Frank A. Gotch

Design and Statistical Issues of the Hemodialysis (HEMO) Study

The Hemodialysis Study is a multicenter clinical trial of hemodialysis prescriptions for patients with end stage renal disease. Participants from over 65 dialysis facilities associated with 15 clinical centers in the United States are randomized in a 2 x 2 factorial design to dialysis prescriptions targeted to a standard dose or a high dose, and to either low or high flux membranes. The primary outcome variable is mortality; major secondary outcomes are defined based on hospitalizations due to cardiovascular or infectious complications, and on the decline of serum albumin. The Outcome Committee, consisting of study investigators, uses a blinded review system to classify causes of death and hospitalizations related to the major secondary outcomes. The dialysis dose intervention is directed by the Data Coordinating Center using urea kinetic modeling programs that analyze results from dialysis treatments to monitor adherence to the study targets, adjust suggested dialysis prescriptions, and assist in trouble-shooting problems with the delivery of dialysis. The study design has adequate power to detect reductions in mortality rate equal to 25% of the projected baseline mortality rate for both of the interventions.

A pharmacodynamic model of erythropoietin therapy for uremic anemia

Fifty‐seven patients receiving chronic high‐flux hemodialysis began receiving recombinant a‐human erythropoietin (rHuEPO). The mean initial rHuEPO dose used in 54 évaluable patients was 9963 ± 4364 U/week; the final dose was 8972 ± 4058 U/week. Treatment over a mean period of 154 ± 40 days (84 to 224 days) resulted in an average increase in hematocrit from 24.7% ± 3.7% to 32.5% ± 4.4%. We present a model for these data that describes changes in hematocrit during rHuEPO therapy and that allows simultaneous estimation of red blood cell lifespan and rHuEPO‐induced increases in red blood cell production rate. Analysis of the hematocrit values of the patients with the model, by use of NONMEM, a computer program for analysis of population data, reveals a nonlinear dose‐response relationship with large interindividual variability (coefficient of variation) of about 50%. The estimated mean red blood cell lifespan is 64 days, with interindividual variability of about 30% (coefficient of variation). The intraindividual random variability in hematocrit about its prediction is ±5% of the prediction. For clinical dose adjustment, we present a method that uses only simple calculations.

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.

Evolution of the single-pool urea kinetic model.

Our interest in urea kinetic modeling (UKM) was stimulated some 30 years ago at the time of the advent of hollow fiber kidneys with greatly improved urea transport. This led to examination of the interaction between time and clearance in computing the dialysis dose. In early studies a fixed‐volume single‐pool UKM was used but this frequently gave spurious high volumes and led to the advent of the variable‐volume single‐pool model. The role of volume calculation in assessment of the delivered dialysis dose and the value of normalized protein catabolic rate (nPCR) calculation are reviewed. More recently quantification of double‐pool effects has become simplified and now is widely used for UKM. The National Cooperative Dialysis Study (NCDS) resulted in the concept of dose quantification by Kt/V. This is reviewed, including the controversy surrounding interpretation of the NCDS. Currently there is great interest in more frequent dialysis, 4–6 days/week. The development of a new dose parameter, the standard Kt/V (stdKt/V), to enable quantitative comparison of dose with widely varying dose schedules is discussed.

Binding of Hippurate in Normal Plasma and in Uremic Plasma Pre- and Postdialysis

The protein binding of 14C-hippurate has been measured by conventional ultrafiltration techniques in the plasma of normal subjects and in uremic subjects pre- and postdialysis. In addition, the clearance of 14C-hippurate was determined in vitro in both isotonic saline and plasma to assess binding limitations on hippurate removal during dialysis. Binding levels of hippurate in normal subjects of 68+/-1.8% (n = 5) were significantly higher than either postdialysis (48.3+/-15.4%; n = 7) or predialysis (36.6+/-11.7%; n = 7) levels in the same uremic subjects. Actual levels of plasma hippurate were, however, considerably greater in uremics (24.7+/-11.2 mg/dl n = 7) than in normal subjects (congruent to 0.5 mg%). The difference in hippurate binding between pre- and postdialysis samples in uremics was significantly different from zero (p less than 0.01, t = 5.36), indicating depletion of competitive site-binding species during dialysis. The saline clearance of hippuric acid (99.1 +/-0.5 ml/min; n = 6) under standard conditions in a capillary dialyzer (CDAK-4) was consistent with the expected clearance of a solute of its molecular weight. Hippurate clearance in citrated plasma, where binding was determined as 50+/-3%, was 65+/-0.7 ml/min (n = 6), in good agreement with a theoretically predicted clearance of 60 ml/min for this level of binding. High serum levels of hippurate and its derivatives, may depress effective function of various organs. In addition to the normal dietary intake of hippurate and its precursors, patients on dialysis receive a further burden of hippurate precursor in the form of benzyl alcohol, the common preservative in heparin solutions. The large body burdens of hippurate in dialysis patients, coupled with its impaired removal on dialysis due to binding, point to the necessity for a through investigation of the potential toxicity of this compound.

Pro/Con debate: the calculation on calcium balance in dialysis lowers the dialysate calcium concentrations (pro part)

Prior to the advent of calcitriol therapy, haemodialysis (HD) patients were often in negative calcium (Ca) balance between dialyses because of severely impaired Ca absorption [1] that led to the recommendation of dialysate inlet Ca concentration (CdiCa++) 3.0–3.5 mEq/L, higher than plasma concentration [2]. Over the past 25 years since the advent of calcitriol, virtually all haemodialysis patients absorbed a substantial portion of dietary and phosphate binder calcium ingested between dialyses and yet CdiCa++ 3.0 mEq/L has continued to be widely used. The total Ca absorbed between dialyses (CaAbsT) must be removed by the dialyser (JdCaT) to achieve net zero Ca mass balance over the dialysis cycle and prevent chronic Ca overload that likely contributes to the high rate of vascular calcification in haemodialysis patients [3–5]. From this perspective, it follows that the CdiCa++ prescribed should result in neutral Ca mass balance and thus total Ca removed during dialysis (JdCa++), the sum of diffusive (JDiffCa++) and convective Ca++ (JConvCa++) removal, should equal CaAbs in accordance with

The next step from high-flux dialysis: Application of sorbent technology

The current foci of renal replacement therapy with dialysis are middle molecular weight toxins, consisting of small proteins, polypeptides and products of glycosylation and lipoxygenation. Conventional high-flux dialysis is not efficient at removing these molecules, explaining the increased interest in using sorbents to supplement dialysis techniques. Prototype biocompatible sorbents have been developed and investigated for middle molecule removal; these have been shown, in man, to remove β2-microglobulin, angiogenin, leptin, cytokines and other molecules, without reducing platelets and leukocytes. Extensive clinical studies are underway to demonstrate the clinical utility and safety of adding routinely a sorbent hemoperfusion device to hemodialysis.

Daily Hemodialysis Is a Complex Therapy with Unproven Benefits

Accessible online at: www.karger.com/journals/bpu Over the past 18 years, approximately 150 patients have been treated with ‘daily’ (5–6 days/week) hemodialysis worldwide [1]. The number of patients in any one center is very small, usually in the range of 7–10. The dose of dialysis is typically described as a weekly summed Kt/ V, usually estimated by approximation equations rather than formal urea kinetic modeling. The treatment times, blood and dialysate flows and dialyzers used have varied widely. The upper bound on therapy parameters is that reported by Pierratos et al. [2] with 6 dialyses per week, treatment time of about 7 h, Qb 200, Qd 300 with F40– F80 polysulfone dialyzers. The dose is not regularly monitored kinetically but can be estimated to be in the range of Kt/V about 1.2 each dialysis. The lower bound on treatment parameters is 6 dialyses per week with treatment time 2.0 h and Kt/V levels of 0.53 per treatment approximated from the Daugirdas equation [3]. Although there are no hard outcome data, i.e., mortality rate, these small observational studies often report better control of blood pressure and improved quality of life as the major benefits of more frequent dialysis. Improved appetite is variably reported but there are no reported systematic kinetic studies of protein catabolic rate to quantitatively assess change in protein intake. It will be argued here that the current clinical database does not permit valid assessment of the clinical benefits of ‘daily’ dialysis which will require prospective studies with well-defined and randomized dialysis doses. An Overview of the Kinetics of Variable Frequency Dialysis Therapy: The Rationale for Increased Dialysis Frequency

Daily Dialysis: The Long and the Short of It

There is considerable enthusiasm for daily hemodialysis despite the increased time commitment required of patients because of reported improvements in patient well-being, appetite and blood pressure control. To date, this therapy has been largely empirical and has been defined primarily by treatment time (t) and categorized as short daily hemodialysis (SDHD) with t about 2 h and long nocturnal hemodialysis (LNHD) with t 8–9 h. It is the authors’ view that studies comparing clinical outcome with SDHD and LNHD to conventional hemodialysis (CHD) must have dialysis dosage well defined if they are to provide generalizable results. There is a broad range and overlap in the magnitude of solute removal in reported studies of SDHD, LNHD and CHD, which is illustrated here through kinetic consideration of four solutes: (1) urea; (2) inorganic phosphorus (iP); (3) β2-microglobulin (β2M) and (4) Na/water. The following observations can be made: (1) Patient subjective reports of increased appetite and protein intake may correlate poorly with kinetic calculation of protein catabolic rate. (2) A model of iP mass balance was developed and indicates that iP removal with CHD is inadequate; current SDHD is also inadequate to highly excessive depending on the dose of dialysis. (3) β2M removal with SDHD is virtually the same as reported for LNHD, reflecting major differences in dialyzer membranes used. (4) The decrease in predialysis overhydration is a predictable function of the number of dialyses per week and may be one of the most important benefits of more frequent dialysis. (5) The standard Kt/V (stdKt/V) provides a uniform method of dose calculation but the therapy prescription should also include consideration of the other solutes evaluated above.

Kinetic Modeling of Continuous Flow Peritoneal Dialysis

Kinetic models have been derived for analysis of the effects on peritoneal urea clearance (Kp) of continuous single‐pass flow of fresh peritoneal dialysate and continuous flow of peritoneal dialysate recirculating through an external dialyzer. Generalized solution of the models shows that both predict Kp to be a well‐defined function of the peritoneal mass transfer coefficient (MTC) and the dialysance (D) of the external dialyzer, while the MTC is a function of the rate and distribution of dialysate flow. Thus the models should be useful to guide studies to optimize CFPD. Analysis of reported in vivo data indicate that with dialysate flow rate and D both in the range of 200 ml/min, MTC levels of 60–70 ml/min and Kp levels of 50 ml/min can be achieved. If the model predictions are verified in vivo, 8‐hour overnight CFPD 6 nights/week could provide the average‐size anephric patient a weekly stdKt/V of 3.2 which is competitive with daily hemodialysis. Kinetic modeling of ultrafiltration indicated ultrafiltration rates 0.2–0.3 L/hr should be achieved with 1.0–1.25% dextrose dialysate. The model shows average rates of glucose absorption can theoretically be reduced by 33% compared to CAPD with the same amount of fluid removal.