John K. Leypoldt

Serum β-2 Microglobulin Levels Predict Mortality in Dialysis Patients: Results of the HEMO Study

In the randomized Hemodialysis (HEMO) Study, chronic high-flux dialysis, as defined by higher beta-2 microglobulin (beta(2)M) clearance, compared with low-flux dialysis did not significantly alter all-cause mortality in the entire cohort but was associated with lower mortality in long-term dialysis patients. This analysis examined the determinants of serum beta(2)M levels and the associations of serum beta(2)M levels or dialyzer beta(2)M clearance with mortality. In a multivariable regression model that examined 1704 patients, baseline residual kidney urea clearance and dialyzer beta(2)M clearance were strong predictors of predialysis serum beta(2)M levels at 1 mo of follow-up, with regression coefficients of -7.21 (+/-0.69 SE) mg/L per ml/min per 35 L urea volume (P < 0.0001) and -1.94 (+/-0.30) mg/L per ml/min (P < 0.0001),respectively. In addition, black race and baseline years on dialysis correlated positively whereas age, diabetes, serum albumin, and body mass index correlated negatively with serum beta(2)M levels (P < 0.05). In time-dependent Cox regression models, mean cumulative predialysis serum beta(2)M levels but not dialyzer beta(2)M clearance were associated with all-cause mortality (relative risk = 1.11 per 10-mg/L increase in beta(2)M level; 95% confidence interval 1.05 to 1.19; P = 0.001), after adjustment for residual kidney urea clearance and number of prestudy years on dialysis. This association is supportive of the potential value of beta(2)M as a marker to guide chronic hemodialysis therapy.

Effects of High-Flux Hemodialysis on Clinical Outcomes: Results of the HEMO Study

Among the 1846 patients in the HEMO Study, chronic high-flux dialysis did not significantly affect the primary outcome of the all-cause mortality (ACM) rate or the main secondary composite outcomes, including the rates of first cardiac hospitalization or ACM, first infectious hospitalization or ACM, first 15% decrease in serum albumin levels or ACM, or all non-vascular access-related hospitalizations. The high-flux intervention, however, seemed to be associated with reduced risks of specific cardiac-related events. The relative risks (RR) for the high-flux arm, compared with the low-flux arm, were 0.80 [95% confidence interval (CI), 0.65 to 0.99] for cardiac death and 0.87 (95% CI, 0.76 to 1.00) for the composite of first cardiac hospitalization or cardiac death. Also, the effect of high-flux dialysis on ACM seemed to vary, depending on the duration of prior dialysis. This report presents secondary analyses to further explore the relationship between the flux intervention and the duration of dialysis with respect to various outcomes. The patients were stratified into a short-duration group and a long-duration group, on the basis of the mean duration of dialysis of 3.7 yr before randomization. In the subgroup that had been on dialysis for >3.7 yr, randomization to high-flux dialysis was associated with lower risks of ACM (RR, 0.68; 95% CI, 0.53 to 0.86; P = 0.001), the composite of first albumin level decrease or ACM (RR, 0.74; 95% CI, 0.60 to 0.91; P = 0.005), and cardiac deaths (RR, 0.63; 95% CI, 0.43 to 0.92; P = 0.016), compared with low-flux dialysis. No significant differences were observed in outcomes related to infection for either duration subgroup, however, and the trends for beneficial effects of high-flux dialysis on ACM rates were considerably weakened when the years of dialysis during the follow-up phase were combined with the prestudy years of dialysis in the analysis. For the subgroup of patients with <3.7 yr of dialysis before the study, assignment to high-flux dialysis had no significant effect on any of the examined clinical outcomes. These data suggest that high-flux dialysis might have a beneficial effect on cardiac outcomes. Because these results are derived from multiple statistical comparisons, however, they must be interpreted with caution. The subgroup results that demonstrate that patients with different durations of dialysis are affected differently by high-flux dialysis are interesting and require further study for confirmation.

Effect of dialysis membranes and middle molecule removal on chronic hemodialysis patient survival

The type of dialysis membrane used for routine therapy has been recently shown to correlate with the survival of chronic hemodialysis patients. We examined whether this effect of dialysis membrane could be explained by differences in dialyzer removal of middle molecules using data from the 1991 Case Mix Adequacy Study of the United States Renal Data System. The sample analyzed included patients who had been treated by hemodialysis for 1 year or more, who were dialyzed with the 19 most commonly used dialyzers in 1991, and for whom delivered urea Kt/V could be calculated from predialysis and postdialysis blood urea nitrogen concentrations. Vitamin B12 (1,355 daltons) was used as a marker for middle molecules, and the clearance of vitamin B12 was estimated based on in vitro data. After adjustments for case mix, comorbidities, and urea Kt/V, the relative risk of mortality for a 10% higher calculated total cleared volume of vitamin B12 was 0.953 (P < 0.0001 v 1.000). Similar results were obtained when middle molecule removal was adjusted for body size. We conclude that both small and middle molecule removal indices appear to be independently associated with the risk of mortality in chronic hemodialysis patients. Differences in mortality when using different types of dialysis membrane may be explained by differences in middle molecule removal.

Reducing symptoms during hemodialysis by continuously monitoring the hematocrit

Previous studies have demonstrated that patients on hemodialysis develop intradialytic symptoms when the blood volume decreases to a critical level. Using a continuous monitor (CRIT-LINE; In-Line Diagnostics, Riverdale, UT) to determine the instantaneous hematocrit and blood volume, we observed that certain intradialytic symptoms occurred at a patient-specific hematocrit. In the present study, we exploited this hematocrit threshold concept to decrease the occurrence of lightheadedness, cramping, and nausea, regardless of blood pressure changes. In the first phase of the study, hematocrit threshold was established in six hypotension-prone patients. Five patients entered into the second phase in which ultrafiltration rates were increased 25 percent above prescribed values at the beginning of the experimental sessions. Subsequently during the experimental sessions, ultrafiltration rates were manipulated to maintain the instantaneous hematocrit value 2 units below the established hematocrit threshold. Sessions without ultrafiltration rate adjustments based on hematocrit served as controls. There were no differences between experimental (n = 27) and control (n = 28) sessions with respect to treatment time (230 minutes v 229 minutes), fluid volume removed (3,351 mL v 3,383 mL), and maximum percentage change in systemic blood pressure (-26 percent v -24 percent). However, there were less symptoms during the experimental sessions (26 percent v 57 percent; P = 0.038). These data suggest that a twofold reduction in intradialytic symptoms can be achieved using continuous hematocrit monitoring without altering treatment times or volume removed in hypotension-prone patients.

Hematocrit as an indicator of blood volume and a predictor of intradialytic morbid events.

Hematocrit (H) levels can change during hemodialysis, and these changes in H are inversely related to changes in blood volume (BV). The objectives of this study were to determine whether mean arterial pressure (MAP) decreases with decreasing BV and rising H during hemodialysis, and to determine the relationship between dialysis induced intravascular volume depletion and intradialytic morbid events (IME), defined as hypotension, cramping, or lightheadedness that led to dialysis staff intervention. We monitored H continuously using a noninvasive optical technique in 93 hemodialysis sessions in 16 patients. IME occurred in 48 sessions. MAP decreased with increasing H in 10 of 16 patients (P < 0.05), but the relationship between MAP and H varied among the patients. The rate of BV change during sessions without morbidity (5.6 +/- 3.6 [SD] %/hr) was lower (P < 0.001) than that preceding IME in the other sessions (12.2 +/- 5.5 [SD] %/hr). Twelve of 16 patients who exhibited recurrent IME during this study experienced these events when H reached a patient specific threshold. It is concluded that MAP decreases with decreasing BV and increasing H in many patients on hemodialysis, and that a high rate of BV change often indicates that IME are forthcoming. It is further hypothesized that a patient specific H threshold is indicative of a critical BV level below which certain patients experience IME.

Association between Serum β2-Microglobulin Level and Infectious Mortality in Hemodialysis Patients

BACKGROUND AND OBJECTIVES Secondary analysis of the Hemodialysis Study showed that serum beta(2)-microglobulin levels predicted all-cause mortality and that high-flux dialysis was associated with decreased cardiac deaths in hemodialysis patients. This study examined the association of serum beta(2)-microglobulin levels and dialyzer beta(2)-microglobulin kinetics with the two most common causes of deaths: Cardiac and infectious diseases. Cox regression analyses were performed to relate cardiac or infectious deaths to cumulative mean follow-up predialysis serum beta(2)-microglobulin levels while controlling for baseline demographics, comorbidity, residual kidney function, and dialysis-related variables. RESULTS The cohort of 1813 patients experienced 180 infectious deaths and 315 cardiac deaths. The adjusted hazard ratio for infectious death was 1.21 (95% confidence interval 1.07 to 1.37) per 10-mg/L increase in beta(2)-microglobulin. This association was independent of the prestudy years on dialysis. In contrast, the association between serum beta(2)-microglobulin level and cardiac death was not statistically significant. In similar regression models, higher cumulative mean Kt/V of beta(2)-microglobulin was not significantly associated with either infectious or cardiac mortality in the full cohort but exhibited trends suggesting an association with lower infectious mortality (relative risk 0.93; 95% confidence interval 0.86 to 1.01, for each 0.1-U increase in beta(2)-microglobulin Kt/V) and lower cardiac mortality (relative risk 0.93; 95% confidence interval 0.87 to 1.00) in the subgroup with >3.7 prestudy years of dialysis. CONCLUSIONS These results generally support the notion that middle molecules are associated with systemic toxicity and that their accumulation predisposes dialysis patients to infectious deaths, independent of the duration of maintenance dialysis.

Predicting treatment dose for novel therapies using urea standard Kt/V.

Calculation of urea standard Kt/V (stdKt/V) as a dose measure for guiding novel hemodialysis or hemofiltration therapy prescription is complex since this parameter depends on the magnitude of posttreatment urea rebound. We propose here a two‐step procedure for calculating urea stdKt/V from single‐pool urea Kt/V values (spKt/V) determined from serum urea concentrations in pretreatment and posttreatment blood samples. First, the dependence of urea stdKt/V on equilibrated Kt/V (eKt/V) was derived from a fixed‐volume single‐pool model. Second, an empirical equation for predicting urea eKt/V from urea spKt/V values was determined using multiple linear regression and available data during 4‐hour hemodialysis, 2‐hour hemodialysis, and 2‐hour hemofiltration treatments. This empirical (rate/dose) equation is likely more robust for novel therapies than other equations derived from only data during conventional (4‐hour) hemodialysis treatments. The combination of these formulas allowed construction of nomograms for calculating urea stdKt/V from spKt/V during novel therapies. These principles were further illustrated by calculating the predicted treatment dose for daily (six times per week) hemofiltration therapy required to achieve a given urea stdKt/V.

Factors that affect postdialysis rebound in serum urea concentration, including the rate of dialysis: results from the HEMO Study.

Previous studies have suggested that postdialysis urea rebound is related to K/V, the rate of dialysis, but a systematic analysis of factors that affect rebound has not been reported. With the use of 30-min and, in a subset, 60-min postdialysis samples, postdialysis urea rebound was measured to (1) determine how well previously proposed equations based on the rate of dialysis (K/V) predict rebound in a large sample of patients with varying characteristics, (2) determine whether other factors besides K/V affect rebound, and (3) estimate more precise values for coefficients in prediction equations for rebound. Rebound was calculated relative to both immediate and 20-s postdialysis samples to study early components of rebound unrelated to access recirculation. The equilibrated Kt/V (eKt/V) computed by fitting the two-pool variable volume model to the 30-min postdialysis sample agreed well with eKt/V based on the 60-min postdialysis sample. Using the pre-, post-, and 30-min postdialysis samples for 1245 patients with arteriovenous (AV) accesses, the median intercompartmental mass transfer coefficient (Kc) was 797 ml/min for rebound computed relative to the 20-s postdialysis samples and 592 ml/min relative to the immediate postdialysis samples. K/V was the strongest predictor of rebound among 22 factors considered. Other factors associated with greater rebound for 1331 patients using AV accesses or venous catheters included access type, black race, male gender, absence of congestive heart failure, greater age, ultrafiltration rate, and low predialysis or intradialysis systolic BP. Equations of the form eKt/V = single-pool Kt/V - B x (K/V) were fit to the data. With AV access, the optimum values for the slope term (B) were 0.39 and 0.46 (in h(-1)) for single-pool Kt/V calculated based on 20-s postdialysis or immediate postdialysis samples, respectively. For patients using venous catheters, the respective values for B were 0.22 and 0.29. Postdialysis urea rebound can be predicted with acceptable accuracy from a postdialysis sample using a zero-intercept, K/V-based rate equation. Several patient or treatment-specific factors predict enhanced or reduced rebound. Rate equation slope coefficients for K/V of 0.39 (AV access) and 0.22 (venous access) are proposed when a 15- to 20-s slow-flow method is used to draw the postdialysis blood. Slightly higher K/V slope coefficients (0.46 and 0.29, respectively) should be used if a shorter (e.g., 10 s) slow-flow period is used.

Kinetics of β2-Microglobulin and Phosphate during Hemodialysis: Effects of Treatment Frequency and Duration

Current understanding of β2‐microglobulin (β2M) and phosphate (or inorganic phosphorus) kinetics during hemodialysis is reviewed. The postdialysis:predialysis concentration ratio for β2M is determined by dialyzer clearance for β2M, treatment time, patient body size (specifically, extracellular fluid volume), and total ultrafiltration volume during the treatment. Evaluation of these treatment parameters can be used to calculate dialyzer clearance for β2M; however, such calculated values are only approximations, since they neglect intradialytic generation, nonrenal (nondialyzer) clearance, and postdialysis rebound of β2M. The detailed kinetics of β2M during hemodialysis are best described using a two‐compartment model. Theoretical predictions from such two‐compartment models suggest that the product of dialyzer clearance for β2M and weekly treatment duration, independent of treatment frequency, is the main determinant of plasma β2M concentrations. The kinetics of phosphate removal during hemodialysis are incompletely understood. Phosphate is removed from both extracellular and intracellular compartments during hemodialysis; the plasma phosphate concentration levels off after the first 1 or 2 hours of treatment and plasma concentrations can rebound even before therapy is complete. Increases in dialyzer clearance of phosphate have been previously achieved only by increasing dialysis membrane surface area or by the use of hemodiafiltration. A four‐compartment model of phosphate kinetics proposed recently by Spalding et al. suggests that the major barrier to phosphate removal is limited transfer of phosphate between the intracellular and extracellular compartments, although other complex factors also play important roles. Theoretical predictions using the model of Spalding et al. suggest that increasing either treatment frequency or treatment duration can increase phosphate removal. The kinetics of β2M are representative of middle molecules whose removal during hemodialysis is governed predominantly by clearance at the dialyzer. In contrast, phosphate removal is limited primarily by its sequestration in the intracellular compartment (and possibly other compartments), not by its clearance at the dialyzer. The kinetics of phosphate may therefore be representative of uremic toxins whose removal is limited by sequestration into compartments or by protein binding. Enhanced removal of both of these uremic toxins using a given therapy will require treatments of increased frequency and longer duration.

Ultrafiltration method for measuring vascular access flow rates during hemodialysis

BACKGROUND The vascular access blood flow rate (QA) has been shown to be an important predictor of vascular access failure; therefore, the routine measurement of QA may prove to be a useful clinical method of vascular access assessment. METHODS We have developed a new ultrafiltration (UF) method for determining QA during HD from changes in arterial hematocrit (H) after abrupt changes in the UF rate with the dialysis blood lines in the normal (DeltaHn) and reverse (DeltaHr) configurations. This method accounts for cardiopulmonary recirculation and requires neither intravenous saline injections nor accurate knowledge of the dialyzer blood flow rate. Clinical studies were conducted in 65 chronic HD patients from three different dialysis programs to compare QA determined by the UF method with that determined by saline dilution using an ultrasound flow sensor. RESULTS Arterial H increased (P<0.0001) after abrupt increases in the UF rate when the lines were in the normal and reverse configurations. An increase in the UF rate from the minimum setting to 1.8 liter/hr resulted in a DeltaHn of 0.3+/-0.2 (mean +/- SD) H units and a DeltaHr of 1.6+/-1.0 H units. Q(A) values determined by the UF method (1050+/-460 ml/min) were 16+/-25% higher (P<0.001) than those determined by saline dilution (950+/-440 ml/min); the calculated QA values by the UF and saline dilution methods correlated highly with each other (R = 0.92, P<0.0001). The average coefficient of variation for duplicate measurements of QA determined by the UF method in a subset of these patients (N = 21) was approximately 10% when assessed in either the same dialysis session or consecutive sessions. CONCLUSIONS The results from this study show that changes in arterial H after abrupt changes in the UF rate can be used to assess Q(A).