compared with LD-NaHCO3 at week 28. However, mean ACR increased by 12% in the lower-dose group and 30% in the higher-dose group. CONCLUSIONS: Both NaHCO3 doses were well tolerated over 28 weeks with no significant difference in adverse events or hospitalization compared with placebo. The higher dose lowered urinary ammonium excretion and increased serum bicarbonate more than the lower dose but was associated with a greater increase in ACR. The higher 0.8 meq/kg of lean body wt per day dose of NaHCO3 may be a reasonable choice for future trials.

A Simple Equation to Estimate Urinary Flow Rate Using Urine Creatinine.

BACKGROUND: Accurate assessment of urine flow remains challenging in both inpatient and outpatient settings. We hypothesized we could derive an equation that would accurately estimate urine flow rate (eV) through derivation from other existing equations commonly used in nephrology clinical practice. METHODS: The eV equation was derived using the Cockcroft-Gault and the measured creatinine clearance (CrCl = UCrV/PCr) equations. Within the African American Study of Kidney Disease and Hypertension (AASK; n = 570) and COMBINE (n = 133) clinical trials, we identified participants with concordant estimated and measured creatinine excretion rates to define a subset with highly accurate 24-h urine collections, to assure a reliable gold standard. We then compared eV to measured 24-h urine flow rates in these trials. RESULTS: In AASK, we found a high correlation between eV and measured urine flow rate (V; r = 0.91, p < 0.001); however, Bland-Altman plots showed that eV was 9.5 mL/h lower than V, on average. Thus, we added a correction factor to the eV equation and externally validated the new equation in COMBINE. eV and V were again highly correlated (r = 0.91, p < 0.001), and bias was improved (mean difference 5.3 mL/h). Overall, 80% of individuals had eV that was within 20% of V. CONCLUSIONS: A simple equation using urine creatinine, demographics, and body weight can accurately predict urine flow rate and may have clinical utility in situations where it is difficult to accurately measure the urine flow rate.

Effects of Nicotinamide and Lanthanum Carbonate on Serum Phosphate and Fibroblast Growth Factor-23 in CKD: The COMBINE Trial.

BACKGROUND: Higher serum phosphate and fibroblast growth factor-23 (FGF23) levels may be modifiable to prevent cardiovascular disease in CKD. Short-term studies have reported modest efficacy in phosphate and FGF23 reduction with intestinal phosphate binders in CKD. METHODS: To investigate effects of lanthanum carbonate (LC; a phosphate binder) and/or nicotinamide (NAM; an inhibitor of active intestinal phosphate transport) on serum phosphate and FGF23 in stage 3b/4 CKD, we conducted a randomized trial among individuals with eGFR 20-45 ml/min per 1.73 m2 to NAM (750 mg twice daily) plus LC (1000 mg thrice daily), NAM plus LC placebo, LC plus NAM placebo, or double placebo for 12 months. Dual primary end points were change from baseline in serum phosphate and intact FGF23 concentrations. RESULTS: Mean eGFR for the 205 participants was 32ml/min per 1.73 m2. At baseline, serum phosphate was 3.7 mg/dl and median FGF23 was 99 pg/ml (10th, 90th percentiles: 59, 205). Mean rates of change in phosphate increased slightly over 12 months in all groups and did not differ significantly across arms. Similarly, percent changes in FGF23 per 12 months increased for all arms except LC plus placebo, and did not differ significantly across arms. Gastrointestinal symptoms limited adherence. Adverse events rates were similar across arms. CONCLUSIONS: LC and/or NAM treatment did not significantly lower serum phosphate or FGF23 in stage 3b/4 CKD over 12 months. Although these agents appeared safe, intestinal symptoms limited adherence. Reducing phosphate and FGF23 in nondialysis CKD will require new approaches.

The effect of increased frequency of hemodialysis on vitamin C concentrations: an ancillary study of the randomized Frequent Hemodialysis Network (FHN) daily trial.

BACKGROUND: Reports on vitamin C in HD patients have shown effects of vitamin C deficiency in association with scurvy symptoms. Dialyzability of water soluble vitamins is high, and substantial losses in those who are dialyzed more frequently were hypothesized. The randomized FHN Daily Trial compared the effects of in-center HD six versus three times per week. We studied baseline correlations between vitamin C and potentially associated parameters, and the effect of more frequent HD on circulating vitamin C concentrations. METHODS: We studied vitamin C levels at baseline and months, 3, 5 and 11. Patients enrolled between 2007 and 2009 into the randomized FHN Daily trial in the East Coast consortium were approached for participation. Predialysis plasma samples were processed with metaphosphoric acid and frozen at - 70 °C for measurement with HPLC. Regression models between baseline log-transformed vitamin C and hemoglobin, CRP, eKt/V, ePCR and PTH, and a linear mixed-effects model to estimate the effect size of more frequent HD on plasma vitamin C, were constructed. RESULTS: We studied 44 subjects enrolled in the FHN Daily trial (50 ± 12 years, 36% female, 29% Hispanics and 64% blacks, 60% anuric). Vitamin C correlated significantly with predialysis hemoglobin (r = 0.3; P = 0.03) and PTH (r = - 0.3, P = 0.04), respectively. Vitamin C did not significantly differ at baseline (6×/week, 25.8 ± 25.9 versus 3×/week, 32.6 ± 39.4 µmol/L) and no significant treatment effect on plasma vitamin C concentrations was found [- 26.2 (95%CI -57.5 to 5.1) µmol/L at Month 4 and - 2.5 (95%CI -15.6 to 10.6) µmol/L at Month 12. CONCLUSIONS: Based on data from this large randomized-controlled trial no significant effect of the intervention on circulating plasma vitamin C concentrations was found, allaying the concerns that more frequent HD would affect the concentrations of water-soluble vitamins and adversely affect patient's well-being. Correlations between vitamin C and hemoglobin and PTH support the importance of vitamin C for normal bone and mineral metabolism, and anemia management.

Intimal Hyperplasia, Stenosis, and Arteriovenous Fistula Maturation Failure in the Hemodialysis Fistula Maturation Study.

Intimal hyperplasia and stenosis are often cited as causes of arteriovenous fistula maturation failure, but definitive evidence is lacking. We examined the associations among preexisting venous intimal hyperplasia, fistula venous stenosis after creation, and clinical maturation failure. The Hemodialysis Fistula Maturation Study prospectively observed 602 men and women through arteriovenous fistula creation surgery and their postoperative course. A segment of the vein used to create the fistula was collected intraoperatively for histomorphometric examination. On ultrasounds performed 1 day and 2 and 6 weeks after fistula creation, we assessed fistula venous stenosis using pre-specified criteria on the basis of ratios of luminal diameters and peak blood flow velocities at certain locations along the vessel. We determined fistula clinical maturation using criteria for usability during dialysis. Preexisting venous intimal hyperplasia, expressed per 10% increase in a hyperplasia index (range of 0%-100%), modestly associated with lower fistula blood flow rate (relative change, -2.5%; 95% confidence interval [95% CI], -4.6% to -0.4%; P=0.02) at 6 weeks but did not significantly associate with stenosis (odds ratio [OR], 1.07; 95% CI, 1.00 to 1.16; P=0.07) at 6 weeks or failure to mature clinically without procedural assistance (OR, 1.07; 95% CI, 0.99 to 1.15; P=0.07). Fistula venous stenosis at 6 weeks associated with maturation failure (OR, 1.98; 95% CI, 1.25 to 3.12; P=0.004) after controlling for case mix factors, dialysis status, and fistula location. These findings suggest that postoperative fistula venous stenosis associates with fistula maturation failure. Preoperative venous hyperplasia may associate with maturation failure but if so, only modestly.

Limited reduction in uremic solute concentrations with increased dialysis frequency and time in the Frequent Hemodialysis Network Daily Trial.

The Frequent Hemodialysis Network Daily Trial compared conventional three-times weekly treatment to more frequent treatment with a longer weekly treatment time in patients receiving in-center hemodialysis. Evaluation at one year showed favorable effects of more intensive treatment on left ventricular mass, blood pressure, and phosphate control, but modest or no effects on physical or cognitive performance. The current study compared plasma concentrations of uremic solutes in stored samples from 53 trial patients who received three-times weekly in-center hemodialysis for an average weekly time of 10.9 hours and 30 trial patients who received six-times weekly in-center hemodialysis for an average of 14.6 hours. Metabolomic analysis revealed that increased treatment frequency and time resulted in an average reduction of only 15 percent in the levels of 107 uremic solutes. Quantitative assays confirmed that increased treatment did not significantly reduce levels of the putative uremic toxins p-cresol sulfate or indoxyl sulfate. Kinetic modeling suggested that our ability to lower solute concentrations by increasing hemodialysis frequency and duration may be limited by the presence of non-dialytic solute clearances and/or changes in solute production. Thus, failure to achieve larger reductions in uremic solute concentrations may account, in part, for the limited benefits observed with increasing frequency and weekly treatment time in Frequent Hemodialysis Daily Trial participants.

Patients receiving frequent hemodialysis have better health-related quality of life compared to patients receiving conventional hemodialysis.

Most patients with end-stage kidney disease value their health-related quality of life (HRQoL) and want to know how it will be affected by their dialysis modality. We extended the findings of two prior clinical trial reports to estimate the effects of frequent compared to conventional hemodialysis on additional measures of HRQoL. The Daily Trial randomly assigned 245 patients to receive frequent (six times per week) or conventional (three times per week) in-center hemodialysis. The Nocturnal Trial randomly assigned 87 patients to receive frequent nocturnal (six times per week) or conventional (three times per week) home hemodialysis. All patients were on conventional hemodialysis prior to randomization, with an average feeling thermometer score of 70 to 75 (a visual analog scale from 0 to 100 where 100 is perfect health), an average general health scale score of 40 to 47 (a score from 0 to 100 where 100 is perfect health), and an average dialysis session recovery time of 2 to 3 hours. Outcomes are reported as the between-treatment group differences in one-year change in HRQoL measures and analyzed using linear mixed effects models. After one year in the Daily Trial, patients assigned to frequent in-center hemodialysis reported a higher feeling thermometer score, better general health, and a shorter recovery time after a dialysis session compared to standard thrice-weekly dialysis. After one year in the Nocturnal Trial, patients assigned to frequent home hemodialysis also reported a shorter recovery time after a dialysis session, but no statistical difference in their feeling thermometer or general health scores compared to standard home dialysis schedules. Thus, patients receiving day or nocturnal hemodialysis on average recovered approximately one hour earlier from a frequent compared to conventional hemodialysis session. Patients treated in an in-center dialysis facility reported better HRQoL with frequent compared to conventional hemodialysis.

Long-Term Effects of Frequent In-Center Hemodialysis.

The Frequent Hemodialysis Network Daily Trial randomized 245 patients to receive six (frequent) or three (conventional) in-center hemodialysis sessions per week for 12 months. As reported previously, frequent in-center hemodialysis yielded favorable effects on the coprimary composite outcomes of death or change in left ventricular mass and death or change in self-reported physical health. Here, we determined the long-term effects of the 12-month frequent in-center hemodialysis intervention. We determined the vital status of patients over a median of 3.6 years (10%-90% range, 1.5-5.3 years) after randomization. Using an intention to treat analysis, we compared the mortality hazard in randomized groups. In a subset of patients from both groups, we reassessed left ventricular mass and self-reported physical health a year or more after completion of the intervention; 20 of 125 patients (16%) randomized to frequent hemodialysis died during the combined trial and post-trial observation periods in contrast to 34 of 120 patients (28%) randomized to conventional hemodialysis. The relative mortality hazard for frequent versus conventional hemodialysis was 0.54 (95% confidence interval, 0.31 to 0.93); with censoring of time after kidney transplantation, the relative hazard was 0.56 (95% confidence interval, 0.32 to 0.99). Bayesian analysis suggested a relatively high probability of clinically significant benefit and a very low probability of harm with frequent hemodialysis. In conclusion, a 12-month frequent in-center hemodialysis intervention significantly reduced long-term mortality, suggesting that frequent hemodialysis may benefit selected patients with ESRD.

Multiple preoperative and intraoperative factors predict early fistula thrombosis in the Hemodialysis Fistula Maturation Study.

OBJECTIVE: Early thrombosis (ET) contributes to autogenous arteriovenous fistula (AVF) failure. We studied patients undergoing AVF placement in the Hemodialysis Fistula Maturation Study, a prospective, observational cohort study, using a nested case-control analysis to identify preoperative and intraoperative predictors of ET. METHODS: ET cases were compared with controls, who were matched for gender, age, diabetes, dialysis status, and surgeon fistula volume. ET was defined as thrombosis diagnosed by physical examination or ultrasound within 18 days of AVF creation. Conditional logistic regression models were fit to identify risk factors for ET. RESULTS: Thirty-two ET cases (5.3%) occurred among 602 study participants; 198 controls were matched. ET was associated with female gender (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.19-6.38; P = .018), fistula location (forearm vs upper arm; OR, 2.76; 95% CI, 1.05-7.23; P = .039), feeding artery (radial vs brachial; OR, 2.64; 95% CI, 1.03-6.77; P = .043) and arterial diameter (OR, 1.52; 95% CI, 1.02-2.26; P = .039, per mm smaller). The draining vein diameter was nonlinearly associated with ET, with highest risk in 2- to 3-mm veins. Surprisingly, ET risk was lower in diabetics (OR, 0.19; 95% CI, 0.07-0.47; P = .0004), lower with less nitroglycerin-mediated brachial artery dilation (OR, 0.42; 95% CI, 0.20-1.92; P = .029 for each 10% lower) and higher with lower carotid-femoral pulse wave velocity (OR, 1.49; 95% CI, 1.02-2.20; P = .041, for each m/s lower). Intraoperative protamine use was associated with a higher ET risk (OR, 3.26; 95% CI, 1.28-∞; P = .038). Surgeon's intraoperative perceptions were associated with ET: surgeons' greater concern about maturation success (likely, marginal, unlikely) was associated with higher thrombosis risk (OR, 8.09; 95% CI, 4.03-∞; P < .0001, per category change), as were absence vs presence of intraoperative thrill (OR, 21.0; 95% CI, 5.07-∞; P = .0001) and surgeons' reported frustration during surgery (OR, 6.85; 95% CI, 2.70-∞; P = .0004). Decreased extent of intraoperative thrill (proximal, mid or distal third of the forearm or upper arm, based on AVF placement) was also associated with ET (OR, 2.91; 95% CI, 1.31-∞; P = .007, per diminished level). Oral antithrombotic medication use was not significantly associated with ET. CONCLUSIONS: ET was found to be associated with female gender, forearm AVF, smaller arterial size, draining vein diameter of 2 to 3 mm, and protamine use. Paradoxically, diabetes and stiff, noncompliant feeding arteries were associated with a lower frequency of ET. Absent or attenuated intraoperative thrill, and both surgeon frustration and concern about successful maturation during surgery, were correlated strongly with ET.

Access-related hand ischemia and the Hemodialysis Fistula Maturation Study.

OBJECTIVE: Access-related hand ischemia (ARHI) is a major complication after hemodialysis access construction. This study was designed to prospectively describe its incidence, predictors, interventions, and associated access maturation. METHODS: The Hemodialysis Fistula Maturation Study is a multicenter prospective cohort study designed to identify predictors of autogenous arteriovenous access (arteriovenous fistula [AVF]) maturation. Symptoms and interventions for ARHI were documented, and participants who received interventions for ARHI were compared with other participants using a nested case-control design. Associations of ARHI with clinical, ultrasound, vascular function, and vein histologic variables were each individually evaluated using conditional logistic regression; the association with maturation was assessed by relative risk, Pearson χ(2) test, and multiple logistic regression. RESULTS: The study cohort included 602 participants with median follow-up of 2.1 years (10th-90th percentiles, 0.7-3.5 years). Mean age was 55.1 ± 13.4 (standard deviation) years; the majority were male (70%), white (47%), diabetic (59%), smokers (55%), and on dialysis (64%) and underwent an upper arm AVF (76%). Symptoms of ARHI occurred in 45 (7%) participants, and intervention was required in 26 (4%). Interventions included distal revascularization with interval ligation (13), ligation (7), banding (4), revision using distal inflow (1), and proximalization of arterial inflow (1). Interventions were performed ≤7 days after AVF creation in 4 participants (15%), between 8 and 30 days in 6 (23%), and >30 days in 16 (63%). Female gender (odds ratio, 3.17; 95% confidence interval, 1.27-7.91; P = .013), diabetes (13.62 [1.81-102.4]; P = .011), coronary artery disease (2.60 [1.03-6.58]; P = .044), higher preoperative venous capacitance (per %/10 mm Hg, 2.76 [1.07-6.52]; P = .021), and maximum venous outflow slope (per [mL/100 mL/min]/10 mm Hg, 1.13 [1.03-1.25]; P = .011) were significantly associated with interventions; a lower carotid-femoral pulse wave velocity and the outflow vein diameter in the early postoperative period (days 0-3) approached significance (P < .10). Intervention for ARHI was not associated with AVF maturation failure (unadjusted risk ratio, 1.18 [0.69-2.04], P = .56; adjusted odds ratio, 0.97 [0.41-2.31], P = .95). CONCLUSIONS: Remedial intervention for ARHI after AVF construction is uncommon. Diabetes, female gender, capacitant outflow veins, and coronary artery disease are all associated with an increased risk of intervention. These higher risk patients should be counseled preoperatively, their operative plans should be designed to reduce the risk of hand ischemia, and they should be observed closely.

The effect of frequent hemodialysis on self-reported sleep quality: Frequent Hemodialysis Network Trials.

BACKGROUND: Many patients who receive maintenance hemodialysis experience poor sleep. Uncontrolled studies suggest frequent hemodialysis improves sleep quality, which is a strong motivation for some patients to undertake the treatment. We studied the effects of frequent in-center ('daily') and nocturnal home hemodialysis on self-reported sleep quality in two randomized trials. METHODS: Participants were randomly assigned to frequent (six times per week) or conventional (three times per week) hemodialysis in the Frequent Hemodialysis Network Daily (n = 245) and Nocturnal (n = 87) Trials. We used the Medical Outcomes Study Sleep Problems Index II (SPI II), a validated and reliable instrument in patients with end-stage renal disease, to measure self-reported sleep quality. The SPI II is scored from 0-100, with a higher value indicating poorer quality of sleep. A mean relative decline in SPI II would suggest improved sleep quality. The primary sleep outcome was the change in the SPI II score over 12 months. RESULTS: In the Daily Trial, after adjustment for baseline SPI II, subjects randomized to frequent as compared with conventional in-center hemodialysis experienced a 4.2 [95% confidence interval (CI) 0.4-8.0] point adjusted mean relative decline in SPI II at 4 months and a 2.6 (95% CI -2.3-7.5) point adjusted mean relative decline at 12 months. In the Nocturnal Trial, subjects randomized to frequent nocturnal as compared with conventional home hemodialysis experienced 2.9 (95% CI -3.4-9.3) and 4.5 (95% CI -3.2-12.2) point mean relative declines at Months 4 and 12, respectively. CONCLUSIONS: Although a possible benefit of frequent in-center hemodialysis was observed at 4 months, neither frequent in-center hemodialysis nor home nocturnal hemodialysis demonstrated significant improvements in self-reported sleep quality compared with conventional hemodialysis at 12 months.

T-Wave Alternans, Heart Rate Turbulence, and Ventricular Ectopy in Standard versus Daily Hemodialysis: Results from the FHN Daily Trial.

BACKGROUND: Hemodialysis (HD) patients are at high risk of sudden cardiac death (SCD). HD 6-times/week (6x/wk) may reduce SCD risk compared to usual 3-times/week HD (3x/wk) by mechanisms unknown. T-wave alternans (TWA), heart rate turbulence (HRT), and ventricular ectopy (VE) are elevated in HD patients, but their response to 6x/wk HD has not been assessed. METHODS: Baseline and 1-year Holter recordings were analyzed from enrollees in the Frequent Hemodialysis Network Daily Trial, a randomized trial comparing 3x/wk to 6x/wk in 245 chronic HD patients. TWA, HRT, and VE were assessed using MARS software. RESULTS: Sixty-eight patients (34 with 6x/wk) had complete baseline and 1-year Holter recordings. Mean age was 50 ± 13 years and 38% were female. Maximum TWA in the 3x/wk and 6x/wk groups were 52.4 µV at baseline and 51.2 µV at 1-year versus 54.0 and 49.9 µV, respectively (P = 0.28). The proportion of abnormal HRT (scores of 1 or 2) in the 3x/wk group decreased from 65% to 56% at 1-year versus 53% to 53% in the 6x/wk group (P = 0.58). Mean %VE changed from 1.6% to 2.9% in the 3x/wk group from baseline to 1-year and from 2.1% to 3.7% in the 6x/wk group (P = 0.85). CONCLUSIONS: There were no significant differences in HRT or VE at 1-year in chronic HD patients randomized to 6x/wk versus 3x/wk and a trend in TWA reduction. Additional studies are needed to evaluate the impact and mechanisms of SCD in HD.

The Effect of Increased Frequency of Hemodialysis on Volume-Related Outcomes: A Secondary Analysis of the Frequent Hemodialysis Network Trials.

In previous reports of the Frequent Hemodialysis Network trials, frequent hemodialysis (HD) reduced extracellular fluid (ECF) and left ventricular mass (LVM), with more pronounced effects observed among patients with low urine volume (UVol). We analyzed the effect of frequent HD on interdialytic weight gain (IDWG) and a time-integrated estimate of ECF load (TIFL). We also explored whether volume and sodium loading contributed to the change in LVM over the study period. Treatment effects on volume parameters were analyzed for modification by UVol and the dialysate-to-serum sodium gradient. Predictors of change in LVM were determined using linear regression. Frequent HD reduced IDWG and TIFL in the Daily Trial. Among patients with UVol <100 ml/day, reduction in TIFL was associated with LVM reduction. This suggests that achievement of better volume control could attenuate changes in LVM associated with mortality and cardiovascular morbidity. TIFL may prove more useful than IDWG alone in guiding HD practice. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=441966.

Long-term Effects of Frequent Nocturnal Hemodialysis on Mortality: The Frequent Hemodialysis Network (FHN) Nocturnal Trial.

BACKGROUND: Few data are available regarding the long-term mortality rate for patients receiving nocturnal home hemodialysis. STUDY DESIGN: Posttrial observational study. SETTING & PARTICIPANTS: Frequent Hemodialysis Network (FHN) Nocturnal Trial participants who consented to extended follow-up. INTERVENTION: The FHN Nocturnal Trial randomly assigned 87 individuals to 6-times-weekly home nocturnal hemodialysis or 3-times-weekly hemodialysis for 1 year. Patients were enrolled starting in March 2006 and follow-up was completed by May 2010. After the 1-year trial concluded, FHN Nocturnal participants were free to modify their hemodialysis prescription. OUTCOMES & MEASUREMENTS: We obtained dates of death and kidney transplantation through July 2011 using linkage to the US Renal Data System and queries of study centers. We used log-rank tests and Cox regression to relate mortality to the initial randomization assignment. RESULTS: Median follow-up for the trial and posttrial observational period was 3.7 years. In the nocturnal arm, there were 2 deaths during the 12-month trial period and an additional 12 deaths during the extended follow-up. In the conventional arm, the numbers of deaths were 1 and 4, respectively. In the nocturnal dialysis group, the overall mortality HR was 3.88 (95% CI, 1.27-11.79; P=0.01). Using as-treated analysis with a 12-month running treatment average, the HR for mortality was 3.06 (95% CI, 1.11-8.43; P=0.03). Six-month running treatment data analysis showed an HR of 1.12 (95% CI, 0.44-3.22; P=0.7). LIMITATIONS: These results should be interpreted cautiously due to a surprisingly low (0.03 deaths/patient-year) mortality rate for individuals randomly assigned to conventional home hemodialysis, low statistical power for the mortality comparison due to the small sample size, and the high rate of hemodialysis prescription changes. CONCLUSIONS: Patients randomly assigned to nocturnal hemodialysis had a higher mortality rate than those randomly assigned to conventional dialysis. The implications of this result require further investigation.

Non-Linear Heart Rate Variability Indices in the Frequent Hemodialysis Network Trials of Chronic Hemodialysis Patients.

BACKGROUND: Non-linear heart rate variability (HRV) indices were hypothesized to correlate with cardiac function, fluid overload and physical performance in hemodialysis patients. METHODS: Twenty-four-hour Holter electrocardiograms were recorded in patients enrolled in the Frequent Hemodialysis Network (FHN) Daily Dialysis Trial. Correlations between non-linear HRV indices and left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), extracellular volume (ECV)/total body water (TBW) ratio, the SF-36 Physical Health Composite (PHC) and Physical Functioning (PF) scores were tested. RESULTS: We studied 210 subjects (average age 49.8 ± 13.5 years, 62% men, 42% diabetics). In non-diabetic patients, multiscale entropy (MSE) slope sample entropy (SampEn) and approximate entropy (ApEn) correlated positively with LVEF, PF and PHC and inversely with LVEDV and ECV/TBW. Spectral power slope correlated positively with ECV/TBW (r = 0.27). Irregularity measures (MSE ApEn and MSE SampEn) correlated positively with LVEDV (r = 0.19 and 0.20). CONCLUSION: Non-linear HRV indices indicated an association between a deteriorated heart rate regulatory system and impaired cardiac function, fluid accumulation and poor physical condition.

Effects of daily hemodialysis on heart rate variability: results from the Frequent Hemodialysis Network (FHN) Daily Trial.

BACKGROUND: End-stage renal disease is associated with reduced heart rate variability (HRV), components of which generally are associated with advanced age, diabetes mellitus and left ventricular hypertrophy. We hypothesized that daily in-center hemodialysis (HD) would increase HRV. METHODS: The Frequent Hemodialysis Network (FHN) Daily Trial randomized 245 patients to receive 12 months of six versus three times per week in-center HD. Two hundred and seven patients had baseline Holter recordings. HRV measures were calculated from 24-h Holter electrocardiograms at both baseline and 12 months in 131 patients and included low-frequency power (LF, a measure of sympathetic modulation), high-frequency power (HF, a measure of parasympathetic modulation) and standard deviation (SD) of the R-R interval (SDNN, a measure of beat-to-beat variation). RESULTS: Baseline to Month 12 change in LF was augmented by 50% [95% confidence interval (95% CI) 6.1-112%, P =0.022] and LF + HF was augmented by 40% (95% CI 3.3-88.4%, P = 0.03) in patients assigned to daily hemodialysis (DHD) compared with conventional HD. Changes in HF and SDNN were similar between the randomized groups. The effects of DHD on LF were attenuated by advanced age and diabetes mellitus (predefined subgroups). Changes in HF (r = -0.20, P = 0.02) and SDNN (r = -0.18, P = 0.04) were inversely associated with changes in left ventricular mass (LVM). CONCLUSIONS: DHD increased the LF component of HRV. Reduction of LVM by DHD was associated with increased vagal modulation of heart rate (HF) and with increased beat-to-beat heart rate variation (SDNN), suggesting an important functional correlate to the structural effects of DHD on the heart in uremia.