The association of the sodium "setpoint" to interdialytic weight gain and blood pressure in hemodialysis patients.

INTRODUCTION: Hemodialysis patients lack the normal mechanisms to regulate body water volume and osmolality. The dialysis treatment is expected to adequately regulate both body water volume and body Na+ content, which is the primary action determining body water osmolality. Data in subjects with normal renal function indicate that an individual has a specific osmolality value above which thirst is generated and fluid will be ingested. This specific osmolality value or "setpoint" varies among individuals, but is quite reproducible within an individual. It was postulated that hemodialysis patients also may have a Na+ 'setpoint', which if increased by the use of higher dialysate Na+ concentration, might be associated with increased interdialytic weight gain and blood pressure. METHODS: Monthly laboratory and treatment data were abstracted on 58 hemodialysis patients and included pre- and post-dialysis serum Na+ concentrations, interdialytic weight gain and blood pressure over 9 to 16 months. The Na+ concentrations were averaged to determine the individual Na+ 'setpoint' and the Na+ gradient (Dialysis Na+ concentration - mean Na+ concentration) was determined for each patient. RESULTS: Linear regression analyses showed that there was a statistically significant association between the magnitude of the Na+ gradient and interdialytic weight gain and blood pressure. CONCLUSIONS: These data suggest that interdialytic weight gain in individual patients may be associated with the use of dialysate Na+ concentration in excess of the patient's desired Na+ 'setpoint'. More individualization of dialysate Na+ concentration may be indicated.

Metabolic consequences of body size and body composition in hemodialysis patients.

Small body mass index is associated with increased mortality in chronic hemodialysis patients. The reasons for this observation are unclear but may be related to body composition. This study aimed to investigate the body composition in chronic hemodialysis patients. The difference between body mass and the sum of muscle, bone, subcutaneous, and visceral adipose tissue masses, measured by whole body magnetic resonance imaging, was defined as the high metabolic rate compartment representing the visceral mass. Protein catabolic rate was calculated from urea kinetics. Forty chronic hemodialysis patients (mean age 54.7 years; 87.5% African Americans; 45% females) were studied. High metabolic rate compartment expressed in percent of body weight was inversely related to body weight (r=-0.475; P=0.002) and body mass index (r=-0.530; P<0.001). In a multiple linear regression model, protein catabolic rate was significantly correlated only with high metabolic rate compartment (r=0.616; P<0.001). Assuming that protein catabolic rate in addition to protein intake reflects urea and uremic toxin generation, it follows that high metabolic rate compartment is the major compartment involved in their generation. Consequently, uremic toxin production rate may be relatively higher in patients with low body weight and low body mass index as compared to their heavier counterparts. The poorer survival observed in smaller dialysis patients may be related to these relative differences.

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.

Single-pass continuous flow peritoneal dialysis using two catheters.

With a renewed interest in continuous flow peritoneal dialysis (CFPD), our standard practice of implanting a second catheter in those patients facing access failure provided us the opportunity to perform acute studies on CFPD in these patients, since it temporarily provided us with two catheters. Four patients were studied, with a total of five studies performed. A standard protocol was followed utilizing 1.5% dextrose solution, a 2 L fill, an inflow rate of 200 ml/min with a proportionate outflow for a 4-hour session. A full drain was performed at the end of the study. Our results provided us with a mean effective peritoneal clearance for urea (KpeU) and creatinine (KpeCr) of 40 ml/min and 28 ml/min, respectively, and a mean ultrafiltration rate (Qf) of 13.4 ml/min. Our average mass transfer coefficient (MTC) for urea was 40 ml/min, consistent with kinetic modeling and historical data. The Kpe, MTC, and Qf achieved are significantly higher than other investigators, which could possibly be explained by those obtained by two separate catheters resulting in adequate mixing of the dialysate. These clinical results provide a solid foundation for the future development of this PD modality.

Clinical experience with continuous flow and flow-through peritoneal dialysis.

Concern over the inherent inefficiency of solute removal by conventional peritoneal dialysis (PD) has led to renewed interest in continuous flow PD (CFPD). We present clinical data from two experiences with CFPD. In the first, two catheters were used to recirculate a fixed intraperitoneal volume through an external circuit comprised of a standard hemodialysis system. The second patient had a dual-lumen PD catheter and was studied during two sessions of flow-through PD (FTPD) using sterile PD solution. Urea clearances with both techniques were around 30 ml/min, which is consistent with data reported in the literature. Significant streaming of dialysate from port to port within the peritoneal cavity limited clearances. CFPD offers a potentially safe and effective alternative to daily or nightly home hemodialysis.

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.

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.

Whither goest Kt/V?

Uremia is characterized by gross contamination of body water with a wide spectrum of retained solutes normally excreted by the kidney. The rationale for dialysis therapy is that these retained solutes have concentration-dependent toxicity, which can be ameliorated through removal by dialysis. Apart from the well-established clinical consequences of abnormalities in fluid, electrolyte, acid base metabolism, and retained beta 2-microglobulin (beta 2 m), there is very little understanding of solute-specific uremic toxicity. Evidence is reviewed to demonstrate the following: (1) Many aspects of the uremic syndrome are controlled by adequate dialysis of low molecular weight solutes. (2) Urea can serve as a generic molecule to quantitate the fractional clearance of body water by dialysis (Kt/V) of retained low molecular weight solutes. (3) Urea has no concentration-dependent toxicity, and the generation rate of putative toxic low molecular weight solutes is not proportional to urea generation. The major clinical consequences and controversies stemming from these interrelationships are reviewed. Kinetic approaches to determine Kt/V dose equivalency between intermittent and continuous dialysis therapy are reviewed. We conclude that Kt/V can and will be generalized to describe the kinetics of other solutes such as beta2m as our knowledge of uremic toxicity grows, and hence, it is predicted that it will goeth and goeth and goeth.

Urea is the best molecule to target adequacy of peritoneal dialysis.

For hemodialysis, a large base of data shows the validity of modelling the dialysis dose and reliably estimating protein intake from equilibrated Kt/V urea (eKt/VU), the total dialyzer urea clearance provided during each treatment divided by the urea distribution volume. An eKt/VU of 1.05 thrice weekly is judged adequate, but is still under study. In continuous ambulatory peritoneal dialysis (CAPD), two dosage criteria are widely recognized: continuous ("standard") Kt/VU (stdKt/VU = 2.0 weekly), and total creatinine (Cr) clearance normalized to body surface area (KCrT = 70 L/week/1.73 m2). The CANUSA study concluded that a stdKt/VU of 2.1 and a KCrT of 70 L/week/1.73 m2 gave equivalent clinical outcomes. The Dialysis Outcomes Quality Initiative (DOQI) recommends values of 2.0 and 60 L/week/1.73 m2 respectively. An analysis of these two parameters for males and females over a wide range of body surface areas (BSAs) was done and the analysis showed: (1) The U and Cr dose criteria are incommensurable--that is, they can virtually never be achieved simultaneously in anephric patients. (2) The Cr criterion varies widely with the sex of the patient and with the BSA-dependent variation in stdKt/VU over a range of 2.1 to 3.0. (3) The U criterion always produces a KCrT < 60 L/week/1.73 m2 in females and 60-70 L/week/1.73 m2 in males. With respect to U and Cr, the CANUSA results were concluded to be valid in patients with substantial residual renal function, but probably not applicable to anephric patients where the doses are clearly incommensurable.

Relationship between apparent (single-pool) and true (double-pool) urea distribution volume.

BACKGROUND: The volume of urea distribution (V) is usually derived from single-pool variable volume urea kinetics. A theoretical analysis has shown that modeled single-pool V (Vsp) is overestimated when the urea reduction ratio (URR) is greater than 65 to 70% and is underestimated when the URR is less than 65%. The "true" volume derived from double-pool kinetics (Vdp) does not exhibit this effect. An equation has been derived to adjust Vsp to the expected Vdp. METHODS: To validate these theoretical predictions, we examined data from the Hemodialysis (HEMO) Study to assess the performance of Vdp as estimated from Vsp using the previously published prediction equation. For increased precision, both Vsp and Vdp were factored by anthropometric volume (Va). Patients were first dialyzed with a target equilibrated dialysis dose (eKt/V) of 1.45 during a baseline period and were then randomly assigned to eKt/V targets of either 1. 05 (a URR of approximately 67%) or 1.45 (a URR of approximately 75%). A blood sample was obtained one hour after starting dialysis during one dialysis in each patient. RESULTS: Vsp/Va was (mean +/- SD) 1.014 +/- 0.127 in 795 patients during the baseline period when the URR was approximately 1.45. During the first modeled dialysis after randomization, the Vsp/Va fell to 0.961 +/- 0.138 in the group with an eKt/V target of 1.05, but did not change significantly under the high eKt/V goal. The correction of Vsp to Vdp using the prediction equation resulted in a Vdp/Va ratio of 0.96 to 0.98 in all three circumstances without significant differences. When a blood sample was drawn one hour after starting dialysis, the apparent Vsp/Va ratio at one hour was much lower at 0.708 +/- 0.139. However, the mean Vdp/Va ratio, computed using the correction equation, was 0.968 +/- 0.322, which was similar to the Vdp/Va ratio calculated from the postdialysis blood urea nitrogen. CONCLUSIONS: These data suggest that the previously derived formula for adjusted Vsp is valid experimentally. The Vsp/Vdp correction should be useful for prescribing hemodialysis with either a very low Kt/V (for example, daily and early incremental dialysis) or a very high Kt/V.

Measurement of blood access flow rate during hemodialysis from conductivity dialysance.

An on line clearance monitor automated for measurements of conductivity dialysance (Dcn) was used to measure blood access flow rate (cnQac) during hemodialysis. From mathematical analysis of transport, it was shown that cnQacc = [(Dcn*Decn)/(Dcn - Decn)] [1/bwf], where Dcn is measured with standard cocurrent flow of dialyzer blood (Qb) and Qac; Decn is measured with countercurrent Qb/Qac; and bwf is fractional blood water content. An identical equation was derived to measure Qac from urea dialysance (uQac, Du, Deu). In vitro studies showed excellent correlation between volumetric measurement of Qac (vQac) and cnQac, r = 0.98, n = 29, and between uQac and cnQac, r = 0.97, n = 28. In vivo studies showed comparable agreement between uQac and cnQacc, r = 0.97, n = 14. In two of the patients studied, there was unsuspected severe midgraft stenosis (no recirculation in cocurrent flow) with a Qac of 89 and 202 ml/min disclosed by both cnQac and uQac measurements. Mathematical analysis also showed that when Qb is greater than Qac and there is recirculation in cocurrent flow, the above equations always return the value Qac = Qb. An equation was derived to calculate cnQac without reversal of blood lines in this case, using Dcn calculated from the dialyzer transport coefficient and flow rates.

Peritoneal dialysis adequacy: a model to assess feasibility with various modalities.

BACKGROUND: The current standard of adequacy for peritoneal dialysis (PD) is to provide a weekly normalized urea clearance (Kt/V) of 2.0 or more and a creatinine clearance (CCr) of 60 liter/1.73 m2 or more. As native renal function is lost, it is important to determine the effectiveness of the available therapeutic modalities in achieving these goals. METHODS: A model to assess our ability to provide a weekly Kt/Vurea of 2.0 or more and a CCr of 60 liter/1.73 m2 or more to anuric patients undergoing continuous ambulatory PD (CAPD) and automated PD (PD Plus) was developed. The body surface area (BSA) distribution was obtained from 38,768 patients undergoing dialysis during January 1997. The distribution of peritoneal transport rates (PTRs) was obtained from 2531 peritoneal equilibration tests performed during 1996. The weekly Kpt/Vurea was calculated for the various PTR groups and the range of BSA with four PD prescriptions: CAPD 8 liters, CAPD 10 liters, PD Plus 12 liters, and PD Plus 15 liters, using a previously validated kinetic program (PackPD). RESULTS: The predicted percentage of patients capable of achieving the adequacy goals for Kt/V and CCr, respectively, were 24.8 and 11. 2 for CAPD 8 liters, 54.2 and 33.0 for CAPD 10 liters, 77.8 and 54.9 for PD Plus 12 liters, and 93.2 and 72.9 for PD Plus 15 liters. CONCLUSIONS: Most patients can attain the current adequacy standards of therapy with automated PD, but few (less than 25%) can do so with standard CAPD in the absence of residual renal function.

Imprecision of the hemodialysis dose when measured directly from urea removal. Hemodialysis Study Group.

BACKGROUND: The postdialysis blood urea nitrogen (BUN; Ct) is a pivotal parameter for assessing hemodialysis adequacy by conventional blood-side methods, but Ct is relatively unstable because of hemodialysis-induced disequilibrium. The uncertainty associated with this method is potentially reduced or eliminated by measuring urea removed on the dialysate side, a more direct approach that can determine adequacy from the fraction of urea removed and by substituting an estimate of the equilibrated postdialysis BUN (Ceq) for Ct. For a patient with a known urea volume (V), Ceq, the equilibrated Kt/V (eKt/V), and the solute removal index (SRI) can be calculated from the predialysis BUN (C0), total urea nitrogen removed (A), and V from simple mass balance calculations (dialysate/volume method). However, a theoretical error analysis showed that relatively small errors in A, C0, or V are magnified when SRI or eKt/V is calculated using this method, especially at higher eKt/V values (for example, if eKt/V = 1.4 per dialysis, a 7% dialysate collection error causes a 20% error in eKt/V). METHODS: During three to four baseline dialyses in each of 39 patients enrolled in the pilot phase of the HEMO Study, "A" was measured using an instrument that sampled dialysate frequently (Biostat), and V was calculated from A, C0, and Ceq (median CV for V = 5.6%). The mean V was then applied to the dialysate/volume method to estimate eKt/V and SRI during two to five subsequent dialyses per patient (comparison dialyses). The accuracy and precision of these estimates were assessed by comparing them with eKt/V and SRI derived from a direct measurement of Ceq drawn 30 minutes after dialysis (reference method), from mathematical curve-fitting of sequential dialysate urea concentrations (dialysate curve-fit method), and from another blood-side method that estimates eKt/V from single pool Kt/V and the fractional rate of solute removal (rate method): eKt/V = spKt/V - 0.6.K/V + 0.03. RESULTS: During 128 comparison dialyses, median absolute errors for calculated eKt/V compared with the reference method were 0.169, 0.061, and 0.071 for the dialysate/volume method, the rate method, and the dialysate curve-fitting method, respectively. The corresponding correlation coefficients were 0.47, 0.88, and 0.81. For SRI, median absolute errors were 0.044, 0.018, and 0.027, and the correlation coefficients were 0.54, 0.85, and 0.74 for the three methods. CONCLUSIONS: The precision of eKt/V and SRI measurements was significantly lower for the dialysate/volume method compared with the blood-side methods. Inclusion of the dialysate curve analysis provided by the Biostat restored precision to the dialysate method to a level comparable to that of the blood-side methods. New techniques employing dialysate urea analysis should include a concentration profile to avoid these inherent methodological errors and assure the accuracy of eKt/V and SRI.

Effects of hemodialyzer reuse on clearances of urea and beta2-microglobulin. The Hemodialysis (HEMO) Study Group.

Although dialyzer reuse in chronic hemodialysis patients is commonly practiced in the United States, performance of reused dialyzers has not been extensively and critically evaluated. The present study analyzes data extracted from a multicenter clinical trial (the HEMO Study) and examines the effect of reuse on urea and beta2-microglobulin (beta2M) clearance by low-flux and high-flux dialyzers reprocessed with various germicides. The dialyzers evaluated contained either modified cellulosic or polysulfone membranes, whereas the germicides examined included peroxyacetic acid/acetic acid/hydrogen peroxide combination (Renalin), bleach in conjunction with formaldehyde, glutaraldehyde or Renalin, and heated citric acid. Clearance of beta2M decreased, remained unchanged, or increased substantially with reuse, depending on both the membrane material and the reprocessing technique. In contrast, urea clearance decreased only slightly (approximately 1 to 2% per 10 reuses), albeit statistically significantly with reuse, regardless of the porosity of the membrane and reprocessing method. Inasmuch as patient survival in the chronic hemodialysis population is influenced by clearances of small solutes and middle molecules, precise knowledge of the membrane material and reprocessing technique is important for the prescription of hemodialysis in centers practicing reuse.