Unraveling the relationship between mortality, hyponatremia, inflammation and malnutrition in hemodialysis patients: results from the international MONDO initiative.

BACKGROUND/OBJECTIVES: Hyponatremia is a risk factor for mortality in hemodialysis (HD) patients. It is not well known to which extent the comorbidities, malnutrition, fluid status imbalance and inflammation are related to hyponatremia and affect outcomes. SUBJECTS/METHODS: We studied 8883 patients from the European subset of the international MONitoring Dialysis Outcomes initiative. Nutritional and fluid statuses were assessed by bioimpedance spectroscopy. Fluid depletion was defined as overhydration⩽-1.1 l and fluid overload as overhydration>+1.1 l, respectively. Malnutrition was defined as a lean tissue index below the 10th percentile of age- and gender-matched healthy controls. Hyponatremia and inflammation were defined as serum sodium levels <135 mEq/l and C-reactive protein levels>6.0 mg/l, respectively. We used logistic regression to test for predictors of hyponatremia and Cox proportional hazards analysis to assess the association with all-cause mortality. RESULTS: Hyponatremia was predicted by the presence of malnutrition (odds ratio (OR)=1.49 (95% confidence interval (CI)=1.30-1.70), inflammation (OR=1.44 (95% CI=1.26-1.64)) and fluid overload ((>+1.1 l to +2.5 l) OR=0.73 (95% CI=0.62-0.85)) but not by fluid depletion (OR=1.34 (95% CI=0.92-1.96)). Malnutrition, inflammation, fluid overload, fluid depletion and hyponatremia (hazard ratio=1.70 (95% CI=1.46-1.99)) were independent predictors for all-cause mortality. CONCLUSIONS: In HD patients, hyponatremia is associated with malnutrition, inflammation and fluid overload. Hyponatremia maintained predictive for all-cause mortality after adjustment for malnutrition, inflammation and fluid status abnormalities. The presence of hyponatremia may assist in identifying HD patients at increased risk of death.

Association between pre hemodialysis serum sodium concentration and blood pressure: results from a retrospective analysis from the international monitoring dialysis outcomes (MONDO) initiative.

A recent study from the United Kingdom indicates an association between pre hemodialysis (HD) serum sodium (SNa(+)) and systolic and diastolic blood pressure (SBP and DBP) in chronic HD patients. We extend this analysis to an international cohort of incident HD patients. The Monitoring Dialysis Outcomes initiative encompasses patients from 41 countries. Over 2 years monthly pre-HD SNa(+) levels were used as predictors of pre-HD SBP and DBP in a linear mixed model (LMM) adjusted for age, gender, interdialytic weight gain, diabetes, serum albumin and calcium. Similar models were constructed with DBP as outcome. Analyses were carried out stratified by continent (North and South America; Europe and Asia). LMMs were also constructed for the entire observation period of 2 years, and separately the first and the second year after HD initiation. We studied 17 050 incident patients and found SNa(+) to have a significant slope estimate in the LMM predicting pre-HD SBP and DBP (ranging from 0.22 to 0.29 and 0.10 to 0.21 mm Hg per mEq l(-1), respectively, between the continents). The findings were similar in subsets of SBP and SNa(+) tertiles, and separately analyzed for the first and second year. Our analysis shows an independent association between SNa, SBP and DBP in a large intercontinental database, indicating that this relation is a profound biological phenomenon in incident and prevalent HD patients, generalizable to an international level and independent of SBP and DBP magnitude.

Effect of changes in the intravascular volume during hemodialysis on blood viscoelasticity.

Adoption of high rate of ultrafiltration (UF) during hemodialysis (HD) may affect the hemorhelogical blood profile, by changing Hematocrit (Hct) and the concentration of plasma proteins, which may in turn interfere with tissue perfusion. The aim of this work is to examine the effect of acute volume change during dialysis on the hemorheological variables. The study included 21 hemodialysis patients. Hematocrit (Hct) and percent decrease in blood volume (BV) were recorded by blood volume monitor. Blood samples were taken before and at the end of dialysis, for measuring plasma fibrinogen and haemorheological variables, which included blood viscosity, plasma viscosity, red cells elasticity and aggregation. The UF volume was 3.52±1.54 L. Hct increased from 34.2±6.1 to 42.1±7.3% (P<0.001), and blood volume (BV) decreased to 85.5±6.4% (P<0.001). Blood and plasma viscosity significantly increased from 3.28±0.69 to 5.48±0.85 mPa.s (P<0.001), and from 1.24 ± 0.16 to 1.65±0.24 mPa.s (P<0.001), respectively. Changes in plasma viscosity were correlated to changes in plasma fibrinogen (r=0.63, P<0.05), while the increase in blood viscosity was correlated to the percent reduction in blood volume (r=0.85, P<0.005). Red cells elasticity increased from 0.26±0.12 to 0.48±0.18 mPa.s (P<0.05), and the aggregation index rose from 0.86±0.31 to 1.25±0.26 (P<0.01). This combination of increased plasma viscosity and red cell aggregability may lower the velocity of erythrocyte transfer inside the tissue capillaries after HD, which may affect tissue perfusion. Moreover, increased elasticity may require more energy from the heart to disaggregate the cells, and this may induce problems in the patients with cardiac dysfunction. In conclusion, the hemorheological variables change after dialysis in the direction which may impede the flow inside the microvessels.

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 Spearman's 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.

Assessment of body composition in dialysis patients by arm bioimpedance compared to MRI and 40K measurements.

This study used multi-frequency bioimpedance spectroscopy (BIS) of the arm and whole body to estimate muscle mass (MM) and subcutaneous adipose tissue (SAT) in 31 hemodialysis (HD) patients comparing these results with magnetic resonance imaging (MRI) and body potassium ((40)K) as gold standards. Total body and arm MM (MM(MRI)) and SAT (SAT(MRI)) were measured by MRI. All measurements were made before dialysis treatment. Regression models with the arm (aBIS) and whole body (wBIS) resistances were established. Correlations between gold standards and the BIS model were high for the arm SAT (r(2) = 0.93, standard error of estimate (SEE) = 3.6 kg), and whole body SAT (r(2) = 0.92, SEE = 3.5 kg), and for arm MM (r(2) = 0.84, SEE = 2.28 kg) and whole body MM (r(2) = 0.86, SEE = 2.28 kg). Total body MM and SAT can be accurately predicted by arm BIS models with advantages of convenience and portability, and it should be useful to assess nutritional status in HD patients.

A method for the estimation of hydration state during hemodialysis using a calf bioimpedance technique.

Although many methods have been utilized to measure degrees of body hydration, and in particular to estimate normal hydration states (dry weight, DW) in hemodialysis (HD) patients, no accurate methods are currently available for clinical use. Biochemcial measurements are not sufficiently precise and vena cava diameter estimation is impractical. Several bioimpedance methods have been suggested to provide information to estimate clinical hydration and nutritional status, such as phase angle measurement and ratio of body fluid compartment volumes to body weight. In this study, we present a calf bioimpedance spectroscopy (cBIS) technique to monitor calf resistance and resistivity continuously during HD. Attainment of DW is defined by two criteria: (1) the primary criterion is flattening of the change in the resistance curve during dialysis so that at DW little further change is observed and (2) normalized resistivity is in the range of observation of healthy subjects. Twenty maintenance HD patients (12 M/8 F) were studied on 220 occasions. After three baseline (BL) measurements, with patients at their DW prescribed on clinical grounds (DW(Clin)), the target post-dialysis weight was gradually decreased in the course of several treatments until the two dry weight criteria outlined above were met (DW(cBIS)). Post-dialysis weight was reduced from 78.3 +/- 28 to 77.1 +/- 27 kg (p < 0.01), normalized resistivity increased from 17.9 +/- 3 to 19.1 +/- 2.3 x 10(-2) Omega m(3) kg(-1) (p < 0.01). The average coefficient of variation (CV) in three repeat measurements of DW(cBIS) was 0.3 +/- 0.2%. The results indicate that cBIS utilizing a dynamic technique continuously during dialysis is an accurate and precise approach to specific end points for the estimation of body hydration status. Since no current techniques have been developed to detect DW as precisely, it is suggested as a standard to be evaluated clinically.

Consequences of overhydration and the need for dry weight assessment.

Despite significant progress in the fields of dialysis technology and medical therapy, mortality of hemodialysis (HD) patients remains high. Chronic overhydration is a major contributor to the high cardiovascular morbidity and mortality observed in HD patients. The difficulty of measuring excess fluid accurately and the determination of 'dry weight' are reflected in the abundant literature on overhydration. Data indicate that a significant proportion of HD patients are not at 'dry weight'. Considering its impact on cardiovascular diseases, the relation between excess fluid, sodium, interdialytic weight gain, hypertension and cardiac diseases needs more attention. Clearly the reduction of sodium intake is of prime importance. This can be achieved by a reduction of dietary sodium intake, individualized dialysate sodium concentration, avoidance of sodium profiling and use of hypertonic saline during dialysis. These measures are expected to result in less thirst and consecutive water intake, thereby facilitating achieving dry weight (DW). In concert, the application of new tools for DW assessment such as continuous intradialytic bioimpedance spectroscopy measurement, means to prevent intradialytic symptoms (e.g. glucose bolus instead of hypertonic saline; improved hemodynamic stability by reduced dialysate temperature) may be operative in reducing morbidity and mortality in HD patients.

Access flow measurement by indicator dilution without indicator injection: effect of switch location.

It is well known that the measurement of access flow by one of the various dilution techniques requires the reversal of blood flow drawn from and returned to the peripheral vascular access. But it was only recently recognized that the line switch itself constitutes a dilution experiment for certain blood and dialysate components and properties, so that a subsequent injection of indicator is no longer required. New switches introduced at different locations in the extracorporeal circulation not only simplify manual operation for standard access flow measurement but also provide an essential tool for the new technique, which is based on continuously measuring certain blood and/or dialysate characteristics and their changes caused by switching the bloodlines. In this study, the effects of switching the bloodlines at two different locations were studied when extracorporeal temperatures were used as a marker. The study shows that the temperature changes depend on the location of the switch relative to the extracorporeal temperature sensors, and that different algorithms to calculate access flow have to be used for the two possible switching positions to account for this dependence.

The impact of visceral mass on survival in chronic hemodialysis patients.

In chronic hemodialysis, patient survival is positively correlated with body weight and body mass index (BMI). This relationship extends even to obese patients with a BMI >30 kg/m2. We have put forward the hypothesis that this survival benefit may be due to a lower average synthesis rate of uremic toxins (expressed as amount per time per unit of body weight) in larger patients, because the relative contribution of the high metabolic rate organs (HMRO) to body weight in these patients is lower and HMRO are most likely to be the prime source of uremic toxins. In addition, the average uremic toxin concentration in larger patients may be lower because of the larger distribution volume. Based on these assumptions, a better survival in patients with a lower HMRO to body weight fraction (HMRO%BW) can be predicted. To test this hypothesis we estimated gender- and race-specific HMRO mass by means of recently published regression models in 2,004 incident hemodialysis patients. Cox proportional hazards models were used to assess the association between age, serum albumin concentration, eKt/V, and HMRO% BW and mortality. High HMRO%BW was significantly associated with increased mortality (hazard ratio 1.323 [95% CI: 1.186 to 1.477]). Mean survival time was longest in the low HMRO%BW tertile (1,031 days [95%CI: 974 to 1,087]), 935 days [95%CI: 886 to 984] in the middle, and 876 days [95%CI: 825 to 926] in the high HMRO%BW tertile (p<0.0001; log rank test). These results support the hypothesis predicting that a low HMRO mass per unit of weight confers a beneficial effect on survival.

A mathematical model comparing solute kinetics in low- and high-BMI hemodialysis patients.

BACKGROUND: Patients with low Body Mass Index (BMI) on maintenance hemodialysis have a higher mortality risk than patients with elevated BMI. We investigated the use of kinetic modeling to test different hypotheses which have been advanced to explain this relationship. METHODS: Equations from a three-pool urea-kinetic mathematical model (hepatic mass, extracellular fluid, muscle mass and adipose tissue) were solved to yield predictive profiles of solute and putative toxin concentrations versus time for patients of different body weights. RESULTS: For the interdialytic interval, our mathematic model suggests that extracellular solute/toxin concentration increases more rapidly in small patients. Additionally, time average concentration (TAC) is higher for this cohort. A lower value of the muscle mass and adipose tissue mass-transfer coefficient (K(MMAT)), which determines the rate of solute release into the extracellular fluid, exacerbates this difference. CONCLUSION: These results suggest that higher mortality for smaller dialysis patients may be mediated by higher time average toxin concentration, especially for solutes with a low mass-transfer coefficient value.

The Kidney Disease: improving Global Outcomes website: comparison of guidelines as a tool for harmonization.

Chronic kidney disease (CKD) is a worldwide public health problem with significant comorbidity and mortality. Improving quality of life and survival of CKD patients necessitates a large number of preventive and therapeutic interventions. To resolve these issues several organizations have developed guidelines, which are difficult to compare comprehensively. The Kidney Disease: Improving Global Outcomes website at http://kdigo.org compares five major guidelines. The section 'compare guidelines' covers 41 topics distributed over five major subjects: (1) general clinics; (2) hemodialysis (HD); (3) vascular access for HD; (4) peritoneal dialysis; and (5) chemistries. The tables compare guideline recommendations and the evidence levels on which they are based, with direct links to each of the guidelines. These data show that the different guideline groups tend to propose similar targets, but that nuances in the guideline statements, their rationale, and grading of evidence levels present some discrepancies, although most guidelines are based on the same literature. We conclude that there is an urgent need to harmonize existing guidelines, and for a global initiative to avoid the parallel development of conflicting guidelines on the same topics. The tables displayed on the website offer a basis for structuring this process, a procedure which has recently been initiated by a body composed of the five guideline development groups.

Frequent Hemodialysis Network (FHN) randomized trials: study design.

Observational studies suggest improvements with frequent hemodialysis (HD), but its true efficacy and safety remain uncertain. The Frequent Hemodialysis Network Trials Group is conducting two multicenter randomized trials of 250 subjects each, comparing conventional three times weekly HD with (1) in-center daily HD and (2) home nocturnal HD. Daily HD will be delivered for 1.5-2.75 h, 6 days/week, with target eK(t)/V(n) > or = 0.9/session, whereas nocturnal HD will be delivered for > or = 6 h, 6 nights/week, with target stdK(t)/V of > or = 4.0/week. Subjects will be followed for 1 year. The composite of mortality with the 12-month change in (i) left ventricular mass index (LVMI) by magnetic resonance imaging, and (ii) SF-36 RAND Physical Health Composite (PHC) are specified as co-primary outcomes. The seven main secondary outcomes are between group comparisons of: change in LVMI, change in PHC, change in Beck Depression Inventory score, change in Trail Making Test B score, change in pre-HD serum albumin, change in pre-HD serum phosphorus, and rates of non-access hospitalization or death. Changes in blood pressure and erythropoiesis will also be assessed. Safety outcomes will focus on vascular access complications and burden of treatment. Data will be obtained on the cost of delivering frequent HD compared to conventional HD. Efforts will be made to reduce bias, including blinding assessment of subjective outcomes. Because no large-scale randomized trials of frequent HD have been previously conducted, the first year has been designated a Vanguard Phase, during which feasibility of randomization, ability to deliver the interventions, and adherence will be evaluated.

Metabolic consequences of body size and body composition in hemodialysis patients.

Small body mass index is associated with increased mortality in chronic hemodialysis patients. The reasons for this observation are unclear but may be related to body composition. This study aimed to investigate the body composition in chronic hemodialysis patients. The difference between body mass and the sum of muscle, bone, subcutaneous, and visceral adipose tissue masses, measured by whole body magnetic resonance imaging, was defined as the high metabolic rate compartment representing the visceral mass. Protein catabolic rate was calculated from urea kinetics. Forty chronic hemodialysis patients (mean age 54.7 years; 87.5% African Americans; 45% females) were studied. High metabolic rate compartment expressed in percent of body weight was inversely related to body weight (r=-0.475; P=0.002) and body mass index (r=-0.530; P<0.001). In a multiple linear regression model, protein catabolic rate was significantly correlated only with high metabolic rate compartment (r=0.616; P<0.001). Assuming that protein catabolic rate in addition to protein intake reflects urea and uremic toxin generation, it follows that high metabolic rate compartment is the major compartment involved in their generation. Consequently, uremic toxin production rate may be relatively higher in patients with low body weight and low body mass index as compared to their heavier counterparts. The poorer survival observed in smaller dialysis patients may be related to these relative differences.

Dialysis rationing in South Africa: a global message.

Dialysis rationing resulting from limited facilities and health-care personnel in low- and middle-income countries such as South Africa must be addressed on several fronts. Prevention of kidney disease is an essential long-term approach, but in the short term, it is necessary to increase access to dialysis and transplantation, and to seek ways to limit the 'brain drain' to the developed world.

Measuring partial body potassium in the arm versus total body potassium.

Skeletal muscle (SM), the body's main structural support, has been implicated in metabolic, physiological, and disease processes in humans. Despite being the largest tissue in the human body, its assessment remains difficult and indirect. However, being metabolically active it contains over 50% of the total body potassium (TBK) pool. We present our preliminary results from a new system for measuring partial body K (PBK) that presently are limited to the arm yet provide a direct and specific measure of the SM. This uniquely specific quantification of the SM mass in the arm, which is shielded from the body during measurement, allows us to simplify the assumptions used in deriving the total SM, thereby possibly improving the modeling of the human body compartments. Preliminary results show that PBK measurements are consistent with those from the TBK previously obtained from the same subjects, thus offering a simpler alternative to computed tomography and magnetic resonance imaging used for the same purposes. The PBK system, which can be set up in a physician's office or bedside in a hospital, is completely passive, safe, and inexpensive; it can be used on immobilized patients, children, pregnant women, or other at-risk populations.

Application of bioimpedance techniques to peritoneal dialysis.

Peritoneal dialysis (PD) has been used as a home dialysis therapy for renal replacement for more than 30 years. In a recent assessment of treatment quality, the mortality of patients on PD was referenced as being higher than of those on hemodialysis. Several reports suggest that a high proportion of PD patients are overhydrated. Clinical assessment of dry weight in PD patients is difficult and further complicated by the paucity of signs and symptoms indicative of dehydration (such as intradialytic hypotension or muscle cramps). Monitoring tools used for fluid status estimation during hemodialysis, e.g. online blood volume and blood pressure measurement, are not readily available in PD patients. Bioimpedance analysis technique has been considered as a potential tool to measure body fluid non-invasively, inexpensively and simply. Although Bioimpedance analysis has been used in clinical studies for more than 20 years, the knowledge of the electrical properties of body tissues is still evolving. In this review we aim to clarify the principles of different bioimpedance techniques and to introduce their applications in PD patients.

Longer treatment time and slower ultrafiltration in hemodialysis: associations with reduced mortality in the DOPPS.

Longer treatment time (TT) and slower ultrafiltration rate (UFR) are considered advantageous for hemodialysis (HD) patients. The study included 22,000 HD patients from seven countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Logistic regression was used to study predictors of TT > 240 min and UFR > 10 ml/h/kg bodyweight. Cox regression was used for survival analyses. Statistical adjustments were made for patient demographics, comorbidities, dose of dialysis (Kt/V), and body size. Europe and Japan had significantly longer (P < 0.0001) average TT than the US (232 and 244 min vs 211 in DOPPS I; 235 and 240 min vs 221 in DOPPS II). Kt/V increased concomitantly with TT in all three regions with the largest absolute difference observed in Japan. TT > 240 min was independently associated with significantly lower relative risk (RR) of mortality (RR = 0.81; P = 0.0005). Every 30 min longer on HD was associated with a 7% lower RR of mortality (RR = 0.93; P < 0.0001). The RR reduction with longer TT was greatest in Japan. A synergistic interaction occurred between Kt/V and TT (P = 0.007) toward mortality reduction. UFR > 10 ml/h/kg was associated with higher odds of intradialytic hypotension (odds ratio = 1.30; P = 0.045) and a higher risk of mortality (RR = 1.09; P = 0.02). Longer TT and higher Kt/V were independently as well as synergistically associated with lower mortality. Rapid UFR during HD was also associated with higher mortality risk. These results warrant a randomized clinical trial of longer dialysis sessions in thrice-weekly HD.

Segment-specific resistivity improves body fluid volume estimates from bioimpedance spectroscopy in hemodialysis patients.

Discrepancies in body fluid estimates between segmental bioimpedance spectroscopy (SBIS) and gold-standard methods may be due to the use of a uniform value of tissue resistivity to compute extracellular fluid volume (ECV) and intracellular fluid volume (ICV). Discrepancies may also arise from the exclusion of fluid volumes of hands, feet, neck, and head from measurements due to electrode positions. The aim of this study was to define the specific resistivity of various body segments and to use those values for computation of ECV and ICV along with a correction for unmeasured fluid volumes. Twenty-nine maintenance hemodialysis patients (16 men) underwent body composition analysis including whole body MRI, whole body potassium (40K) content, deuterium, and sodium bromide dilution, and segmental and wrist-to-ankle bioimpedance spectroscopy, all performed on the same day before a hemodialysis. Segment-specific resistivity was determined from segmental fat-free mass (FFM; by MRI), hydration status of FFM (by deuterium and sodium bromide), tissue resistance (by SBIS), and segment length. Segmental FFM was higher and extracellular hydration of FFM was lower in men compared with women. Segment-specific resistivity values for arm, trunk, and leg all differed from the uniform resistivity used in traditional SBIS algorithms. Estimates for whole body ECV, ICV, and total body water from SBIS using segmental instead of uniform resistivity values and after adjustment for unmeasured fluid volumes of the body did not differ significantly from gold-standard measures. The uniform tissue resistivity values used in traditional SBIS algorithms result in underestimation of ECV, ICV, and total body water. Use of segmental resistivity values combined with adjustment for body volumes that are neglected by traditional SBIS technique significantly improves estimations of body fluid volume in hemodialysis patients.

The role of improved water quality on inflammatory markers in patients undergoing regular dialysis.

Hemodialysis utilizes large quantities of water for the preparation of dialysis fluid. Such water meets national standards and international standards but a considerable disparity exists between such standards with respect to microbiological purity. This study collated and retrospectively analyzed the impact of upgrading water systems from that specified in the US standards to those specified in European standards on clinical measures associated with inflammation in four metropolitan dialysis units for two periods. Two periods were compared, three months prior to and six months post upgrading the water treatment systems. The monthly total erythropoietin dosage and intravenous iron supplementation for each patient were also compared over these periods. Variables with significant pre-post differences were assessed using multivariate models to control for confounding factors. The results indicated significant increases in hemoglobin, ferritin and TSat (all p < 0.0001) and albumin (p = 0.0001) were associated with improvement in water quality. Decreases in CRP and creatinine (both p < 0.0001) were also noted. These findings suggest that the current regulations in the United States set the microbiological limits of water and dialysis fluid inappropriately high, and the limits should be revised downwards, since such an approach is reflected in improvement in markers of inflammation.