Ultrafiltration Rate Levels in Hemodialysis Patients Associated with Weight-Specific Mortality Risks.

BACKGROUND: We hypothesized that the association of ultrafiltration rate with mortality in hemodialysis patients was differentially affected by weight and sex and sought to derive a sex- and weight-indexed ultrafiltration rate measure that captures the differential effects of these parameters on the association of ultrafiltration rate with mortality. METHODS: Data were analyzed from the US Fresenius Kidney Care (FKC) database for 1 year after patient entry into a FKC dialysis unit (baseline) and over 2 years of follow-up for patients receiving thrice-weekly in-center hemodialysis. To investigate the joint effect of baseline-year ultrafiltration rate and postdialysis weight on survival, we fit Cox proportional hazards models using bivariate tensor product spline functions and constructed contour plots of weight-specific mortality hazard ratios over the entire range of ultrafiltration rate values and postdialysis weights (W). RESULTS: In the studied 396,358 patients, the average ultrafiltration rate in ml/h was related to postdialysis weight (W) in kg: 3W+330. Ultrafiltration rates associated with 20% or 40% higher weight-specific mortality risk were 3W+500 and 3W+630 ml/h, respectively, and were 70 ml/h higher in men than in women. Nineteen percent or 7.5% of patients exceeded ultrafiltration rates associated with a 20% or 40% higher mortality risk, respectively. Low ultrafiltration rates were associated with subsequent weight loss. Ultrafiltration rates associated with a given mortality risk were lower in high-body weight older patients and higher in patients on dialysis for more than 3 years. CONCLUSIONS: Ultrafiltration rates associated with various levels of higher mortality risk depend on body weight, but not in a 1:1 ratio, and are different in men versus women, in high-body weight older patients, and in high-vintage patients.

Residual Renal Phosphate Clearance in Patients Receiving Hemodialysis or Hemodiafiltration.

OBJECTIVES: Substantial levels of residual renal clearance and urine output may occur in patients treated with hemodialysis or hemodiafiltration. However, the relationships among residual renal urea, creatinine, and phosphate clearances, respectively, and between clearances and urine volume have not been well described. METHODS: We performed a prospective, cross-sectional study which enrolled hemodialysis and hemodiafiltration patients with a urine volume of >100 mL/day, in whom at least 2 residual renal clearances were obtained over a 6-month observation period. Urine was collected for 24 hours prior to the midweek treatment session and concentrations of urea, creatinine, and phosphate were measured. RESULTS: Thirty-eight patients (24 men, 14 women) with a mean age of 70.4 ± 12.4 (SD) years were included in this analysis. All patients were dialyzed 3 times per week with mean treatment duration of 243 ± 7.89 minutes. Twenty patients were undergoing hemodiafiltration and 18 patients high-flux hemodialysis. In total, 102 dialysis sessions, of which 52 were hemodiafiltration, and urine collections were analyzed. Mean urine volume was 457 ± 254 mL per 24 hours. Residual renal clearance rates of urea (Kr Urea), creatinine (Kr Cr), and phosphate (Kr Phos) were 1.60 ± 0.979, 4.69 ± 3.79, and 1.98 ± 1.36 mL/minute, respectively. Mean ratios of Kr Cr/Kr Urea, Kr Phos/Kr Urea, and Kr Phos/Kr Cr were 2.83 ± 1.21, 1.23 ± 0.387, and 0.477 ± 0.185, respectively. There was a modest correlation between Kr Phos and daily urine volume (r = 0.605, P = .001). CONCLUSIONS: In maintenance hemodialysis and hemodiafiltration patients, residual renal phosphate clearance is approximately 23% higher than residual renal urea clearance. Urine volume is a modestly accurate surrogate for estimating residual renal phosphate clearance, but only when urine volume is <300 mL/day.

Comparison of modeled versus reported phosphate removal and modeled versus postdialysis serum phosphate levels in conventional hemodialysis.

BACKGROUND: We compared predictions of phosphate removal by a 2-pool kinetic model with measured phosphate removal in spent dialysate as reported by others. METHODS: Twenty-six studies were identified that reported phosphate removal in 35 groups of patients. In almost all studies, patients were dialyzed for close to 4 h (range 3 to 6 h). For each study, group mean values of predialysis serum phosphate, body size, dialyzer K0 A urea, blood and dialysate flow rates, and session lengths were input into the kinetic model. Predictions of group mean phosphate removal and postdialysis serum phosphate were compared with reported measured values. RESULTS: Mean (by patient group) predicted phosphate removal was 931 ± 170 mg/treatment, somewhat higher (p < 0.001) than the reported measured value, 900 mg ± 287. The ratio of predicted/measured removal averaged 1.15 ± 0.427. In 5/35 patient groups (3/26 studies) the predicted/measured phosphate removal was greater than 1.50. If these groups were excluded, the mean measured phosphate removal was 990 mg versus 966 predicted, with a ratio of predicted/measured removal averaging 0.993. Measured group mean postdialysis serum phosphate values (reported in 25/35) were 2.64 ± 0.54, not significantly different from predicted (2.60 ± 0.24 mg/dl, p = NS). CONCLUSIONS: For conventional 4-h dialysis treatments, phosphate removal and postdialysis serum phosphate values predicted by a 2-pool kinetic model are similar to reported measured values.

Ultrafiltration Rate Thresholds Associated With Increased Mortality Risk in Hemodialysis, Unscaled or Scaled to Body Size.

Introduction: One proposed threshold ultrafiltration rate (UFR) of concern in hemodialysis patients is 13 ml/h per kg. We evaluated associations among UFR, postdialysis weight, and mortality to determine whether exceeding such a threshold would result in similar levels of risk for patients of different body weights. Methods: Data were analyzed in this retrospective cohort study for 1 year following dialysis initiation (baseline) and over 2 years of follow-up in incident patients receiving thrice-weekly in-center hemodialysis. Patient-level UFR was averaged over the baseline period. To investigate the joint effect of UFR and postdialysis weight on survival, we fit Cox proportional hazards models using bivariate tensor product spline functions, adjusting for sex, race, age, diabetes, and predialysis serum albumin, phosphorus, and systolic blood pressure (BP). We constructed contour plots of mortality hazard ratios (MHRs) over the entire range of UFR values and postdialysis weights. Results: In the studied 2542 patients, UFR not scaled to body weight was strongly associated with MHR, whereas postdialysis weight was inversely associated with MHR. MHR crossed 1.5 when unscaled UFR exceeded 1000 ml/h, and this relationship was largely independent of postdialysis weight in the range of 80 to 140 kg. A UFR warning level associated with a lower MHR of 1.3 would be 900 ml/h, whereas the UFR associated with an MHR of 1.0 was patient-size dependent. The MHR when exceeding a UFR threshold of 13 ml/h per kg was dependent on patient weight (MHR = 1.20, 1.45, and >2.0 for a 60, 80, and 100 kg patient, respectively). Conclusion: UFR thresholds based on unscaled UFR give more uniform risk levels for patients of different sizes than thresholds based on UFR/kg.

Comparison of measured vs kinetic-model predicted phosphate removal during hemodialysis and hemodiafiltration.

BACKGROUND: To what extent hemodiafiltration (HDF) improves management of hyperphosphatemia over hemodialysis (HD) is a subject of ongoing investigation. METHODS: We modified a previously described phosphate kinetic model to include incorporation of EUDIAL recommended equations for hemodiafiltration (HDF) clearance. We used the model to predict the recovery of phosphate from spent dialysate/hemofiltrate and compared this with averaged data from five published studies. Mean study average predialysis serum phosphate was 1.81 ± 0.20 mmol/L. Session length was close to 240 min per treatment. All HDF was done postdilution, at an average rate of 65 ± 24 mL/min. RESULTS: Measured mean phosphate removal was 1039 ± 136 mg (33.5 ± 4.41 mmol, slightly lower than the model-predicted mean value of 1092 ± 127 mg (35.3 ± 4.09 mmol). The measured ratio of phosphate removal with HDF compared with HD averaged 1.15 ± 0.22, ranging from 1.01 to 1.44. Using mean study input parameters for patient size and treatment characteristics, the predicted ratio of phosphate removal with HDF compared with HD averaged 1.095 ± 0.029, ranging from 1.05 to 1.13. CONCLUSIONS: Addition of EUDIAL-recommended convective clearance equations to a phosphate kinetic model predicts a 10% or greater benefit in terms of phosphate removal for HDF compared with HD at typical dialysis and hemodiafiltration treatment settings. These predictions are similar to the HDF advantage reported in the literature in studies where phosphate removal has been measured in spent dialysate.

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.

Equations to Estimate the Normalized Creatinine Generation Rate (CGRn) in 3/Week Dialysis Patients With or Without Residual Kidney Function.

OBJECTIVE: Normalized creatinine generation rate (CGRn) can be computed for a variety of dialysis schedules using a recently described kinetic modeling program. However, the availability of estimating equations might facilitate broader study of this metric. We developed equations to estimate CGRn based on modeling and then tested them against modeled CGRn values in the Frequent Hemodialysis Network Nocturnal Trial baseline (3/week) dataset. DESIGN AND METHODS: We used a "what-if" derivation of a previously published variable volume 2-pool creatinine kinetic model to generate predicted predialysis values of serum creatinine that would result from creatinine generation rates of 250-2000 mg/day in patients with creatinine distribution volumes of 20 to 50 L, dialyzed from 60 to 480 min per treatment three times a week. Then, in patients with residual kidney function, we calculated an "anuric expected predialysis serum creatinine value" before applying the same equations. We then compared estimated CGRn values as predicted by this approach with modeled values in patient data from the Frequent Hemodialysis Network Nocturnal Trial. RESULTS: The estimating equations for CGRn yielded results similar to those obtained with formal modeling, in both anuric patients and those with residual kidney function, with mean percent error of 0.845 ± 6.15 (SD) in anuric patients, and ‒0.29 ± 4.90 in patients with a mean creatinine clearance of 5.44 ± 4.82 mL/min, with R-squared values of 0.96 in both anuric patients and those with residual renal clearance of creatinine. CONCLUSIONS: In patients dialyzed 3/week, CGRn can be estimated using prediction equations. Use of these equations may facilitate broader investigation of CGRn as a measure of nutritional status and outcome.

Routine Kt/V and Normalized Protein Nitrogen Appearance Rate Determined From Conductivity Access Clearance With Infrequent Postdialysis Serum Urea Nitrogen Measurements.

RATIONALE & OBJECTIVES: Conventional monitoring of hemodialysis dose is implemented using urea kinetic modeling based on single-pool Kt/V, which requires both pre- and postdialysis serum urea nitrogen (SUN) measurements. We compared this conventional approach to one in which Kt/V is calculated using conductivity clearance, thereby reducing the need for regular postdialysis SUN measurements. STUDY DESIGN: Comparative study of 2 diagnostic tests. SETTING & PARTICIPANTS: Prevalent patients receiving maintenance hemodialysis for at least 2 years for whom both urea reduction ratio (URR) and average conductivity clearance (Kecn) were measured. TESTS COMPARED: During the initial 8 months (baseline interval), average Kecn and URR were used to calculate a median patient-specific, modeled, calibration solute distribution volume (Vcal). During months 9 to 16 (period 1) and 17 to 24 (period 2), Kt/V was conventionally computed using URR and also by a new method using Vcal and Kecn without postdialysis SUN values. We examined the percentage error between these 2 methods of calculating Kt/V. OUTCOMES: Concordance between the 2 methods of calculating Kt/V. RESULTS: Among 1,093 patients, mean individual-level median single-pool Kt/V values derived using the conventional method during the baseline interval, period 1, and period 2 were 1.62±0.24 (SD), 1.66±0.24, and 1.67±0.24, respectively. During periods 1 and 2, patient-level median Kt/V values derived using Kecn were 1.64±0.24 and 1.65±0.24, respectively. Percent differences between patient-level median values of Kt/V (conductivity minus conventional URR methods) were-0.63%±7.7% and-0.75%±8.4% for periods 1 and 2. Normalized protein nitrogen appearance were comparable between the 2 methods. LIMITATIONS: Data were collected over 2 years. Study was limited to in-center hemodialysis patients dialyzed 3 times per week. Dialysis session length was not adjusted for treatment interruptions. CONCLUSIONS: A new method of calculating Kt/V based on Kecn that requires fewer postdialysis SUN measurements provided diagnostic data comparable to those from conventional use of URR and has the potential to avoid errors related to postdialysis blood sampling and measurement.

Quantifying the Effect of Plasma Viscosity on In Vivo Dialyzer Performance.

Dialyzer manufacturers characterize performance of their devices based on measurements of clearance using crystalloid solutions. Typically, in vitro dialyzer mass transfer area coefficients for urea (K0A) are substantially higher than values measured in vivo. The reason for this reduction has not been clearly determined. We hypothesized that the known effect of viscosity on reducing solute diffusivity might partially or fully account for this reduction. In vitro dialyzer clearances of urea, glucose, and lactate were measured using crystalloid solutions as well as bovine blood with varying hematocrit and plasma viscosity under a wide range of operating conditions. Viscosities of crystalloid solutions, of blood plasma, and of whole blood were measured at 37°C at a shear rate of 100/s. Diffusivity and relative K0A values (K0Arel) in eight dialyzers were computed for each solute under these different conditions. Plasma was 1.84 times more viscous compared with crystalloid solution (ηrel = 1.84), suggesting a correction multiplier of 1/ηrel = 0.54 for in vivo K0A relative to the in vitro value. Experimental K0Arel at that ηrel was on average reduced to 52% of crystalloid in vitro K0A values. The multiplier 0.52 measured in this study is close to the multiplier 0.55 predicted for average plasma viscosities and also close to the multiplier 0.54 assumed for urea kinetic modeling to provide reasonable urea distribution volumes. The known effect of viscosity on solute diffusivity is therefore sufficient to explain the reduction in dialyzer K0A for urea and glucose in vivo compared with in vitro measurements.

Modeled Daily Ingested, Absorbed and Bound Phosphorus: New Measures of Mineral Balance in Hemodialysis Patients.

BACKGROUND: Control of predialysis serum phosphorus in hemodialysis patients is challenging. We explored the utility of a novel kinetic phosphorus modeling program. METHODS: As part of a quality assurance program, urea kinetic modeling results were combined with those from phosphorus kinetic modeling to compute modeled daily ingested phosphorus (DIP) and components making up this metric, including absorbed, bound, and nonabsorbed, nonbound phosphorus. RESULTS: In 182 hemodialysis patients, DIP averaged 1,089 ± 348 mg/day in men and 934 ± 292 in women (p < 0.002) and correlated substantially with body weight. DIP/kg bodyweight (12.8 ± 3.40 mg/kg) was not significantly different between the sexes. Prescribed equivalent binder dose (EBD) was 4.98 ± 3.61 and 4.53 ± 3.02 g/day in men and women, respectively (p NS). Protein catabolic rate (PCR) was significantly higher in men (64.4 ± 18) g/day vs. women (48.2 ± 15.6, p < 0.001), and the DIP/PCR ratio was 17.4 ± 4.81 in men vs. 20.1 ± 5.76 in women (p < 0.001). Presence of residual kidney function was associated with a lower prescribed EBD dose (4.08 ± 2.62 vs. 5.38 ± 3.81 g/day, p < 0.01). Self-reported poor binder compliance was associated with higher DIP or DIP/kg as well as higher prescribed EBD. In anuric patients, DIP/kg was increased in patients consuming diets with high phosphate additive content and those reporting poor compliance with the prescribed dose of phosphate binders. CONCLUSIONS: The combination of urea kinetic and phosphorus modeling can be used to estimate measures related to phosphorus intake. High DIP/PCR or DIP/kg body weight values in anuric patients suggest consumption of a diet high in phosphorus additives or noncompliance with the prescribed amount of phosphorus binders.

The TiME Trial: A Fully Embedded, Cluster-Randomized, Pragmatic Trial of Hemodialysis Session Duration.

BACKGROUND: Data from clinical trials to inform practice in maintenance hemodialysis are limited. Incorporating randomized trials into dialysis clinical care delivery should help generate practice-guiding evidence, but the feasibility of this approach has not been established. METHODS: To develop approaches for embedding trials into routine delivery of maintenance hemodialysis, we performed a cluster-randomized, pragmatic trial demonstration project, the Time to Reduce Mortality in ESRD (TiME) trial, evaluating effects of session duration on mortality (primary outcome) and hospitalization rate. Dialysis facilities randomized to the intervention adopted a default session duration ≥4.25 hours (255 minutes) for incident patients; those randomized to usual care had no trial-driven approach to session duration. Implementation was highly centralized, with no on-site research personnel and complete reliance on clinically acquired data. We used multiple strategies to engage facility personnel and participating patients. RESULTS: The trial enrolled 7035 incident patients from 266 dialysis units. We discontinued the trial at a median follow-up of 1.1 years because of an inadequate between-group difference in session duration. For the primary analysis population (participants with estimated body water ≤42.5 L), mean session duration was 216 minutes for the intervention group and 207 minutes for the usual care group. We found no reduction in mortality or hospitalization rate for the intervention versus usual care. CONCLUSIONS: Although a highly pragmatic design allowed efficient enrollment, data acquisition, and monitoring, intervention uptake was insufficient to determine whether longer hemodialysis sessions improve outcomes. More effective strategies for engaging clinical personnel and patients are likely required to evaluate clinical trial interventions that are fully embedded in care delivery.

Intradialytic hypotension and splanchnic shifting: Integrating an overlooked mechanism with the detection of ischemia-related signals during hemodialysis.

In the most simple analysis, a patient's hematocrit during hemodialysis will rise when the rate of ultrafiltration exceeds the rate at which the fluid is mobilized from extravascular spaces; the greater the rise in hematocrit, the lower blood volume is and the more likely intradialytic hypotension (IDH) is to occur. A secondary mechanism of IDH may be due to sudden shift of blood volume away from the heart under conditions of borderline cardiac filling. A substantial portion of blood volume resides in the splanchnic venous system. During the early part of dialysis, a centripetal shift of red cells from this anatomical region to the central circulation has been documented to occur. The magnitude of this shift is unpredictable, and it may depend on the level of splanchnic vasoconstriction predialysis. The amount of splanchnic shift may also be reduced in patients with autonomic dysfunction. Once this central shift in blood volume has occurred, it can be reversed during further ultrafiltration due to ischemia-induced release of vasodilatory molecules that cause dilation of upstream splanchnic arterioles; this causes increased transmission of arterial pressure to the splanchnic veins, acutely increasing their capacity. The increased splanchnic venous capacity may cause a sudden shift of blood away from the central circulation to fill these veins under conditions where cardiac filling has already been reduced. The result can be severe IDH due to insufficient cardiac filling and cardiac output. One fruitful preventive approach might be to continuously monitor the blood or dialysate for the sudden appearance of such ischemia-related molecules or other signals which may herald not only dialysis hypotension but tissue stunning, warning that the fluid removal rate should be immediately reduced.

Eliminating the need for routine monthly postdialysis serum urea nitrogen measurement: A method for monitoring Kt/V and normalized protein catabolic rate using conductivity determined dialyzer clearance.

Many dialysis machines can compute dialyzer sodium clearances at multiple time points during a dialysis treatment using conductivity. For a given treatment, the average dialyzer sodium clearance (K), when combined with treatment time (t), and the estimated urea distribution volume (V, usually based on either anthropometry or bioimpedance), can be used to estimate Kt/V, an important measure of hemodialysis adequacy. While this conductivity-derived value for Kt/V correlates moderately with Kt/V calculated from predialysis and postdialysis serum urea nitrogen (SUN) values (urea reduction ratio, URR), the ultrafiltration volume, and session length it is, unfortunately, not sufficiently accurate to replace URR-based Kt/V. Here we underline the potential utility of an alternative method to estimate Kt/V (a variant of a technique originally proposed by Gotch and Levin and their colleagues) using conductivity-derived sodium clearance (K) that does not require routine measurement of the postdialysis SUN but which should closely track Kt/V computed in the usual fashion. The increased accuracy with the new method is explained by the use of a patient-specific value of V, which is an average value calculated from several dialysis sessions where both conductivity dialyzer clearance and predialysis and postdialysis SUN have been measured. Once this patient-specific conductivity/URR-based value for V has been determined, it can be used to calculate Kt/V for subsequent treatments in which conductivity-based dialyzer clearances are measured, but around which predialysis and postdialysis SUN values have not been obtained. (If the predialysis SUN values for such a subsequent treatment are also measured, then a normalized protein catabolic rate that closely tracks the value from conventional urea modeling, can also be determined.) By reducing the number of postdialysis SUN measurements needed to monitor hemodialysis adequacy this new method of estimating Kt/V by conductivity should save staff time and laboratory costs, increase patient and staff safety, and decrease error rates associated with improper postdialysis blood sampling technique.

Changes in Total Protein Concentration Due to Fluid Removal During and Shortly after Hemodialysis.

BACKGROUND: Changes in plasma volume during hemodialysis are complex and have been shown to depend on the rate of fluid removal and the degree of fluid overload. We examined changes in total protein concentration during and shortly after a dialysis treatment in archived data from the HEMO study. METHODS: During follow-up months 4 and 36 of the HEMO study, additional blood samples were obtained during a typical dialysis session at 30 and 60 min after dialysis. In 315 studies from 282 patients where complete data were available, we calculated the concentration change in total protein and compared it to the modeled change in both total body water and extracellular fluid space as derived from 2-pool urea kinetic modeling. RESULTS: The mean postdialysis modeled urea volume (V) was 31.1 ± 6.18 L. Mean fluid removal was 2.76 ± 1.27 kg, over a session length of 207 ± 28 min. The ratio of predialysis V to postdialysis V averaged 1.090 ± 0.040. The mean TP ratios (post/pre) at 0, 30, and 60 min postdialysis averaged 1.121 ± 0.070 (SD), 1.091 ± 0.090, and 1.091 ± 0.086. The dialysate to serum sodium gradient, studied in a different group of treatments where this information was available, had no impact on these findings, nor did the length of the interdialytic interval. CONCLUSIONS: On average, after equilibration, the change in plasma volume due to fluid removal is similar to the modeled change in total body water (urea space), irrespective of dialysate to serum sodium gradient. This supports previous observations that during dialysis with ultrafiltration, plasma volume contracts to a lesser degree than the interstitial volume and that some fluid may be removed from spaces other than the extracellular fluid.