The Effect of Increased Frequency of Hemodialysis on Volume-Related Outcomes: A Secondary Analysis of the Frequent Hemodialysis Network Trials.

In previous reports of the Frequent Hemodialysis Network trials, frequent hemodialysis (HD) reduced extracellular fluid (ECF) and left ventricular mass (LVM), with more pronounced effects observed among patients with low urine volume (UVol). We analyzed the effect of frequent HD on interdialytic weight gain (IDWG) and a time-integrated estimate of ECF load (TIFL). We also explored whether volume and sodium loading contributed to the change in LVM over the study period. Treatment effects on volume parameters were analyzed for modification by UVol and the dialysate-to-serum sodium gradient. Predictors of change in LVM were determined using linear regression. Frequent HD reduced IDWG and TIFL in the Daily Trial. Among patients with UVol <100 ml/day, reduction in TIFL was associated with LVM reduction. This suggests that achievement of better volume control could attenuate changes in LVM associated with mortality and cardiovascular morbidity. TIFL may prove more useful than IDWG alone in guiding HD practice. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=441966.

How can we improve the solute and fluid transport prescriptions in hemodialysis to improve patient outcomes?.

Improvements in the dialysis prescription can only be achieved by changes in solute and water transport which provide better control of the metabolic uremic abnormalities that are amenable to dialysis. The key abnormalities identified here are protein catabolites, fluid and electrolyte balance, calcium and phosphorus balance and bone metabolism and acid-base balance. The history of the dialysis prescription is reviewed and changes which might improve the control of these metabolic systems are described. This review concludes there is no support for the recommendation of the routine application of long treatment time and routine use of hemodiafiltration.

Application of kinetic modeling to mineral metabolism management.

Patients with CKD face many consequences of renal failure, including disorders of bone and mineral metabolism. The current approach to management of these mineral metabolism issues lacks comprehensive quantitative assessment, so a kinetic modeling program has been designed to quantify intake and removal of phosphorus and calcium, as well as provide recommendations for treatment and prescriptions based on total mass balance and serum concentrations. This program is known as phosphorus kinetic modeling or PKM. The modeling program and associated graphical reports have been developed as a tool for clinicians in the management of mineral metabolism in CKD patients.

The KDIGO guideline for dialysate calcium will result in an increased incidence of calcium accumulation in hemodialysis patients.

The recently published KDIGO (Kidney Disease: Improvement of Global Outcomes) guideline (GL) for dialysate calcium suggests a narrow range of dialysate inlet calcium concentrations (C(di)Ca(++)) of 2.50-3.00 mEq/l. The work group's primary arguments supporting the GL were (1) there is a negligible flux of body Ca(++) during dialysis and (2) C(di)Ca(++) of 2.50 mEq/l will generally result in neutral Ca(++) mass balance (Ca(MB)). We believe we have shown that both of these arguments are incorrect. Kinetic modeling and analysis of dialyzer Ca(++) transport during dialysis (J(d)Ca(++)) demonstrates that more than 500 mg of Ca can be transferred during a single dialysis and that on average 76% of this Ca flux is from the miscible calcium pool rather than plasma pool. Kinetic modeling of intestinal calcium absorption (Ca(Abs)) shows a strong dependence of Ca(Abs) on the dose of vitamin D analogs and weaker dependence on the level of Ca intake (Ca(INT)). We used the Ca(Abs) model to calculate Ca(Abs) as a function of total Ca(INT) and prescribed doses of vitamin D analogs in 320 hemodialysis patients. We then calculated total dialyzer calcium removal (TJ(d)Ca(++)) and the C(di)Ca(++) that would be required to achieve TJ(d)Ca(++)=Ca(Abs), that is, Ca(MB)=0 over the whole dialysis cycle (that is, covering both the intra- and the inter-dialytic period). The results indicate that 70% of patients on Ca-based binders and 20-50% of patients on non-Ca-based binders would require C(di)Ca(++) <2.50 mEq/l to prevent long-term Ca accumulation.

Calcium balance in dialysis is best managed by adjusting dialysate calcium guided by kinetic modeling of the interrelationship between calcium intake, dose of vitamin D analogues and the dialysate calcium concentration.

Calcium mass balance (Ca(MB)) is determined by the difference between Ca absorbed between dialyses (Ca(Abs)) and the Ca removed during dialysis (J(d)Ca(2+)). A mathematical model to quantify (1) Ca(Abs) as a function of Ca intake (Ca(INT)) and the doses of vitamin D analogues, and (2) J(d)Ca(2+) as a function of Ca(2+) dialysance, the mean plasma Ca(2+) ((M)C(pi)Ca(2+)) minus dialysate Ca(2+) (C(di)Ca(2+)), ultrafiltration rate (Q(f)) and treatment time is developed in this paper. The model revealed a basic design flaw in clinical studies of Ca-based as opposed to non-Ca-based binders in that C(di)Ca(2+) must be reduced with the Ca-based binders in order to avoid a positive Ca(MB) relative to the non-Ca-based binders. The model was also used to analyze Ca(MB) in 320 Renal Research Institute hemodialysis patients and showed that all patients irrespective of type of binder were in positive Ca(MB) between dialyses (mean +/- SD 160 +/- 67 mg/day) with current doses of vitamin D analogues prescribed. Calculation of the optimal C(di)Ca(2+) for the 320 Renal Research Institute patients revealed that in virtually all instances, the C(di)Ca(2+) required for neutral Ca(MB), where Ca removal during dialysis was equal to Ca accumulation between dialyses, was less than 2.50 mEq/l and averaged about 2.00 mEq/l. This sharply contradicts the recent KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease - Mineral and Bone Disorder, that suggests a C(di)Ca(2+) of 2.5-3.0 mEq/l. Review of the KDIGO work group discussions shows that this discrepancy stems from the unwarranted work group assumption that intradialytic Ca(MB) is zero. We strongly believe that this guideline for dialysate Ca(2+) is inappropriate and should be modified to more realistically reflect the needs of dialysis patients.

Solute clearances and fluid removal in the frequent hemodialysis network trials.

BACKGROUND: The Frequent Hemodialysis Network (FHN) is conducting 2 randomized clinical trials, a daytime in-center trial ("daily") comparing 6 versus 3 treatments/wk, and a home nocturnal trial comparing 6 nocturnal treatments versus 3 conventional treatments/wk. The goal of this study was to project separation between the treatment and control arms of these studies for measures of dialysis dose by using simulations based on 2-compartment variable-volume models. SETTING & PARTICIPANTS: Data from the most recent hemodialysis treatment in 100 patients dialyzed 3 times/wk at facilities of the Renal Research Institute in New York and from 2 data sets (n = 154 and 115 patients) from the Hemodialysis (HEMO) trial. DESIGN: Observational study. PREDICTOR: Dialysis prescriptions for the treatment and control arms in the FHN trials. DIALYSIS REGIMEN OUTCOMES: Treatment time, ultrafiltration rate, standard Kt/V/wk for urea (stdKt/V(urea)), and continuous clearance estimates based on ratios of urea, creatinine, and normalized beta(2)-microglobulin generation rates (denoted by Gn) to time-averaged concentrations (TACs) of these solutes during 1 treatment week. RESULTS: The expected differences between median values in the experimental and control groups were weekly treatment time: daily trial, 29%; nocturnal trial, 234%; ultrafiltration rate: daily, -20%; nocturnal, -69%; stdKt/V(urea): daily, 52%; nocturnal, 133%; Gn(urea)/TAC(urea): daily, 34%; nocturnal, 130%; Gn(cr)/TAC(cr): daily, 31%; nocturnal, 135%; and Gn(beta2)/TAC(beta2): daily, 8%; nocturnal, 67%. LIMITATIONS: Use of simulated data and assumption of equivalent volumes and ultrafiltration rates between treatment arms. CONCLUSIONS: The nocturnal 6-times-weekly regimen produces substantially greater separation between the treatment and control arms than the daytime 6-times-weekly regimen for a wide range of treatment parameters. However, the 6-times-weekly interventions in both FHN trials will produce substantially greater separation than in the HEMO trial, where separations in median weekly treatment time and stdKt/V(urea) between the 3-times-weekly high- and standard-dose groups were 18% and 17%, respectively. The FHN trials will test whether substantial increases in solute clearance and other effects of frequent hemodialysis materially influence selected intermediate outcome measures.

What is important in dialysis? Efficiency: blood flow, KoA and Kt/V?

The relationships of clinical outcome to Kt/V and treatment time (t) in the two large randomized controlled trials of dialysis (National Cooperative Dialysis Study, NCDS, and the Hemodialysis Study, HEMO) were reviewed and compared to several major observational studies (OS). The HEMO study was originally conceived to determine whether outcome was improved by increasing Kt/V to 1.40, 40% higher than spKt/V >1.00 which was concluded to be adequate in the NCDS. However, OS suggested improvement in outcome up to and higher than Kt/V 1.40, so the HEMO dose targets were changed to 1.40 and 1.70. HEMO showed there was no change in outcome over this dose range but when the data were analyzed as a dose targeting OS, there was spurious improvement in outcome over the total range studied. Thus it cannot be concluded that Kt/V >1.0 results in improvement in clinical outcome since the range 1.00-1.40 has not been studied and both levels found adequate in randomized controlled trials. The borderline inverse correlation of outcome to treatment time in NCDS was shown to be meaningless because Kt/V was not successfully separated from t.

Calcium and phosphorus kinetics in hemodialysis therapy.

The kinetics of interdialytic calcium (Ca) absorption and intradialytic flux are examined with particular emphasis on achievement of near zero Ca mass balance over complete dialysis cycles. It is concluded that a rational approach to management of mineral metabolism in hemodialysis consists of: (1) appropriate doses of vitamin D3 analogs to facilitate now normal Ca absorption and avoid both Ca overload and depletion; (2) adequate phosphorus (P) binder to normalize serum calcium and the Ca P product; (3) in most instances modest reduction of dialysate Ca to the level of 2.00-2.25 are appropriate to assure zero Ca balance, and (4) use of a calcimimetic to control secondary hyperparathyroidism.

Red blood cell lifespan, erythropoiesis and hemoglobin control.

Erythropoietin (EPO) and iron deficiency as causes of anemia in patients with limited renal function or end-stage renal disease are well addressed. The concomitant impairment of red blood cell (RBC) survival has been largely neglected. Properties of the uremic environment like inflammation, increased oxidative stress and uremic toxins seem to be responsible for the premature changes in RBC membrane and cytoskeleton. The exposure of antigenic sites and breakdown of the phosphatidylserine asymmetry promote RBC phagocytosis. While the individual response to treatment with EPO-stimulating agents (ESA) depends on both the RBC's lifespan and the production rate, uniform dosing algorithms do not meet that demand. The clinical use of mathematical models predicting ESA-induced changes in hematocrit might be greatly improved once independent estimates of RBC production rate and/or lifespan become available, thus making the concomitant estimation of both parameters unnecessary. Since heme breakdown by the hemoxygenase pathway results in carbon monoxide (CO) which is exhaled, a simple CO breath test has been used to calculate hemoglobin turnover and therefore RBC survival and lifespan. Future research will have to be done to validate and implement this method in patients with kidney failure. This will result in new insights into RBC kinetics in renal patients. Eventually, these findings are expected to improve our understanding of the hemoglobin variability in response to ESA.

Comparison of hemodialysis blood access flow rates using online measurement of conductivity dialysance and ultrasound dilution.

BACKGROUND: Routine access flow (AF) surveillance is recommended by the Kidney Disease Outcomes Quality Initiative as one of several components for an arteriovenous vascular access maintenance program. A reliable, but affordable, measurement tool is needed for outpatient hemodialysis facilities. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: 50 adult patients with 27 grafts and 23 fistulas from a single center who consented to sequential AF measurements, all performed within the first 90 minutes of the hemodialysis treatment. INDEX TEST: AF measured by using online conductivity dialysance (OLC-AF). REFERENCE TEST: AF measured by using ultrasound dilution (UD-AF). RESULTS: Mean UD-AF was 1,086 +/- 629 mL/min, and mean OLC-AF was 951 +/- 575 mL/min, with a mean difference of 135 +/- 229 mL/min. OLC-AF correlated significantly with UD-AF (0.93; P < 0.0001), becoming tighter for flows less than 1,000 mL/min (0.95; P < 0.0001). The coefficient of variation for sequential measurement by using UD was 6.4%, and for OLC, 11.5%, with the difference becoming insignificant (7.6% versus 8.8%; P = 0.5) for flows less than 1,000 mL/min. The average of 2 sequential UD-AF measurements correlated tightly with that of OLC-AF (0.99; P < 0.0001). LIMITATIONS: Tests were performed by 2 highly trained coordinators in a single clinic with a small sample size, and clinical outcomes were not evaluated. CONCLUSION: The OLC method is a reasonable alternative to UD for flow surveillance of arteriovenous hemodialysis accesses and provides an option for widespread implementation of a vascular access surveillance program. Additional studies are needed to determine whether routine use impacts on clinical outcomes.

The basic, quantifiable parameter of dialysis prescription is Kt/V urea; treatment time is determined by the ultrafiltration requirement; all three parameters are of equal importance.

There have only been two randomized controlled trials studying outcome as a function of dose in hemodialysis (HD). The first was the National Cooperative Dialysis Study which showed that adequate dialysis was achieved with spKt/V >1.00. The second study was HEMO which was originally designed to study spKt/V 1.2 compared to spKt/V 1.45. Unfortunately by the time HEMO was started, observational studies (OS) had convinced the nephrology community that the minimum adequate dose of spKt/V was 1.40, so the lower target was increased to 1.4 and the upper target to 1.7. The study showed no difference in outcome, although OS have now demonstrated that outcome improves up to spKt/v 2.00. Analysis of HEMO as treated showed that there is a fundamental flaw in dose-targeted OS in that the optimal dose always, but spuriously, increases as the studied dose increases due to dose-targeting bias. Similar flaws exist in the association of treatment time to outcome.

Size matters: body composition and outcomes in maintenance hemodialysis patients.

In hemodialysis patients a low body mass index (BMI) is correlated with an unfavorable clinical outcome, a phenomenon known as "reverse epidemiology". Mechanisms underlying this observation are unclear. We propose the following: uremic toxin generation occurs predominantly in visceral organs and the mass of key uremiogenic viscera (gut, liver) relative to body weight is higher in small people. Consequently, the rate of uremic toxin generation per unit of BMI is higher in patients with a low BMI. Body water, mainly determined by muscle mass, serves as a dilution compartment for uremic toxins. Therefore, the concentration of uremic toxins is higher in small subjects. Uremic toxins are taken up by adipose and muscle tissues, subsequently metabolized and stored. Thus, the larger the ratio of fat and muscle mass to visceral mass, the lower the concentration of uremic toxins and the better the survival. To test this hypothesis, studies on uremic toxin kinetics in relation to body composition are needed.

Association of achieved dialysis dose with mortality in the hemodialysis study: an example of "dose-targeting bias".

In the intention-to-treat analysis of the Hemodialysis Study, all-cause mortality did not differ significantly between the high versus standard hemodialysis dose groups. The association of mortality with delivered dose within each of the two randomized treatment groups was examined, and implications for observational studies were considered. Time-dependent Cox regression was used to relate the relative risk (RR) for mortality to the running mean of the achieved equilibrated Kt/V (eKt/V) over the preceding 4 mo. eKt/V was categorized by quintiles within each dose group. Analyses were controlled for case-mix factors and baseline anthropometric volume. Within each randomized dose group, mortality was elevated markedly when achieved eKt/V was in the lowest quintile (RR, 1.93; 95% confidence interval [CI], 1.40 to 2.66; P < 0.0001 in the standard-dose group; RR, 2.04; 95% CI, 1.50 to 2.76; P < 0.0001 in the high-dose group; RR relative to the middle quintiles). The mortality rate in the lowest eKt/V quintile of the high-dose group was higher than in the full standard-dose group (RR, 1.59; 95% CI, 1.29 to 1.96; P < 0.0001). Each 0.1 eKt/V unit below the group median was associated with a 58% higher mortality in the standard-dose group (P < 0.001) and a 37% higher mortality in the high-dose group (P < 0.001). The magnitude of these dose-mortality effects was seven- to 12-fold higher than the upper limit of the 95% CI from the intention-to-treat analysis. The effects were attenuated in lagged analyses but did not disappear. When dialysis dose is targeted closely, as under the controlled conditions of the Hemodialysis Study, patients with the lowest achieved dose relative to their target dose experience markedly increased mortality, to a degree that is not compatible with a biologic effect of dose. The possibility of similar (albeit smaller) biases should be considered when analyzing observational data sets relating mortality to achieved dose of dialysis.

Factors for increased morbidity and mortality in uremia: hyperphosphatemia.

Hyperphosphatemia is a metabolic abnormality present in the majority of patients treated by dialysis. Inorganic phosphorus (iP) can be categorized as a true uremic toxin given its known in vivo and in vitro effects and the ability to reduce these effects by normalizing iP levels. However, despite regular and adequate dialysis treatment, the goal of normalization of phosphorus levels rarely is achieved. This article briefly evaluates the significance of hyperphosphatemia in hemodialysis patients, current therapeutic approaches, and describes a new model for evaluating the dialysis prescription for iP balance.

A one-year trial of in-center daily hemodialysis with an emphasis on quality of life.

BACKGROUND/AIMS: Hemodialysis is associated with acute changes in several physiologic factors. Previous studies have suggested significant clinical and quality of life (QOL) benefits of daily hemodialysis (DHD) compared with 3 times weekly hemodialysis (CHD). We conducted a prospective trial to evaluate the effects of switching chronic hemodialysis patients to in-center DHD for a 12-month period. METHODS: There were no exclusion criteria. Patients received hemodialysis 6 times per week. The study set a standardized weekly Kt/V (stdKt/V) goal of 3.0. A broad array of clinical parameters was determined. QOL was assessed with multiple instruments. RESULTS: Eleven subjects completed 12 months and 12 completed 6 months on DHD. Significant changes relative to baseline at 12 months of DHD included decreased BP and improvements in QOL parameters by multiple techniques. 100% of patients at 12 months wished to continue DHD. CONCLUSIONS: DHD offers advantages over CHD with respect to improved QOL and BP control.

Mechanisms determining the ratio of conductivity clearance to urea clearance.

BACKGROUND: Effective conductivity clearance (K(ecn)) has been reported to be a surrogate for effective urea clearance (K(eu)), where both are usually defined respectively as the dialyzer conductivity and urea clearances (K(cn), K(u)) corrected for access recirculation (R(ac)). However, many investigators have reported K(ecn)/K(eu) to be <1 and postulated anatomic distribution of Na in plasma water, cardiopulmonary recirculation (R(cp)), and high rates of urea clearance (K(u)) as causes. The aims of these studies were to devise analytic models of these mechanisms and to clinically evaluate the modeled relationships. METHODS: We modeled and measured: (1) Na osmotic distribution volume flow rate (Q(osmNa)) in dialyzer blood flow; (2) the separate and combined effects of R(ac) and R(cp) on K(u) and K(cn); and (3) a novel mechanism reducing the conductivity diffusion gradient during measurement of K(cn) by recirculation through the dialyzer (R(s)) of a change in systemic blood conductivity (Delta Cn(s)) induced by the abrupt changes in dialysate inlet Na (Delta C(diNa)) required for the measurement of K(cn). RESULTS: The ratio Q(osmNa)/Q(bi)= 1.00 +.03, N= 19 (Q(bi)= total blood water flow rate). Modeling showed that the effects of R(ac), R(cp), and R(s) on K(cn) can be quantified as K(ecn)= K(cn)(1 -Delta Cn(bi)/Delta Cn(di)), where Delta C(nbi) is any change in conductivity in the dialyzer blood inlet stream during a measurement, and the effect of a combination of these mechanisms is the product of the effects of individual mechanisms. A single-step dialysate profile (with R(ac)= 0) resulted in measured Delta C(biNa)/Delta C(diNa)= 2.5/15, K(ecn)/K(eu)= 0.83, N= 21 because of R(s) and R(cp), but with a two-step, high/low profile (P(h/L)) we found these respective values to be -0.6/20 and 0.97, N= 19. The ratio K(ecn)/K(eu3)= 1.06 +.02, M + SE, N= 35 (K(eu3)= Ku corrected to reflect both access and cardiopulmonary recirculation). The ratio K(ecn)/K(eu1) (K(eu1) is K(u) corrected to reflect access recirculation only) = 1.01 +.07, N= 297, with no bias on Bland Altman analysis. CONCLUSION: We conclude that (1) the osmotic Na distribution volume in blood is total blood water; (2) K(ecn) measured with a short, high/low, and asymmetric dialysate profile shows R(ac) effect but neither R(cp) nor R(s) effects on K(ecn) and K(ecn)/K(eu)= 1.0; (3) the K(ecn)/K(eu) ratio is strongly dependent on the type of dialysate profile used, which must be optimized to minimize net Na transfer to and from blood during measurement of conductivity clearance to avoid erroneous underestimation of K(ecn) and K(ecn)/K(eu) ratios <1.

Dialysis dose and the effect of gender and body size on outcome in the HEMO Study.

BACKGROUND: Gender and body size have been associated with survival in hemodialysis populations. In recent observational studies, overall mortality was similar in men and women and higher in small patients. The effect of dialysis dose in each of these subgroups has not been tested in a clinical trial. METHODS: The HEMO Study was a controlled trial of dialysis dose and membrane flux in 1846 hemodialysis patients followed up for 6.6 years in 15 centers throughout the United States. We examined the effect of dialysis dose on mortality and on selected secondary outcomes in subgroups of patients. RESULTS: Adjusting for age only, overall mortality was lower in patients with higher body weight (P < 0.001), higher body mass index (P < 0.001), and higher body water content determined by the Watson formula (Vw) (P < 0.001), but was not associated with gender (P= 0.27). The RR of mortality comparing the high dose with the standard dose group was related to gender (P= 0.014). Women randomized to the high dose had a lower mortality rate than women randomized to the standard dose (RR = 0.81, P= 0.02), while men randomized to the high dose had a nonsignificant trend for a higher mortality rate than men randomized to the standard dose (RR = 1.16, P= 0.16). Analysis of both genders combined showed no overall dose effect (R = 0.96, P= 0.52), as reported previously. Vw was greater than 35 L in 84% of men compared with 17% of women. However, the RR of mortality for the high versus standard dose remained lower in women than in men after adjustment for the interaction of dose with Vw or with other size parameters, including weight and body mass index. Conversely, the dose effect was not significantly related to size parameters after controlling for the relationship of the dose comparison with gender. CONCLUSION: The data suggest that mortality and morbidity might be reduced by increasing the dialysis dose above the current standard in women but not in men. This effect was not explained by differences between men and women in age, race, or in several indices of body size. Because multiple comparisons were considered in this analysis, the role of gender on the effect of dialysis dose is suggestive and invites further study.

Dialyzer performance in the HEMO Study: in vivo K0A and true blood flow determined from a model of cross-dialyzer urea extraction.

Inlet and outlet blood urea concentrations (Cin and Cout) can be used to directly measure dialyzer performance if simultaneous blood flow measurements (Qb) are available. Dialyzer clearance, for example, is the product of the urea extraction ratio [ER = (Cin - Cout)/Cin] and Qb. Urea concentrations are measured routinely in all hemodialysis clinics, but Qb is usually reported as the product of the pump rotational speed and pump segment stroke volume, which can be inaccurate at high flow rates. Dialyzer urea extraction is also a function of Qb, dialysate flow (Qd), and the membrane permeability-area coefficient (K0A) for urea. To determine true in vivo values for Qb and K0A in the absence of direct flow measurements, we developed a model based on an existing mathematical equation for hemodialyzer ER under conditions of countercurrent flow. Qb, K0A, and other variables were adjusted to fit the modeled ER to ER measured in 1,285 patients treated with Qb that ranged from 200 to 450 ml/min during the HEMO Study. Fitting was performed by least squares nonlinear regression using parametric and nonparametric methods for estimating true flow. As Qb rose above 250 ml/min, both methods for estimating actual Qb showed increasing deviations from the flow reported by the blood pump meter. Modeled values for K0A differed significantly among dialyzer models, ranging from 71% to 96% of the in vitro values. The previously described 14% increase in K0A, as Qd increased in vitro from 500 to 800 ml/min, was much less in vivo, averaging only 5.5 +/- 1.5% higher. Dialyzer reprocessing was associated with a 6.3 +/- 1.0% reduction in K0A and an approximate 2% fall in urea clearance per 10 reuses (p < 0.001). Multiple regression analysis showed a small but significant dialysis center effect on ER but no independent effects of other variables, including the ultrafiltration rate, diabetic status, race, ethnicity, sex, method of reuse, treatment time, access recirculation, and use of central venous accesses. The new algorithm allowed a more accurate determination of true Qb and in vivo K0A in the absence of direct flow measurements in a large population treated with a wide range of blood flow rates. Application of this technique for more than 1000 patients in the HEMO Study confirmed that in vitro measurements using simple crystalloid solutions cannot readily substitute for in vivo measurements of dialyzer function, and permitted a more accurate calculation of each patient's prescribed dialysis dose and urea volume.