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.

Creatinine generation from kinetic modeling with or without postdialysis serum creatinine measurement: results from the HEMO study.

BACKGROUND: A convenient method to estimate the creatinine generation rate and measures of creatinine clearance in hemodialysis patients using formal kinetic modeling and standard pre- and postdialysis blood samples has not been described. METHODS: We used data from 366 dialysis sessions characterized during follow-up month 4 of the HEMO study, during which cross-dialyzer clearances for both urea and creatinine were available. Blood samples taken at 1 h into dialysis and 30 min and 60 min after dialysis were used to determine how well a two-pool kinetic model could predict creatinine concentrations and other kinetic parameters, including the creatinine generation rate. An extrarenal creatinine clearance of 0.038 l/kg/24 h was included in the model. RESULTS: Diffusive cross-dialyzer clearances of urea [230 (SD 37 mL/min] correlated well (R2 = 0.78) with creatinine clearances [164 (SD 30) mL/min]. When the effective diffusion volume flow rate was set at 0.791 times the blood flow rate for the cross-dialyzer clearance measurements at 1 h into dialysis, the mean calculated volume of creatinine distribution averaged 29.6 (SD 7.2) L], compared with 31.6 (SD 7.0) L for urea (P < 0.01). The modeled creatinine generation rate [1183 (SD 463) mg/day] averaged 100.1 % (SD 29; median 99.3) of that predicted in nondialysis patients by an anthropometric equation. A simplified method for modeling the creatinine generation rate using the urea distribution volume and urea dialyzer clearance without use of the postdialysis serum creatinine measurement gave results for creatinine generation rate [1187 (SD 475) mg/day; that closely matched the value calculated using the formally modeled value, R2 = 0.971]. CONCLUSIONS: Our analysis confirms previous findings of similar distribution volumes for creatinine and urea. After taking extra-renal clearance into consideration, the creatinine generation rate in dialysis patients is similar to that in nondialysis patients. A simplified method based on urea clearance and urea distribution volume not requiring a postdialysis serum creatinine measurement can be used to yield creatinine generation rates that closely match those determined from standard modeling.

Assessing the Adequacy of Small Solute Clearance for Various Dialysis Modalities, with Inclusion of Residual Native Kidney Function.

Measurement of small molecule clearance remains important in the clinical care of patients requiring long-term dialysis. Many patients maintain a significant degree of residual native kidney function and may have nontraditional schedules with or without combined dialysis modalities. In this review, we examine and outline methods for comparing small molecule clearances among various dialysis prescriptions and modalities, with inclusion of residual kidney urea clearance.

Dose Targeting Metrics in Conventional and Intensive Maintenance Dialysis.

Hemodialysis has come a long way since its early days and is a life sustaining therapy for millions of people with end-stage kidney disease throughout the world. Although thrice weekly hemodialysis remains the most common form of renal replacement therapy, other therapies such as more frequent, prolonged dialysis modalities have seen a rise recently. In this review, we compare and contrast methods for measuring the dialysis dose, with a focus on small molecule clearance (Kt/Vurea ) among various dialysis modalities. We also describe newer on-line methods to measure dialysis and limitations to current adequacy measurement. Distinguishing dialysis adequacy from adequate treatment of the patient is also emphasized.

Metabolic Profiling of Impaired Cognitive Function in Patients Receiving Dialysis.

Retention of uremic metabolites is a proposed cause of cognitive impairment in patients with ESRD. We used metabolic profiling to identify and validate uremic metabolites associated with impairment in executive function in two cohorts of patients receiving maintenance dialysis. We performed metabolic profiling using liquid chromatography/mass spectrometry applied to predialysis plasma samples from a discovery cohort of 141 patients and an independent replication cohort of 180 patients participating in a trial of frequent hemodialysis. We assessed executive function with the Trail Making Test Part B and the Digit Symbol Substitution test. Impaired executive function was defined as a score ≥2 SDs below normative values. Four metabolites-4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline-were associated with impaired executive function at the false-detection rate significance threshold. After adjustment for demographic and clinical characteristics, the associations remained statistically significant: relative risk 1.16 (95% confidence interval [95% CI], 1.03 to 1.32), 1.39 (95% CI, 1.13 to 1.71), 1.24 (95% CI, 1.03 to 1.50), and 1.20 (95% CI, 1.05 to 1.38) for each SD increase in 4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline, respectively. The association between 4-hydroxyphenylacetate and impaired executive function was replicated in the second cohort (relative risk 1.12; 95% CI, 1.02 to 1.23), whereas the associations for phenylacetylglutamine, hippurate, and prolyl-hydroxyproline did not reach statistical significance in this cohort. In summary, four metabolites related to phenylalanine, benzoate, and glutamate metabolism may be markers of cognitive impairment in patients receiving maintenance dialysis.

The Saga of Two Centuries of Urea: Nontoxic Toxin or Vice Versa?

In the early 1700s, a substance ultimately identified as urea was reported for the first time in urine. About a century later, in 1828, synthesis of this organic compound was achieved, thus giving rise to modern organic chemistry. In parallel, physicians showed that urine comes from the kidneys and contains large amounts of urea, which is produced outside of the kidneys, establishing the humoral approach of renal physiology. Urea was the first uremic retention solute to be identified and it has been used as a marker of renal disease ever since. However, progress in the knowledge of urea metabolism has shown that it is susceptible to many extrarenal variations and, therefore, it cannot be a reliable marker of renal function. It reflects protein intake in the stable patient and has been used to assess nutrition and dialysis efficacy in renal patients. Although it has been studied for almost 200 years, its toxicity has been largely debated. An indirect toxicity occurring through carbamylation of lysine residues is now well established and some evidence from recent work also supports direct toxicity of urea, offering additional rationale for interventional prevention of uremic complications.

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 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.

Improved equation for estimating single-pool Kt/V at higher dialysis frequencies.

RATIONALE: To measure adequacy in patients dialyzed other than three times per week, guidelines recommend the use of 'standard' Kt/V, which commonly is estimated from treatment Kt/V, time and frequency; however, the accuracy of equations that predict treatment Kt/V in patients being dialyzed other than three times per week has not been evaluated. METHODS: In patients enrolled in the Frequent Hemodialysis Network (FHN) Daily and Nocturnal Trials who were being dialyzed three, four or six times per week, we tested the accuracy of the following Kt/V prediction equation: Kt/V = -ln(R - GFAC × T_hours) + (4-3.5 × R) × 0.55 × weight loss/V, where R = post-dialysis/pre-dialysis blood urea nitrogen and GFAC, originally set to 0.008 for a 3/week schedule (Daugirdas, J Am Soc Nephrol 1993), is a factor that adjusts for urea generation. RESULTS: With the above equation, there was <0.1% mean error in predicted treatment Kt/V for 3/week patients, but mean errors were -5, -9 and -13% for the 6/week daily, 4/week nocturnal and 6/week nocturnal patients. Modeling simulations were performed to optimize the GFAC term for dialysis schedule and length of the preceding interdialysis interval (PIDI). After substituting schedule- and interval-optimized GFAC terms, the treatment Kt/V prediction errors were reduced to -0.81, +0.1 and -1.3% for the three frequent dialysis schedules tested. CONCLUSION: For frequent dialysis schedules, the urea generation factor (GFAC) of one commonly used Kt/V prediction equation should be adjusted based on length in days of the PIDI and number of treatments per week.

Dialysate flow rate and delivered Kt/Vurea for dialyzers with enhanced dialysate flow distribution.

BACKGROUND AND OBJECTIVES: Previous in vitro and clinical studies showed that the urea mass transfer-area coefficient (K(o)A) increased with increasing dialysate flow rate. This observation led to increased dialysate flow rates in an attempt to maximize the delivered dose of dialysis (Kt/V(urea)). Recently, we showed that urea K(o)A was independent of dialysate flow rate in the range 500 to 800 ml/min for dialyzers incorporating features to enhance dialysate flow distribution, suggesting that increasing the dialysate flow rate with such dialyzers would not significantly increase delivered Kt/V(urea). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a multi-center randomized clinical trial to compare delivered Kt/V(urea) at dialysate flow rates of 600 and 800 ml/min in 42 patients. All other aspects of the dialysis prescription, including treatment time, blood flow rate, and dialyzer, were kept constant for a given patient. Delivered single-pool and equilibrated Kt/V(urea) were calculated from pre- and postdialysis plasma urea concentrations, and ionic Kt/V was determined from serial measurements of ionic dialysance made throughout each treatment. RESULTS: Delivered Kt/V(urea) differed between centers; however, the difference in Kt/V(urea) between dialysate flow rates of 800 and 600 ml/min was NS by any measure (95% confidence intervals of -0.064 to 0.024 for single-pool Kt/V(urea), -0.051 to 0.023 for equilibrated Kt/V(urea), and -0.029 to 0.099 for ionic Kt/V). CONCLUSIONS: These data suggest that increasing the dialysate flow rate beyond 600 ml/min for these dialyzers offers no benefit in terms of delivered Kt/V(urea).

Modeled urea distribution volume and mortality in the HEMO Study.

BACKGROUND AND OBJECTIVES: In the Hemodialysis (HEMO) Study, observed small decreases in achieved equilibrated Kt/V(urea) were noncausally associated with markedly increased mortality. Here we examine the association of mortality with modeled volume (V(m)), the denominator of equilibrated Kt/V(urea). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Parameters derived from modeled urea kinetics (including V(m)) and blood pressure (BP) were obtained monthly in 1846 patients. Case mix-adjusted time-dependent Cox regressions were used to relate the relative mortality hazard at each time point to V(m) and to the change in V(m) over the preceding 6 months. Mixed effects models were used to relate V(m) to changes in intradialytic systolic BP and to other factors at each follow-up visit. RESULTS: Mortality was associated with V(m) and change in V(m) over the preceding 6 months. The association between change in V(m) and mortality was independent of vascular access complications. In contrast, mortality was inversely associated with V calculated from anthropometric measurements (V(ant)). In case mix-adjusted analysis using V(m) as a time-dependent covariate, the association of mortality with V(m) strengthened after statistical adjustment for V(ant). After adjustment for V(ant), higher V(m) was associated with slightly smaller reductions in intradialytic systolic BP and with risk factors for mortality including recent hospitalization and reductions in serum albumin concentration and body weight. CONCLUSIONS: An increase in V(m) is a marker for illness and mortality risk in hemodialysis patients.

In-center hemodialysis six times per week versus three times per week.

BACKGROUND: In this randomized clinical trial, we aimed to determine whether increasing the frequency of in-center hemodialysis would result in beneficial changes in left ventricular mass, self-reported physical health, and other intermediate outcomes among patients undergoing maintenance hemodialysis. METHODS: Patients were randomly assigned to undergo hemodialysis six times per week (frequent hemodialysis, 125 patients) or three times per week (conventional hemodialysis, 120 patients) for 12 months. The two coprimary composite outcomes were death or change (from baseline to 12 months) in left ventricular mass, as assessed by cardiac magnetic resonance imaging, and death or change in the physical-health composite score of the RAND 36-item health survey. Secondary outcomes included cognitive performance; self-reported depression; laboratory markers of nutrition, mineral metabolism, and anemia; blood pressure; and rates of hospitalization and of interventions related to vascular access. RESULTS: Patients in the frequent-hemodialysis group averaged 5.2 sessions per week; the weekly standard Kt/V(urea) (the product of the urea clearance and the duration of the dialysis session normalized to the volume of distribution of urea) was significantly higher in the frequent-hemodialysis group than in the conventional-hemodialysis group (3.54±0.56 vs. 2.49±0.27). Frequent hemodialysis was associated with significant benefits with respect to both coprimary composite outcomes (hazard ratio for death or increase in left ventricular mass, 0.61; 95% confidence interval [CI], 0.46 to 0.82; hazard ratio for death or a decrease in the physical-health composite score, 0.70; 95% CI, 0.53 to 0.92). Patients randomly assigned to frequent hemodialysis were more likely to undergo interventions related to vascular access than were patients assigned to conventional hemodialysis (hazard ratio, 1.71; 95% CI, 1.08 to 2.73). Frequent hemodialysis was associated with improved control of hypertension and hyperphosphatemia. There were no significant effects of frequent hemodialysis on cognitive performance, self-reported depression, serum albumin concentration, or use of erythropoiesis-stimulating agents. CONCLUSIONS: Frequent hemodialysis, as compared with conventional hemodialysis, was associated with favorable results with respect to the composite outcomes of death or change in left ventricular mass and death or change in a physical-health composite score but prompted more frequent interventions related to vascular access. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT00264758.).

Can rescaling dose of dialysis to body surface area in the HEMO study explain the different responses to dose in women versus men?

BACKGROUND AND OBJECTIVES: In the Hemodialysis (HEMO) Study, the lower death rate in women but not in men assigned to the higher dose (Kt/V) could have resulted from use of "V" as the normalizing factor, since women have a lower anthropometric V per unit of surface area (V/SA) than men. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The effect of Kt/V on mortality was re-examined after normalizing for surface area and expressing dose as surface area normalized standard Kt/V (SAn-stdKt/V). RESULTS: Both men and women in the high-dose group received approximately 16% more dialysis (when expressed as SAn-stdKt/V) than the controls. SAn-stdKt/V clustered into three levels: 2.14/wk for conventional dose women, 2.44/wk for conventional dose men or 2.46/wk for high-dose women, and 2.80/wk for high-dose men. V/SA was associated with the effect of dose assignment on the risk of death; above 20 L/m(2), the mortality hazard ratio = 1.23 (0.99 to 1.53); below 20 L/m(2), hazard ratio = 0.78 (0.65 to 0.95), P = 0.002. Within gender, V/SA did not modify the effect of dose on mortality. CONCLUSIONS: When normalized to body surface area rather than V, the dose of dialysis in women in the HEMO Study was substantially lower than in men. The lowest surface-area-normalized dose was received by women randomized to the conventional dose arm, possibly explaining the sex-specific response to dialysis dose. Results are consistent with the hypothesis that when dialysis dose is expressed as Kt/V, women, due to their lower V/SA ratio, require a higher amount than men.

Effects of reduced intradialytic urea generation rate and residual renal clearance on modeled urea distribution volume and Kt/V in conventional, daily, and nocturnal dialysis.

Classic urea modeling assumes that both urea generation rate (G) and residual renal urea clearance (Kru) are constant throughout the week, but this may not be true. Reductions in intradialysis G could be caused by lower plasma amino acid levels due to predialysis/intradialysis fasting and also to losses of amino acids into the dialysate. Intradialytic reductions in Kru could be due to lower intravascular volume, blood pressure, or osmotic load. To determine the possible effects of reduced G or Kru during dialysis on the calculation of the volume of distribution (V) and Kt/Vurea, we modeled 3 and 6/week nocturnal, 6/week short daily, and 3/week conventional hemodialysis. A modified 2-pool mathematical model of urea mass balance with a constant time-averaged G was used, but the model was altered to allow adjustment of the ratio of dialytic/interdialytic G (Gd/Gid) and dialytic/total Kru (Krud/Kru) to vary from 1.0 down to near zero. In patients dialyzed six times per week for 400 minutes per session, when Gd/Gid was decreased from 1.0 to 0.05, the predicted urea reduction ratio (URR) increased from 68.9% to 80.2%. To achieve an increased URR of this magnitude under conditions of constant G (Gd/Gid=1.0) required a decrease in modeled urea volume (V) of 36%. At Gd/Gid ratios of 0.8 or 0.6 (corresponding to 20% or 40% reductions in intradialysis G), the modeled URR was increased to 71.0% or 73.3%, causing a 7% or 15% factitious decrease in V. The error was intermediate for the 3/week nocturnal schedule, and was much less pronounced for the 6/week daily and 3/week conventional treatments. Reductions in intradialytic Kru had the opposite effect, lowering the predicted URR and increasing the apparent V, but here the errors were of much lesser amplitude. The results suggest that, particularly for nocturnal dialysis, the standard "constant G" urea kinetic model may need to be modified.

Standard Kt/Vurea: a method of calculation that includes effects of fluid removal and residual kidney clearance.

Standard Kt/V(urea) (stdKt/V) is a hypothetical continuous clearance in patients treated with intermittent hemodialysis based on the generation rate of urea nitrogen and the average predialysis urea nitrogen. Previous equations to estimate stdKt/V were derived using a fixed-volume model. To determine the impact of fluid removal as well as residual urea clearance on stdKt/V, we modeled 245 hemodialysis sessions (including conventional 3/week, in-center 6/week, and at-home nocturnal 6/week) in 210 patients enrolled in the Frequent Hemodialysis Network Daily and Nocturnal clinical trials. To examine the role of fluid removal, modeled stdKt/V was compared to stdKt/V estimated from a previously published simplified equation. In a subgroup of 45 sessions with residual urea clearance over 1.5 ml/min, the contribution of residual urea clearance to stdKt/V was measured. For all dialysis schedules, the fixed-volume equation predicted stdKt/V well when both fluid removal and residual urea clearance were set to zero. When fluid removal was included, modeled stdKt/V was slightly underestimated for all three modes of hemodialysis. The shortfall correlated directly with weekly fluid removal and inversely with modeled urea volume. Modeled stdKt/V compressed residual urea clearance to about 70% of its measured value and the fractional downsizing significantly correlated inversely with treatment Kt/V. Our new equation predicted modeled stdKt/V with a high level of accuracy, even when substantial fluid removal and residual urea clearance were present.

Solute-solver: a web-based tool for modeling urea kinetics for a broad range of hemodialysis schedules in multiple patients.

Practical application of urea kinetic modeling to measure the delivered dose of hemodialysis is hampered by lack of a reference or gold-standard program that would be widely available and freely distributed. We developed and here describe an open-source JavaScript tool, "Solute-Solver," capable of batch processing of urea kinetics calculations. The Solute-Solver online interface is available at (www.ureakinetics.org); in addition, the tool can be used as a standalone HTML file that is designed to be run using a web browser. Solute-Solver is written in uncompiled JavaScript for transparency and easy modification, and the source code is available for download and modification. The program uses fourth-order Runge-Kutta numerical integration applied to a variable-extracellular-volume 2-pool model to compute a variety of clearance measures, including 1-pool and 2-pool Kt/V, "standard" weekly Kt/V, and other equivalent clearance measures. The program accepts comma- or semicolon-delimited input (which can be produced from a spreadsheet) and generates a separator-delimited output file that can be imported back into a spreadsheet or other database. The program also produces individual patient-by-patient report pages. It typically provides kinetic output for 300 patient treatments in 30-60 seconds. Advantages of this program over previously available equations and algorithms include the capacity to properly model such newer dialysis schedules as 6-times-weekly short daily or nocturnal hemodialysis, as well as account for substantial variation in residual renal function. Ultimately, this effort may promote wider use of formal urea modeling and facilitate research that requires measurement of hemodialysis or hemodialysis adequacy, especially involving the newer expressions of continuous equivalent clearance, and expressions of clearance normalized to body surface area.