Jochen G. Raimann

Effect of frequent hemodialysis on residual kidney function

Frequent hemodialysis can alter volume status, blood pressure and the concentration of osmotically active solutes, each of which might affect residual kidney function (RKF). In the Frequent Hemodialysis Network Daily and Nocturnal Trials, we examined the effects of assignment to 6 compared to 3 times per week hemodialysis on follow up RKF. In both trials, baseline RKF was inversely correlated with number of years since onset of ESRD. In the Nocturnal Trial, 63 participants had non-zero RKF at baseline (mean urine volume 0.76 l/d, urea clearance 2.3 ml/min, and creatinine clearance 4.7 ml/min). In those assigned to frequent nocturnal dialysis, these indices were all significantly lower at month 4 and were mostly so at month 12 compared to controls. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared to 18% and 36% in controls. In the Daily Trial, 83 patients had non-zero RKF at baseline (mean urine volume 0.43 l/d, urea clearance 1.2 ml/min, and creatinine clearance 2.7 ml/min). Here, treatment assignment did not significantly influence follow-up levels of the measured indices, although the range in baseline RKF was narrower, potentially limiting power to detect differences. Thus, frequent nocturnal hemodialysis appears to promote a more rapid loss of RKF, the mechanism of which remains to be determined. Whether RKF also declines with frequent daily treatment could not be determined.Frequent hemodialysis can alter volume status, blood pressure, and the concentration of osmotically active solutes, each of which might affect residual kidney function (RKF). In the Frequent Hemodialysis Network Daily and Nocturnal Trials, we examined the effects of assignment to six compared with three-times-per-week hemodialysis on follow-up RKF. In both trials, baseline RKF was inversely correlated with number of years since onset of ESRD. In the Nocturnal Trial, 63 participants had non-zero RKF at baseline (mean urine volume 0.76 liter/day, urea clearance 2.3 ml/min, and creatinine clearance 4.7 ml/min). In those assigned to frequent nocturnal dialysis, these indices were all significantly lower at month 4 and were mostly so at month 12 compared with controls. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared with 18% and 36% in controls. In the Daily Trial, 83 patients had non-zero RKF at baseline (mean urine volume 0.43 liter/day, urea clearance 1.2 ml/min, and creatinine clearance 2.7 ml/min). Here, treatment assignment did not significantly influence follow-up levels of the measured indices, although the range in baseline RKF was narrower, potentially limiting power to detect differences. Thus, frequent nocturnal hemodialysis appears to promote a more rapid loss of RKF, the mechanism of which remains to be determined. Whether RKF also declines with frequent daily treatment could not be determined.

A fresh look at dry weight.

The concept of dry weight (DW) is central to dialysis therapy. The most commonly used definition of DW is the weight below which patients become hypotensive on dialysis. However, this definition is dependent on patient symptoms. A more rigorous definition of DW is the body weight at a physiological extracellular volume (ECV) state. Overhydration is an excess in ECV above that found in healthy subjects. In healthy subjects, within extremes of salt intake, ECV may vary between 280 and 340 mL/kg lean body mass. Sodium accumulation is one of the many consequences of renal failure; it results in increased water intake and an increase in ECV, and an accompanying rise in blood pressure with its clinical sequelae, most prominently cardiovascular and cerebrovascular diseases. Recently characterized endogenous digitalis‐like factors which are released in response to ECV expansion have extended this traditional picture. Efforts to reduce a positive sodium balance include dietary counseling and avoidance of iatrogenic intradialytic sodium loading, such as dialysate sodium exceeding serum levels, sodium profiling, and intravenous saline. Excess ECV is predominantly located in the interstitial compartment and must be removed during dialysis therapy by ultrafiltration. During this process, interstitial fluid redistributes to the intravascular space via uptake in the capillary bed. In addition to that mechanism, we propose that increased lymphatic flow into the venous system contributes to plasma refilling. Both clinical and technical means are used to assess the presence of DW. Continuous segmental calf bioimpedance is a promising new technology for intradialytic DW diagnosis.

Estimation of normal hydration in dialysis patients using whole body and calf bioimpedance analysis.

Prescription of an appropriate dialysis target weight (dry weight) requires accurate evaluation of the degree of hydration. The aim of this study was to investigate whether a state of normal hydration (DW(cBIS)) as defined by calf bioimpedance spectroscopy (cBIS) and conventional whole body bioimpedance spectroscopy (wBIS) could be characterized in hemodialysis (HD) patients and normal subjects (NS). wBIS and cBIS were performed in 62 NS (33 m/29 f) and 30 HD patients (16 m/14 f) pre- and post-dialysis treatments to measure extracellular resistance and fluid volume (ECV) by the whole body and calf bioimpedance methods. Normalized calf resistivity (ρ(N)(,5)) was defined as resistivity at 5 kHz divided by the body mass index. The ratio of wECV to total body water (wECV/TBW) was calculated. Measurements were made at baseline (BL) and at DW(cBIS) following the progressive reduction of post-HD weight over successive dialysis treatments until the curve of calf extracellular resistance is flattened (stabilization) and the ρ(N)(,5) was in the range of NS. Blood pressures were measured pre- and post-HD treatment. ρ(N)(,5) in males and females differed significantly in NS. In patients, ρ(N)(,5) notably increased with progressive decrease in body weight, and systolic blood pressure significantly decreased pre- and post-HD between BL and DW(cBIS) respectively. Although wECV/TBW decreased between BL and DW(cBIS), the percentage of change in wECV/TBW was significantly less than that in ρ(N)(,5) (-5.21 ± 3.2% versus 28 ± 27%, p < 0.001). This establishes the use of ρ(N)(,5) as a new comparator allowing a clinician to incrementally monitor removal of extracellular fluid from patients over the course of dialysis treatments. The conventional whole body technique using wECV/TBW was less sensitive than the use of ρ(N)(,5) to measure differences in body hydration between BL and DW(cBIS).

Challenges to enrollment and randomization of the Frequent Hemodialysis Network (FHN) Daily Trial.

BACKGROUND The US National Institutes of Health (NIH) and Centers for Medicare and Medicaid Services (CMS) sponsored a randomized clinical trial comparing six versus three times per week in-center hemodialysis (the Frequent Hemodialysis Network [FHN] Daily Trial), to test the effects of frequent hemodialysis on an array of intermediate outcomes. Herein we report challenges to enrollment and randomization into the trial. METHODS Screening and enrollment was tracked at all participating dialysis clinics and specific reasons for dropout after baseline assessment were recorded for all enrolled subjects. Reasons for consent refusal were recorded in a subset of (10 out of 65) sites. RESULTS The trial screened 6276 hemodialysis patients on three times weekly hemodialysis in 65 hemodialysis clinics, 3481 (55%) were considered eligible for enrollment, and 3124 (90%) were approached for consent; 378 (12%) consented and 245 were randomized (65% of those enrolled). Prospective subjects chose not to participate primarily because of the anticipated time required for three extra treatments per week and the difficulties in following the protocol. CONCLUSIONS Recruitment into the FHN Daily Trial proved challenging but the goal of 250 randomized subjects was almost met.

Determination of fluid status in haemodialysis patients with whole body and calf bioimpedance techniques.

Aim:  The aim of this study was to demonstrate the ability of widely used bioimpedance techniques to assess dry weight (DW) and to predict a state of normal hydration in haemodialysis patients whose post‐dialysis weight had been gradually reduced from baseline in successive treatments over time.

Blood pressure stability in hemodialysis patients confers a survival advantage: results from a large retrospective cohort study

The association between changes in systolic and diastolic blood pressure, and the use of cardioprotective drugs on survival of incident hemodialysis patients, was examined in this retrospective cohort study. Pre-hemodialysis systolic and diastolic blood pressures were averaged over the first month of hemodialysis. Slopes, reflecting temporal changes, were computed by linear regression of systolic blood pressures and Cox regression was used for survival analyses. Patients were initially stratified into four cohorts (below 120, 120 to 150, 151 to 180, and above 180 mm Hg) and further subdivided into groups with stable (no more than a 1-mm Hg change per month), increasing (over 1-mm Hg per month), and decreasing (less than 1-mm Hg per month) slopes during the first year. Analyses were repeated for patients who were treated with cardioprotective drugs for 1 month or more in the second year. In 10,245 patients (59% prescribed cardioprotective drugs), both increases and decreases in all ranges of blood pressure were associated with worse outcomes, whereas stable blood pressure had a survival advantage at all levels of systolic and diastolic pressures. Use of cardioprotective drugs attenuated changes and improved survival. Validation and sensitivity analyses confirmed the primary findings. Therefore, previous temporal trends need to be considered in patient care, and the use of cardioprotective agents is associated with enhanced survival at all blood pressure levels.

The Impact of Membrane Permeability and Dialysate Purity on Cardiovascular Outcomes

The effects of high-flux dialysis and ultrapure dialysate on survival of hemodialysis patients are incompletely understood. We conducted a randomized controlled trial to investigate the effects of both membrane permeability and dialysate purity on cardiovascular outcomes. We randomly assigned 704 patients on three times per week hemodialysis to either high- or low-flux dialyzers and either ultrapure or standard dialysate using a two-by-two factorial design. The primary outcome was a composite of fatal and nonfatal cardiovascular events during a minimum 3 years follow-up. We did not detect statistically significant differences in the primary outcome between high- and low-flux (HR=0.73, 95% CI=0.49 to 1.08, P=0.12) and between ultrapure and standard dialysate (HR=0.90, 95% CI=0.61 to 1.32, P=0.60). Posthoc analyses suggested that cardiovascular event-free survival was significantly better in the high-flux group compared with the low-flux group for the subgroup with arteriovenous fistulas, which constituted 82% of the study population (adjusted HR=0.61, 95% CI=0.38 to 0.97, P=0.03). Furthermore, high-flux dialysis associated with a lower risk for cardiovascular events among diabetic subjects (adjusted HR=0.49, 95% CI=0.25 to 0.94, P=0.03), and ultrapure dialysate associated with a lower risk for cardiovascular events among subjects with more than 3 years of dialysis (adjusted HR=0.55, 95% CI=0.31 to 0.97, P=0.04). In conclusion, this trial did not detect a difference in cardiovascular event-free survival between flux and dialysate groups. Posthoc analyses suggest that high-flux hemodialysis may benefit patients with an arteriovenous fistula and patients with diabetes and that ultrapure dialysate may benefit patients with longer dialysis vintage.

Sodium Alignment in Clinical Practice—Implementation and Implications

Numerous reports in the general and the dialysis population have shown associations of sodium (Na+) intake, blood pressure, and survival. In addition to dietary Na+ intake, positive Na+ balance during dialysis needs to be considered as a source of Na+. Dialysate Na+ (DNa+) concentrations above the serum Na+ concentration (SNa+) result in diffusive Na+ flux from the dialysate into the patient, which has recently been reported to be associated with increased interdialytic weight gain and mortality. Individualization of the Na+ prescription and Na+ alignment (DNa+ equal to SNa+) prevents positive Na+ balance and improves patient outcomes. Alignment requires the knowledge of patients’ SNa+, which can be estimated from previous SNa+ in the monthly routine laboratory measurements. Na+ alignment was recently implemented in a dialysis clinic of Renal Research Institute. Preliminary results of this initiative have shown a trend of predialysis weight and blood pressure reduction. Expansion of this initiative to all clinics of RRI is currently underway and as of April 2011, four additional clinics have been included. Additional research on adequate Na+ alignment is needed to account for Gibbs–Donnan effects, differences in charge across the dialyzer membrane, and variability in measurement methods. Regular calibration of DNa+ delivery by dialysis machines is necessary to ensure that the dialysis prescription is followed. How to provide dialysis to severely hyponatremic patients remains an open question. Finally, long‐term studies of the effects of Na+ restriction on hospitalization and mortality are required to demonstrate the benefits of aligning DNa+ with SNa+.

The Evils of Intradialytic Sodium Loading

Increased salt intake is related to extracellular fluid expansion and a rise in blood pressure, and has been linked to cardiovascular disease. Several studies have also suggested that sodium can exert detrimental effects via blood pressure-independent mechanisms. Chronic kidney disease patients are particularly susceptible to the negative consequences of sodium loading. While individuals with normal kidney function are able to regulate their sodium balance, hemodialysis patients have to rely virtually entirely on the dialysis procedure for sodium elimination. Tragically, the dialysis procedure has, in many instances, turned into a de facto source of sodium loading rather than a means for sodium removal. The main sources of sodium related to the dialysis procedure are (1) diffusive influx from the dialysate, including inappropriate use of sodium profiling; (2) the use of saline solution for priming and rinsing; and (3) the treatment of intradialytic hypotension and cramps with saline solution. Creating a positive intradialytic sodium balance is effective in acutely reducing the incidence of intradialytic symptoms, but it also sustains a vicious cycle hampering the attainment of dry weight and predisposes the patient to an increased risk of intradialytic complications during the following dialysis session. Avoiding sodium loading in hemodialysis patients is a cornerstone of blood pressure and fluid status management and, therefore, deserves a conscious effort, bearing in mind not only short-term effects but also long-term goals. In the absence of routine means of quantifying sodium balance, sodium profiling should be viewed critically, as it has been shown to induce a positive sodium balance in the majority of cases. A preferred approach under these circumstances may be simple sodium alignment. In combination with the abdication of saline solution for priming, rinsing, and intradialytic infusions, these measures would go a long way to help reduce sodium overload and achieve a more physiologic sodium balance in this patient population.

Saliva urea dipstick test: application in chronic kidney disease.

BACKGROUND A noninvasive test for determining elevated levels of blood urea nitrogen (BUN) may be useful under circumstances in which there is limited access to laboratories. Because saliva urea nitrogen (SUN) parallels BUN, we investigated the diagnostic performance of a semiquantitative SUN dipstick to test for elevated BUN levels in patients with chronic kidney disease (CKD). MATERIALS AND METHODS Patients with CKD Stages 1 to 5D were studied. 50 µl of saliva were transferred onto the SUN test strip (Integrated Biomedical Technology, Elkhart, Indiana, IN, USA). SUN was determined after 1 minute by visual comparison of the color of the moistened test pad with 6 calibrated color blocks. Interobserver reproducibility was evaluated by independent observers, masked to urea concentrations of 6 calibrated urea solutions. Correlation between SUN and BUN was quantified by Spearmans rank correlation coefficient (RS), Kappa Statistic was employed to evaluate within-sample reproducibility of duplicates. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic performance of SUN. RESULTS 68 patients (31 females, 60 ± 14 years; 34 hemodialysis patients, 34 patients CKD Stages 1 - 4) were studied. Interobserver coefficient of variation was 4.9% at SUN levels > 50 mg/dl; within-sample reproducibility was 90%. SUN and BUN were correlated significantly (RS = 0.63; p < 0.01). Elevated BUN was diagnosed with high accuracy by SUN determination (area under the ROC curve: 0.90 (95% CI 0.85 - 0.95)). CONCLUSION Semiquantitative dipstick measurements of SUN can reliably identify CKD patients with elevated BUN levels.