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.

Timely initiation of dialysis: a urea kinetic approach.

The traditional approach of initiating dialysis when the patient begins to manifest uremic symptoms may result in the development of significant malnutrition with detrimental effects on subsequent morbidity and mortality. The recently issued Dialysis Outcome Quality Initiative guidelines suggest that dialysis be initiated when the Kt/V from residual renal function decreases to less than 2.0. We have used the urea kinetic model to show how dialytic dose can be titrated to compensate for declining renal function while maintaining a constant total dose of delivered therapy (Kt/V = 2.0). For hemodialysis (HD), we show that initiating dialysis with once-weekly therapy may be a viable option only for a few months, being replaced by twice-weekly and subsequently with the more typical regimen of thrice-weekly HD. We recommend that the patient be directly initiated with twice-weekly HD to minimize wide swings in the serum concentrations of small-molecular-weight solutes. With continuous ambulatory peritoneal dialysis (CAPD), a hypothetical average-sized patient with high-average transport can be maintained for approximately 8 months with a single 2.5-L nocturnal exchange and from 8 to 17 months with two nocturnal exchanges of 2.5 L each. The use of nocturnal exchanges allows more normal daytime activities and is less intrusive on patient lifestyle. We have shown that both HD and CAPD regimens can be successfully adjusted to achieve a constant total Kt/V of 2.0 for 5 or more years, although CAPD may provide a smoother transition from no dialysis to a complete 10-L regimen.

Increased peritoneal membrane transport is associated with decreased patient and technique survival for continuous peritoneal dialysis patients. The Canada-USA (CANUSA) Peritoneal Dialysis Study Group.

The objective of this study was to evaluate the association of peritoneal membrane transport with technique and patient survival. In the Canada-USA prospective cohort study of adequacy of continuous ambulatory peritoneal dialysis (CAPD), a peritoneal equilibrium test (PET) was performed approximately 1 mo after initiation of dialysis; patients were defined as high (H), high average (HA), low average (LA), and low (L) transporters. The Cox proportional hazards method evaluated the association of technique and patient survival with independent variables (demographic and clinical variables, nutrition, adequacy, and transport status). Among 606 patients evaluated by PET, there were 41 L, 192 LA, 280 HA, and 93 H. The 2-yr technique survival probabilities were 94, 76, 72, and 68% for L, LA, HA, and H, respectively (P = 0.04). The 2-yr patient survival probabilities were 91, 80, 72, and 71% for L, LA, HA, and H, respectively (P = 0.11). The 2-yr probabilities of both patient and technique survival were 86, 61, 52, and 48% for L, LA, HA, and H, respectively (P = 0.006). The relative risk of either technique failure or death, compared to L, was 2.54 for LA, 3.39 for HA, and 4.00 for H. The mean drain volumes (liters) in the PET were 2.53, 2.45, 2.33, and 2.16 for L, LA, HA, and H, respectively (P < 0.001). After 1 mo CAPD treatment, the mean 24-h drain volumes (liters) were 9.38, 8.93, 8.59, and 8.22 for L, LA, HA, and H, respectively (P < 0.001); the mean 24-h peritoneal albumin losses (g) were 3.1, 3.9, 4.3, and 5.6 for L, LA, HA, and H, respectively (P < 0.001). The mean serum albumin values (g/L) were 37.8, 36.2, 33.8, and 32.8 for L, LA, HA, and H, respectively (P < 0.001). Among CAPD patients, higher peritoneal transport is associated with increased risk of either technique failure or death. The decreased drain volume, increased albumin loss, and decreased serum albumin concentration suggest volume overload and malnutrition as mechanisms. Use of nocturnal cycling peritoneal dialysis should be considered in H and HA transporters.

Lower probability of patient survival with continuous peritoneal dialysis in the United States compared with Canada. Canada-USA (CANUSA) Peritoneal Dialysis Study Group.

In a prospective cohort study of 680 incident continuous peritoneal dialysis (PD) patients in North America, dialysis in the United States compared with Canada was associated with a relative risk (RR) of death of 1.93 (95% confidence interval [CI], 1.14 to 3.28). The 2-yr survival probability was 79.7% in Canada and 63.2% in the United States. This difference was not explained by race, age, gender, functional status, insulin-dependent diabetes mellitus, history of cardiovascular disease (CVD), nutritional status, or adequacy of dialysis. Other potential explanatory variables were further evaluated. These included severity of CVD, residual renal function, race, differential transfer to hemodialysis or transplantation, patient compliance, modality selection bias, and incidence of endstage renal disease requiring dialysis. Cardiovascular morbidity and peritonitis probabilities were compared. The CVD severity index was not different between countries; the RR risk associated with dialysis in the United States remained high at 1.87 (95% CI, 1.09 to 3.19). Residual renal function at initiation of dialysis was not different between countries. The 2-yr survival for Caucasians was 77% in Canada and 55% in the United States. There was no difference in the probability of transfer to hemodialysis or transplantation. The RR of a nonfatal cardiovascular event in the United States compared with Canada was 1.80 (95% CI, 1.21 to 2.67). There was no difference in time to first peritonitis. The observed to predicted creatinine ratio, as an estimate of compliance, was 1.13 in Canada and 1.00 in the United States. The prevalence of PD in the study centers was 48% in Canada and 22% in the United States. The incidence of new dialysis patients in 1992 was 100/million population in Canada compared with 211/ million in the United States. The survival difference is not explained by age, gender, insulin-dependent diabetes mellitus, nutritional status, or adequacy of dialysis. Neither is it explained by race, severity of CVD, transfer to hemodialysis, transplantation, or an estimate of compliance. The lower proportion of patients receiving PD in the United States may represent a selection bias of uncertain direction. The higher acceptance rate for dialysis in the United States may explain, in part, the greater cardiovascular morbidity and the decreased survival observed.

Hemodialyzer mass transfer-area coefficients for urea increase at high dialysate flow rates. The Hemodialysis (HEMO) Study.

The dialyzer mass transfer-area coefficient (KoA) for area is an important determinant of urea removal during hemodialysis and is considered to be constant for a given dialyzer. We determined urea clearance for 22 different models of commercial hollow fiber dialyzers (N = approximately 5/model, total N = 107) in vitro at 37 degrees C for three countercurrent blood (Qb) and dialysate (Qd) flow rate combinations. A standard bicarbonate dialysis solution was used in both the blood and dialysate flow pathways, and clearances were calculated from urea concentrations in the input and output flows on both the blood and dialysate sides. Urea KoA values, calculated from the mean of the blood and dialysate side clearances, varied between 520 and 1230 ml/min depending on the dialyzer model, but the effect of blood and dialysate flow rate on urea KoA was similar for each. Urea KoA did not change (690 +/- 160 vs. 680 +/- 140 ml/min, P = NS) when Qh increased from 306 +/- 7 to 459 +/- 10 ml/min at a nominal Qd of 500 ml/min. When Qd increased from 504 +/- 6 to 819 +/- 8 ml/min at a nominal Qh of 450 ml/min, however, urea KoA increased (P < 0.001) by 14 +/- 7% (range 3 to 33%, depending on the dialyzer model) to 780 +/- 150 ml/min. These data demonstrate that increasing nominal Qd from 500 to 800 ml/min alters the mass transfer characteristics of hollow fiber hemodialyzers and results in a larger increase in area clearance than predicted assuming a constant KoA.

Effect of low-frequency ultrasound on peritoneal transport in rabbits.

It has recently been suggested that sonophoresis, or the application of ultrasound (US) in the kilohertz range, could enhance peritoneal mass transport. To examine this hypothesis, six nephrectomized rabbits were exposed to ultrasound while under isoflurane anesthesia. An additional five also had bilateral nephrectomies and were used as a control group. Each group underwent four exchanges of 90 minutes duration with 1.5% dextrose while anesthetized. Dialysate samples were taken at 0, 30, 60, and 90 minutes and assayed for urea, creatinine, glucose, and protein. Blood samples were taken pre- and postexchange. In the US group, 20 kHz ultrasound was applied during exchanges 2 and 3 at 47.5 W and 95 W, respectively, using a Virsonic 475 cell disrupter acoustically coupled to the abdomen through a water column and gel-coated PVC membrane. Results were analyzed by calculating the mass transfer area coefficient (MTAC) and 90-minute D/P values for each exchange. No significant differences were observed in the absolute means of either parameter between the control and US groups. However, when exchanges 2 to 4 were normalized with respect to exchange 1, the resulting urea D/P means were less for the US exchanges compared to the control (p < 0.05). This suggests a possible decrease in transport through US application.

Multicenter clinical validation of an on-line monitor of dialysis adequacy.

Quantitation of hemodialysis by measuring changes in blood solute concentration requires careful timing when taking the postdialysis blood sample to avoid errors from postdialysis rebound and from recirculation of blood through the access device. It also requires complex mathematical interpretation to account for solute disequilibrium in the patient. To circumvent these problems, hemodialysis can be quantified and its adequacy assessed by direct measurement of the urea removed in the dialysate. Because total dialysate collection is impractical, an automated method was developed for measuring dialysate urea-nitrogen concentrations at frequent intervals during treatment. A multicenter clinical trial of the dialysate monitoring device, the Biostat 1000 (Baxter Healthcare Corporation, McGaw Park, IL) was conducted to validate the measurements of urea removed, the delivered dialysis dose (Kt/V), and net protein catabolism (PCR). The results were compared with a total dialysate collection in each patient. During 29 dialyses in 29 patients from three centers, the paired analysis of urea removed, as estimated by the dialysate monitor compared with the total dialysate collection, showed no significant difference (14.7 +/- 4.7 g versus 14.8 +/- 5.1 g). Similarly, measurements of Kt/V and PCR showed no significant difference (1.30 +/- 0.18 versus 1.28 +/- 0.19, respectively, for Kt/V and 42.3 +/- 15.7 g/day versus 52.2 +/- 17.4 g/day for PCR). When blood-side measurements during the same dialyses were analyzed with a single-compartment, variable-volume model of urea kinetics, Kt/V was consistently overestimated (1.49 +/- 0.29/dialysis, P < 0.001), most likely because of failure to consider urea disequilibrium. Because urea disequilibrium is difficult to quantitate during each treatment, dialysate measurements have obvious advantages. The dialysate monitor eliminated errors from dialysate bacterial contamination, simplified dialysate measurements, and proved to be a reliable method for quantifying and assuring dialysis adequacy.

A proposed glossary for dialysis kinetics.

Quantification of the dialysis dose and assessment of nutritional status and response to nutritional therapy have become standard parts of the management of the chronic dialysis patient. Although advances in these areas have led to a more rational basis for therapy, certain misconceptions and points of confusion appear to have occurred. Recognizing the importance of a standard nomenclature to the development of concepts and the communication of research findings, we have attempted to compile a list of terms that are commonly used in the field of dialysis. New terms have been proposed for current ones that do not seem adequate. In addition, we have discussed potential methodologies for obtaining more accurate data for dialysis kinetics and for precise monitoring of nutritional intake and status. It is hoped that this glossary will stimulate discussion that will lead to refinements in terminology and concepts that will, in turn, improve research and practice in nephrology. It is anticipated that many of these definitions and recommendations will be modified or superseded as the management of patients with renal failure continues to advance.

Pitfalls of in vivo dialyzer clearance measurement.

Dialyzer small-molecule clearance measurements are commonly made to help identify the cause of inadequate dialysis prescriptions, to determine the efficacy of reuse procedures, or to choose between different types of dialyzers. Clearance measurements can be blood-side- or dialysate-side-based. While blood-side clearance measurement is the classical technique, it suffers from several serious flaws that decrease its accuracy. Chief among these are the inability to accurately measure the blood flow rate and the difficulty in accounting for the presence of nonaqueous components in the blood. Using a dialysate-based clearance measurement technique overcomes these problems for most solutes, provided appropriate guidelines are followed. This article reviews the theory behind both blood- and dialysate-side techniques as well as discussing the practical application of that theory to clearance measurement.

On-line monitoring of the delivery of the hemodialysis prescription.

The BioStat 1000 is a new device which employs dialysate-based urea kinetics to calculate the dose of dialysis (Kt/V) based on a two-pool model and protein catabolic rate (PCR). Previous methods relying on blood sampling techniques were subject to error and difficult to implement. This paper describes the features of the Biostat and the results of the first clinical validation study with an early prototype. The BioStat was found to compare favorably with the reference method of direct dialysate quantification (mDDQ) which had been modified to obtain a "two-pool" Kt/V. In 31 patients no significant difference was found between mean Kt/V from the mDDQ and the mean Kt/V from the BioStat (1.35 +/- 0.33 versus 1.38 +/- 0.36, respectively). The PCR was also not significantly different (53.4 +/- 18.5 g/day versus 51.8 +/- 16 g/day, respectively). The BioStat was demonstrated to be a convenient method producing reliable results.

Lean body mass estimation by creatinine kinetics.

A new technique for estimating lean body mass (LBM) from creatinine kinetics has been developed. It is based on the principle that creatinine production is proportional to LBM and that, in the steady state, creatinine production is equal to the sum of creatinine excretion (urinary and dialytic) and metabolic degradation. This technique was applied to 17 normal subjects, 26 stable, chronic hemodialysis (HD) patients, and 71 stable, chronic peritoneal dialysis (PD) patients. In the HD group, LBM was also determined by bioimpedance in 11 patients and calculated from total body water, measured as the volume of urea distribution of a sterile urea infusion, in 15 patients. In normal subjects and in the PD group, LBM was assessed by creatinine kinetics as well as by bioimpedance, near infrared, and anthropometric techniques. In the HD patients, LBM by creatinine kinetics correlated significantly with LBM from total body water and the bioimpedance technique. There was no statistical difference between the total body water and creatinine kinetics techniques, but the bioimpedance values were systematically higher than those obtained by the kinetic technique. In the PD group and in normal volunteers, LBM values by creatinine kinetics correlated significantly with the other methods but were lower. Forty-seven percent of the HD patients and 66% of the PD patients had significantly lower LBM by creatinine kinetics than expected for their sex and age. Estimation of LBM by creatinine kinetics is proposed as a simple and convenient technique for the routine nutritional assessment of dialysis patients.

Weekly clearances of urea and creatinine on CAPD and NIPD.

Weekly creatinine clearance (Ccr) and weekly Curea/v (kt/v) are popular indices for quantitating the amount of peritoneal dialysis provided. Studies were undertaken on 44 patients on continuous ambulatory peritoneal dialysis (CAPD) and 10 patients on nightly intermittent peritoneal dialysis (NIPD) to compare relationships of weekly creatinine clearance to weekly urea clearance (Curea) divided by total body water (v). With a long cycle therapy such as CAPD, the ratio of weekly Ccr to weekly kt/v is higher than with a short cycle technique, such as NIPD, in the same patient. If patients are shifted from CAPD to NIPD maintaining the same weekly kt/v, the weekly Ccr will decrease. If patients are shifted from CAPD to NIPD maintaining the same weekly Ccr, then the weekly kt/v will increase. The clinical implications of these observations are unknown, but should be kept in mind for future studies comparing CAPD and NIPD.

Protein catabolic rate calculations in CAPD patients.

Four different approaches to calculating the protein catabolic rate (PCR, in g/kg/day) were investigated in 28 stable continuous ambulatory peritoneal dialysis (CAPD) patients and compared to the dietary protein intake (DPI) from a 3 day diet history. The modified Borah technique is based on the hemodialysis correlation, with the addition of measured effluent protein losses. The Randerson technique is a correlation similar to the Borah hemodialysis correlation, but it was established in a CAPD population. The Teehan technique estimates total nitrogen loss by adding the measured urea nitrogen loss to average values from the literature for protein, amino acid, and non-urea nitrogen losses. The Kjeldahl technique measures total nitrogen loss. All four techniques yielded similar PCR values (0.85-0.92 g/kg/day), none of which was significantly different from the DPI (0.89 g/kg/day). Based on the simplicity of the measurements and calculations, the Randerson technique is recommended for routine monitoring of PCR in CAPD patients.

Body fluid spaces and blood pressure in hemodialysis patients during amelioration of anemia with erythropoietin.

Blood pressure (BP) may increase in hemodialysis patients during treatment of anemia with recombinant human erythropoietin (r-HuEPO). Since fluid volume is a determinant of BP in dialysis patients, changes in body fluid spaces during r-HuEPO therapy could affect BP. Thus, 51Cr-labeled red blood cell (RBC) volume, inulin extracellular fluid (ECF) volume, and urea total body water (TBW), as well as cardiac output, plasma renin activity (PRA), and plasma aldosterone concentration were determined postdialysis before and after r-HuEPO therapy in patients in whom changes in BP could be managed by ultrafiltration alone. Eleven patients entered the study: one had a renal transplant and two required addition of antihypertensive drug therapy and were excluded; eight, of whom two required antihypertensive drug therapy following the study, were included in the analyses. Results revealed an increase in predialysis hemoglobin from 67 to 113 g/L (6.7 to 11.3 g/dL) (P = 0.001) during 18 +/- 6 weeks of therapy. Predialysis diastolic BP increased from 80 to 85 mm Hg (P = 0.07), while postdialysis diastolic BP was unchanged at 73 mm Hg. 51Cr-RBC volume increased, from 0.7 to 1.3 L (P = 0.004). ECF tended to decrease, from 13.7 to 10.8 L (P = 0.064), while TBW decreased to a similar extent, but not significantly, 34.3 to 31.2 L (P = 0.16). Postdialysis ECF volume was positively correlated with mean arterial BP at baseline (r = 0.89, P = 0.007) and after therapy (r = 0.74, P = 0.035). However, the regression lines for this relationship were different (P = 0.022) before and after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Defining adequacy of CAPD with urea kinetics.

The purpose of this paper is to explore the validity of applying urea kinetic indices to CAPD. According to the peak concentration hypothesis, the values of Kt/V required for adequate dialysis are lower for CAPD than for hemodialysis because of the continuous steady state nature of CAPD. Pilot clinical studies were undertaken in 19 patients to correlate the (Kt/V)urea index with clinical assessment of adequacy based on a 12 parameter score. The data shows that the correlation between serum urea nitrogen (Kt/V)urea and protein catabolic rate (PCR) are in keeping with the theoretical predictions of the urea kinetic model. PCR and dietary protein are well correlated. Also, PCR and Kt/V had a high degree of positive correlation. Serum creatinine was inversely correlated with (Kt/V)creatinine. In 74% of the patients, the clinical assessment of adequacy was in agreement with the (Kt/V)urea domains of adequacy established from the peak concentration hypothesis and the urea kinetic model. The lack of correlation in the remaining 26% is being investigated.

The peak concentration hypothesis: a urea kinetic approach to comparing the adequacy of continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis.

The KT/V urea index (K, clearance; T, treatment time; V, volume of urea distribution) has become an established index of hemodialysis (HD) adequacy, values of KT/V less than 0.8 being associated with overt uremic toxicity. For the typical continuous ambulatory peritoneal dialysis (CAPD) regimen of 4 X 2 L exchanges/day, the equivalent KT/V approximately 0.6. Paradoxically, overt uremic toxicity is not commonly observed in CAPD patients with this typical therapy prescription. Application of the urea kinetic model demonstrates that HD and CAPD have the same time-averaged urea concentration at the same KT/V. However, as HD is an intermittent therapy, the urea concentration in HD exceeds the time-averaged concentration for about half the hours in the week. If uremic toxicity is related to the peak rather than the time-averaged urea concentration, a higher KT/V would be required in HD to achieve a peak concentration at or below the steady-state CAPD concentration. This peak concentration hypothesis predicts, based on the results of the National Cooperative Dialysis Study, that underdialysis with CAPD would occur at KT/V less than 0.4 for a protein intake of 1.1 gm/kg/day.

A simplified approach to monitoring in vivo therapy prescription.

The urea kinetic model has been used to individualize therapy prescription. Because the urea kinetic model is complex, the modeling approach to therapy monitoring is not widely practiced. Presented here is a simplified approach to therapy prescription monitoring that is based on the full-fledged urea kinetic model. A Kt/V-PCR domain map (K: clearance, t: time and V: volume of urea distribution; PCR: protein catabolic rate) has been developed with the predialysis urea nitrogen concentration on the abscissa and the post/pre dialysis urea concentration ratio on the ordinate. On this domain map, the therapy index Kt/V is represented by a family of horizontal lines and the PCR is represented by a family of curved lines. In this simplified approach, mid-week measurements of the pre (C1) and post (C2) dialysis urea nitrogen concentrations are plotted on the domain map. The position of the plotted point allows one to read off the Kt/V index and the PCR to determine whether therapy index, diet, or both need to be modified.