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Effects of Dose of Dialysis on Morbidity and Mortality
Effects of Dose of Dialysis on Morbidity and Mortality Raymond M. Hakim, MD, PhD, Julia Breyer, MD, Nuhad Ismail, MD, and Gerald Schulman, MD • The annual mortality rate of patients on hemodialysis in the United States is 24.3%, substantially higher than the mortality of age-matched patients in Europe and Japan. Differences in the dose of dialysis received by US patients has been proposed as an important factor contributing to this high mortality rate. We undertook a prospective effort to increase the dose of dialysis delivered to 130 patients treated at an urban dialysis center affiliated with Vanderbilt University. From 1988 to 1991 the dose of dialysis, represented by the urea kinetic modelling parameter Kt/V (K = dialyzer clearance, t = dialysis time, V = volume of distribution of urea), has been gradually increased from a dose of 0.82 ± 0.32 to 1.33 ± 0.23. Concurrent with this increase, there was a reduction of the gross annual mortality rate from 22.8% in 1988 to 9.1% in 1991. To account for potential differences in patient characteristics during those years, we also calculated the number of expected deaths, based on data from the United States Renal Data System. The ratio of observed to expected deaths, termed the "standardized mortality rate," decreased from a value of 1.03 in 1988 to a value of 0.611 in 1991. In addition, the number of hospital days per patient per year decreased from 15.2 d/patient/yr to 10.3 d/patient/yr. We conclude that increasing the dose of delivered dialysis decreases the hospitalization and mortality rates of hemodialysis-dependent patients. © 1994 by the National Kidney Foundation, Inc. INDEX WORDS: Dialysis dose; morbidity; mortality; biocompatibility; standardized mortality rate.
T
HE mortality rate of end-stage renal disease (ESRD) patients on hemodialysis in the United States remains high. Data compiled by the Health Care Financing Administration (HCFA) and analyzed by the US Renal Data System (USRDS) show that in 1988, the annual mortality rate reached approximately 24.3% per year, an increase from 20.1 % in 1983. 1,2 This is probably an underestimate since the HCFA does not place patients in their registry until 90 days after the start of chronic hemodialysis. During these first 90 days, 10% to 15% of the patients, depending on their age, may die and may not be included in these mortality calculations. I This disturbing trend has taken place despite several technologic improvements in the delivery of dialysis and after publication of the results of the National Cooperative Dialysis Study (NCDS), which suggested a target dose of dialysis for delivery of adequate therapy.3-5 Studies comparing survival for new ESRD patients accepted for hemodialysis between 1982 and 1987 have found striking geographic differences. 6 Five-year survival rates for patients beginning renal replacement therapy in 1982 were 61%,59%, and 40% for Japan, Europe, and the United States, respectively. These geographic differences in survival are particularly marked for patients who are 60 years or older, and do not appear to be based solely on differences in acceptance or transplantation rates for these populations or on higher proportions of elderly or diabetic patients in the United States. 7 ,8
Several lines of evidence suggest that the high mortality rate in the United States may be influenced by the dose of delivered dialysis. A recent analysis of dialysis prescriptions in the United States and Europe found a substantially lower prescribed level of dialysis in the United States for the period from 1986 to 1987. 9 In the NCDS, which prospectively assessed the influence of the dose of dialysis on patient morbidity and mortality, there was a dramatic increase in hospitalizations and drop-outs for those patients whose dose of dialysis was significantly less than the conventional therapy at that time. 3,10 Although there were more deaths in the groups that received less dialysis, in the short period of the study (12 months), differences in mortality were not statistically significant. 1O Most other studies of the relationship between dose of dialysis and morbidity and mortality have been retrospective. I I Mortality was negatively associated with length of hemodialysis session in a national random sample of600 hemodialysis patients from 36 dialysis units treated between 1984 From the Division a/Nephrology, Department a/Medicine, Vanderbilt University Medical Center, Nashville, TN. Received September ]3, 1993: accepted in revised/arm December 21, 1993, This study is partially funded by National Institutes 0/ Health Grant No, HL-36015-7, Address reprint requests to Raymond M. Hakim, MD, PhD, Vanderbilt University Medical Center, S-3307 MCN, 1161 21st Ave S and Garland, Nashville, TN 37232-2372. © 1994 by the National Kidney Foundation, Inc. 0272-6386/94/2305-0005$3.00/0
American Journal of Kidney Diseases, Vol 23, No 5 (May), 1994: pp 661-669
661
HAKIM ET AL
662
and 1985. 12 However, the dose of dialysis could not be calculated in this retrospective study. In addition, in a retrospective analysis of more than 12,000 hemodialysis patients in the United States, dialysis treatment time and the intradialytic urea reduction rate (an index of dialysis dose) inversely correlated with increased mortality. I 1,13.14 Similarly, Shen and Hsu found an 89% 2-year survival rate and a lower hospitalization rate in patients receiving a higher dose of dialysis, 15 while Charra et al reported the best survival data in ESRD patients (75% at 10 years) in patients who were dialyzed overnight. 16 Finally, Ahmed and Cole analyzed hospitalized and nonhospitalized patients over a 34-month period and found the dose of dialysis to be higher in the nonhospitalized patients. 17 Because these studies have been retrospective and inferential, and do not take into account changes in patient comorbid conditions, 18 they suggest, but do not conclusively demonstrate, that the dose of dialysis may have an important impact on morbidity and mortality. In this study, the effect of increasing the dose of dialysis was examined in a prospective fashion in a large urban university-affiliated dialysis facility. Changes in patient mix and comorbid conditions were also taken into account using a newly developed method by the USRDS, which calculates expected mortality based on the etiology of the patient's renal disease and demographic characteristics. 19 MATERIALS AND METHODS
Dialysis Unit The dialysis unit used in this study is an open-staffing facility for chronic dialysis operated by Dialysis Clinic, Inc. However. the medical management of the unit has been determined by Vanderbilt-affiliated nephrologists. The dialysis facility accepts all patients referred to the facility. Patients receiving dialysis in the facility are followed by nephrologists affiliated with different hospitals in Nashville, TN; however, since 1988, the majority of patients have been referred from Vanderbilt University-affiliated hospitals. The dialysis unit is situated in an urban, low-income neighborhood and the majority of the patients dialyzed in the facility reside in surrounding communities. This is reflected by the characteristics of the patient population in 1991; the mean age of the patients was 57.1 ± 14.6 years (age range, 19.8 to 82 years), with males representing 30% of the patients. The percentage of patients whose primary renal diagnosis was diabetes was 23.6%. Reflecting the racial mix of the surrounding communities and the patient population of the referring hospitals, 81 % of the patients dialyzed at the facility are black, 18% are white, and less than I % are Oriental. Also reflecting
the economic status of the surrounding communities, 25% of the patients have only Medicare insurance and 48% have combined Medicare and Medicaid insurance. These patient characteristics have not changed substantially throughout the study period (Table I). For example, the percentage of Medicare- and Medicaid-dependent patients was 52% in 1988,48% in 1989,54% in 1990, and 52% in 1991.
Dialysis Modalities All patients were dialyzed with bicarbonate dialysate using reverse osmosis-treated water and a dialysate flow rate of 500 mL/min. The composition ofthe dialysate is sodium 140 mEq/ L, potassium 2 mEq/L, bicarbonate 39 mEq/L, calcium 3.0 mEq/L, chloride 107 mEq/L, magnesium 1.0 mEq/L, acetate 4 mEq/L, and dextrose 150 mg/dL. In 1991, the concentration of calcium in the dialysate was reduced to 2.7 mEq/L to reduce the incidence of hypercalcemia in patients taking calciumcontaining compounds for control of the serum phosphorus. All treatments were performed with volumetric control machines. Medical rounding was consistently maintained throughout the period by Vanderbilt-affiliated staff nephrologists. The general guidelines include physical rounding by a staff physician at every treatment episode (by shifts) and monthly review oflaboratory results (complete blood cell count, sequential multichannel analyzer-I 8) of all patients on that shift. In general, therefore, the medical care of the patients for each shift was determined by the principal rounding physician. Patients who required hospital admissions were admitted to their referring hospital, predominantly to Vanderbilt University Medical Center. A single dietitian is assigned to the dialysis unit and encounters each patient at least monthly. During the study period, there were no changes in the frequency of the visits of either the nephrologist or the dietitian. Automated reuse of the dialyzers has been practiced using sequential rinsing with reverse osmosis water, 2.5% hypochlorite (bleach) solution, and 4% formaldehyde for sterilization (Seratronics, CA). The average number of reuses was 14 per dialyzer. The same quality control and rejection criteria (decrease of fiber bundle volume to <85% of initial volume) have been maintained throughout the study period. Table 1. Patient Demographics and Primary Renal Diagnoses for Each Year
Age (yr) 20-29 30-39 40-49 50-59 60-69 70-79 >80 Diagnosis (%) Hypertension Diabetes Glomerulonephritis Other
1988
1989
1990
1991
9 8 15 23 24 11 2
12 10 23 26 26 13 4
12 9 25 30 32 15 5
12 9 26 29 33 16 5
42 28 14 16
43 25 12 20
48 23 12 17
46 24 14 16
DOSE OF DIALYSIS AND MORTALITY
663
Determination of Dose of Dialysis
method of measurement was instituted in mid-1989, as the use of high-flux dialyzers and rapid blood flow became prevalent. Under these conditions, as the dialytic clearance increases, there is disequilibrium in the rate of urea diffusion from the intracellular to the vascular space and urea levels "rebound" immediately postdialysis, until they achieve equimolar concentration across all body spaces. This exponential rebound is typically 15% to 20% of urea level immediately postdialysis, and equilibration generally requires several minutes. 24. 26
Prior to 1988, the dose of dialysis was determined by calculating the minimum time required to provide the patient with a dose of dialysis equivalent to Kt/V = 1.0, where K = urea clearance of the dialyzer (determined from the manufacturer's specification prior to 1988), t = dialysis time, and V = volume of distribution of urea (taken as equivalent to total body water and approximated as 60% of body weight). Kt/V is a dimensionless number and represents the fraction of body water cleared of urea during each dialysis. There was no attempt to verify the dose of dialysis delivered to the patient. Since 1988, the dose of delivered dialysis has been determined quarterly by a three-point single compartment, variable volume urea kinetic modeling program (predialysis, postdialysis, and pre-next dialysis urea levels), taking into account any residual renal function. 20•21 The intradialytic exponential decrease in blood urea nitrogen (BUN) concentration provides an estimate of the dose of delivered dialysis, expressed as Kt/ v. The interdialytic change in BUN (postdialysis to pre-next dialysis) allows calculation of net urea nitrogen appearance. Assuming neutral nitrogen balance, urea appearance is a reflection of dietary protein intake: this is often termed the "protein catabolic rate" (PCR) and is actually the protein catabolic rate normalized to a body composition of 58% water. It is expressed as grams of dietary protein per kilogram per day. 17.22 Patients with residual urine output greater than 300 mL/d were asked to collect their urine for an interdialytic period at the time the urea kinetic modeling was determined. This endogenous clearance was included in the calculation of the dose of delivered dialysis and PCR. 2 ) However, less than 5% of patients had residual renal function exceeding 2 to 3 mL/min. For prevalent patients, a minimum target for the delivered dose of dialysis was Kt/V of ~ 1.0. 5 This was achieved by increasing the dialyzer surface area and maximizing blood flow (up to a blood flow of 400 to 450 mL/min) to increase dialytic clearance (K). In general, the increase in dialyzer surface area necessitated the use of large surface area dialyzers, made of biocompatible high flux membranes such as the polysulfone membrane (F-60; Fresenius, Concord, CAl. When necessary, dialysis time (t) was also increased to arrive at the target Kt/V. However, because of the general resistance to increasing dialysis time by most patients, achievement of target Kt/V in prevalent patients was slow and incremental. For all patients starting dialysis after January 1988, the dialysis prescription included dialysis time to be fixed initially at 4 hours. Unless the patients were on a specific clinical study, new patients were dialyzed with a biocompatible, high-flux polysulfone membrane (F-60; Fresenius) at a blood flow rate of ~350 mL/min. For these new patients, dialysis time was maintained at 4 hours until two successive kinetic modeling (over 6 months) demonstrated that Kt/V was 1.4 or higher. If the measured Kt/V was substantially higher than 1.4, dialysis time was reduced by 15-minute decrements and urea kinetic modeling was remeasured to ensure that delivered Kt/V was not less than 1.4. It is important to emphasize that these doses of dialysis were measured from "equilibrated" values of urea concentration determined at least 25 minutes postdialysis. This
Calculations of Mortality Gross mortality was calculated for each year by determining the number of deaths and dividing by the average number of patients in the unit (the mean of the number of patients on January I and the number of patients on December 31 of the same year). This is the method used by the local ESRD Network and the HCFA for all dialysis units. This method may underestimate the mortality rate of a facility if the denominator (ie, the total number of patients dialyzed in the unit) is increasing and may be biased by changes in the distribution of comorbid conditions of the patients, such as the proportion of patients with diabetes, or of older patients. To avoid the confounding influence of patient selection, changing comorbid conditions and demographics, and the possibility that the decrease in gross mortality is biased by the increasing patient population (ie, larger denominator), we compared the observed patient deaths to the table of expected deaths recently published by the USRDS. '9 This analysis assigns a risk of mortality to prevalent patients present on January I at a facility. The assignment of a risk of expected deaths to each patient is based on the age, race, and ESRD diagnosis (diabetes, hypertension, glomerulonephritis, and "other," which includes all patients with a missing diagnosis). Using this table, a ratio of observed to expected mortality can be calculated. '9 This is called the "standardized mortality ratio" (SMR). A value of 1.0 indicates that the observed mortality in a specific dialysis unit is similar to the mortality expected in the United States based on the patient's age, race, gender, and underlying diagnosis. A value lower than 1.0 indicates that the observed mortality in the dialysis unit is less than the expected mortality in the United States. A chi-squared statistic and a probability value can be calculated. '9
Hospitalization Days Hospital records of all Vanderbilt University-affiliated patients were analyzed for the total number of hospital days, and a mean of hospital days per patient per year was calculated for each year since 1988. Causes of hospitalizations were not analyzed separately for each year, but the criteria for hospitalization, including criteria for access related events, have remained the same throughout this period.
RESULTS
The average dose of dialysis, defined as Kt/V and determined for all patients during each year, is shown in Table 2 as mean (± SD) and median values, As can be seen, the median dose of dialysis increased by 25% from 1988 to 1991, All patients
664
HAKIM ET AL Table 2. Average Dialysis Time, Kt/V, and Dialyzer Clearance and Distribution of Doses of Dialysis From 1988 to 1991 Kt/V' Average Dialysis Time (min)
1988 1989 1990 1991
195 196 202 212
Mean ± SD
0.82 0.955 1.012 1.18
± ± ± ±
0.32 0.28 0.40 0.41
Median
< 0.8(%)
0.8-1.0 (%)
> 1.0 (%)
> 1.4 (%)t
0.89 0.91 0.965 1.125
33 28 20 17
42 39 32 18
25 33 48 65
4 8 13 27
In Vivo, Whole Blood Dialyzer Clearance (mL/min)
170 184 196 220
± ± ± ±
27 17 14 20
• Derived from equilibrated values of postdialysis. The percentage of patients with Kt/V > 1.4 is also included in the percentage of patients with Kt/V > 1.0.
t
with a low Kt/V had their dialyzer surface area and blood flow maximized and attempts were made to lengthen their dialysis time. However, in some patients, because of intractable problems with access and consequent limitations of blood flow or because of chronic noncompliance, resistance to increasing their dialysis time, or difficulty in transportation from and to the dialysis unit, Kt/V was less than 1.0. The distribution of patients on different doses of dialysis is also shown in Table 2. Whereas in 1988, 33% of patients had a mean Kt/V of less than 0.8 and only 4% had a Kt/V greater than 1.4, in 1991, 17% of patients had a Kt/V of less than 0.8 and 27% had a Kt/V of greater than 1.4. The average length of dialysis session and the average urea clearance of all dialyzers in use during that time are also shown. Both dialysis time and dialyzer clearance (using higher surface area dia1yzers) increased from 1988 to 1991. All urea kinetic modelling in 1990 and 1991 was calculated using postdialysis equilibrated values of urea. However, because this method involves requesting patients to remain in the dialysis unit at least 25 minutes after termination of dialysis, most dialysis units determine the delivered dose of dialysis from BUN values immediately postdialysis (ie, unequilibrated BUN). To determine the relationship between the dose
of dialysis calculated from BUN values immediately postdialysis to ones calculated from equilibrated BUN values, we measured in 32 patients the rebound in the BUN values from termination of dialysis to 25 minutes following termination of dialysis. The Kt/V calculated from values immediately postdialysis was 18% ± 4% higher than that calculated from equilibrated BUN values. If such a factor is applied to all determinations in patients using rapid dialysis, the equivalent median Kt/V in our unit would be 1.14 for 1990 and 1.33 for 1991. The mortality rates for the years 1988 to 1991 are shown in Table 3. As the median dose of dialysis increased, gross mortality declined from 22.8% to 9.1%. Also shown in Table 3 are the SMRs, which were derived from actual and expected deaths. The SMR gradually decreased from 1.03 in 1988 to 0.611 in 1991 , ie, in 1991 , the observed number of deaths was 61 % of the expected mortality based on the patients' demographic characteristics and renal diagnoses. Because of the small number of observations, the year-by-year comparison did not yield statistical significance. Nevertheless, the chi-squared value of 3.46 calculated for 1991 when the mean Kt/ V was 1.2 is close to the value of 3.84, which would have resulted in a statistically significant probability value of 0.05 . In addition, by com-
Table 3. Gross Mortality and Standardized Mortality Ratio of Dialysis Patients
1988 1989 1990 1991
No. of Patients
Mortality (% )
Observed
Expected
SMR
X2
Probability Value
92 114 128 130
22.8 17.8 15.6 9.1
17 14 17 14
16.5 19.9 21.6 22.9
1.030 0.703 0.785 0.611
0.01 1.76 1.00 3.46
~~:~~~}p > 0.100 :~:~~~}p < 0.050
665
DOSE OF DIALYSIS AND MORTALITY
bining the data for the years 1988 and 1989 and separately for the years 1990 and 1991 (a method suggested by the USRDS), it can be seen that the expected number of deaths for the years 1990 and 1991 was statistically significantly less than observed, whereas the expected and observed numbers of deaths for the years 1988 and 1989 were not significantly different (Table 3). Data obtained during urea kinetic modeling were used to calculate Kt/V and PCR from intradialytic and interdialytic urea appearance, respectively. These parameters were plotted against each other as shown in Fig 1. A strong correlation between the dose of dialysis and protein intake is evident (r = 0.838, P < 0.001), and the leastsquare regression line is represented by the equation PCR = 0.12 + 0.73* (Kt/V). Thus, as the dose of delivered dialysis increased, daily protein intake, as judged by net urea appearance, increased. Recent evidence has suggested that indices of malnutrition, and specifically albumin concentration, inversely correlate with mortality.13.27 To explain the possible relationship between the decreased mortality and increased dose of dialysis, we further analyzed the distribution ofKt/V and
the serum albumin concentration determined predialysis. We averaged the dose of dialysis (Kt/ V) achieved by each patient over a period of 1 year (1990-1991; ie, typically four determinations) and determined the distribution of these "time-averaged Kt/V." Next, we identified the patients who had a time-averaged Kt/V of ~ 1.21 (upper quartile of the distribution) and patients whose average Kt/V over the same time period was sO.86 (lower quartile of the distribution). Biochemical parameters of nutrition (albumin, transferrin concentration, and PCR) of all patients identified in these two subgroups are shown in Table 4. As can be seen in this table, patients with a mean Kt/V of~1.21, averaged over a period of 1 year, had a statistically significant higher albumin level, transferrin concentration, and PCR than patients whose average Kt/V was less than 0.86. These findings are also consistent with the observations, shown in Fig 1, that as the dose of dialysis increases, the protein catabolic rate, a surrogate for protein intake in the stable dialysis patient, also increases. We also investigated the morbidity of these patients by counting the total number of hospital days at Vanderbilt University Medical Center in
>. 0
~
01
~
1.8
.!?)
W
I
a:: u
1.5
1
1.2
-1
0
CD
Fig 1. The relationship of the dose of dialysis (Kt/V) and interdialytic urea appearance (PCR) in hemodialysis patients. The numbers inside the figure refer to the number of data points at each point. The least square fit is best described by the equation PCR = 0.12 + 0.73 • (Kt/V). The relationship is statistically significant (P < 0.001) with a correlation coefficient of 0.838.
tiU Z
.90 .60
W
I0 .30
1 1 1 1 1 1111111 1 1 1 1 2 12 11 1315113311143 1 2 13111 1 111 1 11 2 2 1 1 1 2122 1 3141 1211 211 2 1 2 1 1 121 1 1 1 1 21111314 1121 133 1 221 311311122321 1 1 2 1 2 2 1232233112 3 111211 1 2 1131 21121 1 1 11 4 343221 1 1 1 1 34222353 3241 21 211 1 1 21 1112311 1331 111 21 13 1 1 1 24 1121 1 31112113 341 1 111 11 2123 4111332213121 1 1 1 2 1 22 22 1121 1 1 1 11 1 11 112 1 11 1 11 l' 111 1 1
'1
,
1
l' 1
1
1 11
1
11
1
1 31 1 1 1 11 2 1 1 11 1 1 1 1 1 1 1 1 11 1 1 1
1
1
1
1
0:
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0
0
0.5
1.0
1.5 Kt / V
2.0
2.5
HAKIM ET AL
666 Table 4. Nutritional Parameters and Yearly Average Kt/V
No. of Patients
Yearly Average Kt/V (g/kg/d)
Albumin (g/dL)
Transferrin (mg/dL)
peR
32 32
<0.86 > 1.21
3.5 ± 0.3 3.9 ± 0.2*
220 ± 34 257 ± 64*
0.83 ± 0.19 1.00 ± 0.19*
*
P < 0.05.
a given year and dividing by the number of Vanderbilt-affiliated patients for that year. This is shown in Table 5, which summarizes the total number of hospital days for these patients and the average number of hospital days per patient per year. In general, the criteria for hospitalization of dialysis patients, including the criteria for admissions for access surgery, have not changed over the time period of observation. The average number of hospital days per patient per year decreased from a mean of 15.2 days in 1988 to 11.6 days in 1990 and 10.3 days in 1991 (P < 0.0 I compared with 1988). At the same time, the average length of stay for other patients has remained approximately the same (7 d/patient/ stay) throughout this period of time. DISCUSSION
In this prospective study, it was demonstrated that an increase in the delivered dose of dialysis by an average of25% correlated with a significant decrease in the annual morbidity and mortality rates of hemodialysis-dependent ESRD patients in a large urban facility. This decrease in morbidity and mortality is not related to differences in patient selection since it was also evident in the standardized mortality rate, which takes into account the patients' major comorbid characteristics (age, diagnosis ofESRD, gender, and race). IS A recent study has also concluded that adjustments for patient attributes did not substantially Table 5. Morbidity of Vanderbilt University Medical Center Dialysis Patients
1988 1989 1990 1991
No. of Patients
No. of Hospital Days
Hospital Days/ Patient/Yr
92 114 128 130
1,399 1,319 1,379 1,345
15.2 14.7 11.6 10.3
change the degree of variation of mortality among dialysis centers. 28 The estimation of an adequate dose of dialysis for ESRD patients has been derived from studies such as the NCDS, which was completed in 1982. 3.29 The NCDS study was intended "to develop techniques by which dialysis could be prescribed on an individual and quantitated basis, and by which it would improve the minimum exposure that would keep patients free from dialysis-related complications. ,,30 In that study, the participating patients were dialyzed with less than the "standard dose" of dialysis and their dialysisrelated morbidity was monitored. 1O While the original study used a time-averaged concentration of urea as the parameter of adequacy, further analysis of the results indicated that a delivered dose of dialysis defined by KtjV of approximately 0.9 is sufficient to maintain the morbidity of these patients at an acceptable level. 5 Although there were more deaths in the groups with Kt/V lower than 0.9, this was not statistically significant in the short period of the study (I year). 10,31 It must be recalled, however, that the general applicability of the NCDS may be limited since the randomized patients participating in the study were approximately 10 years younger than the median age of the US ESRD population, were free of major comorbid conditions (such as cardiovascular disease), and were selected for their compliance. In addition, none of the patients in the NCDS study were diabetic, in contrast to the 33% of ESRD patients in the United States who are currently diabetic and to the 23% in our patient population, II More importantly, the dose of dialysis judged to be adequate by the NCDS was determined from predialysis and postdialysis BUN levels (ie, was a delivered dose of dialysis). Subsequently, nephrologists have used these target doses to prescribe dialysis. However, rather than measuring
DOSE OF DIALYSIS AND MORTALITY
actual in vivo clearances (K) and volumes of distribution (V) and access recirculation, nephrologists have relied on the manufacturers' derived in vitro urea clearances of dialyzers and have used standard formulas for the calculation of the volume of distribution. 32 .33 From these, the minimum amount of time (t) to achieve a Kt/V of 0.9 to 1.0 is then prescribed. 34.35 This has led to a significant difference between prescribed and delivered dose of dialysis. 36 Indeed, recent studies suggested that more than 50% of the treatments had a delivered dose of dialysis less than prescribed. 35 .37 In an analysis of a random sample of 3,000 patients, Held et al recently showed that while the median prescribed Kt/V was 1.0, there was a wide distribution of prescriptions; 50% of the patients had prescriptions of Kt/V less than 1.0 and 24% had prescriptions of Kt/V less than 0.8. 38 Because of this relatively inadequate prescription and of the potential factors mentioned above, the median delivered Kt/V was 0.72, again pointing to the large discrepancy between prescribed and delivered dose of dialysis as possibly accounting for the increased mortality in ESRD patients treated by hemodialysis. Thus, prescribed doses of dialysis are often less than that considered adequate by NCDS criteria, and the delivered dose is substantially less than prescribed. 11 It is therefore likely that one of the factors contributing to the high mortality rate of the hemodialysis-dependent population in the United States is inadequate dialysis. 39 ,40 Our study suggests that increasing the dose of delivered dialysis is associated with decreasing mortality and morbidity. Our data are consistent with those recently reported by Collins et aI, who presented retrospective data to show that in a large dialysis program, the relative risk of mortality (adjusted for comorbid conditions, age, and diabetes) was significantly less for patients dialyzed with a calculated Kt/V of greater than 1.2 than for patients with a calculated Kt/V of ~ 1.0 or less. 41 These investigators also showed that it is possible to reduce the high mortality rate in diabetic patients if the dose of dialysis is increased to a mean Kt/V of ~ 1.4.42 In a smaller population, Schleifer et al recently examined retrospectively the influence of increasing dialysis dose from a Kt/V of 1.0 ± 0.2 to a Kt/V of 1.3 ± 0.23 and found that gross yearly mortality decreased from 28% to 11%.43
667
Our study prospectively confirms these findings in a large urban patient population. The relationship between the dose of dialysis and mortality may not be simple. However, the relationship between the dose of dialysis and nutritional parameters may be one of the potential links between increasing the dose of dialysis and improved survival. 10.44 The importance of nutritional parameters in the mortality of dialysis-dependent patients has been recently highlighted by studies by Lowrie and LewY In that study patients with serum albumin concentrations between 3.5 and 4.0 g/dL, considered to be within the range of "normal" in most laboratories, had a relative risk of death twice that for the reference group of patients with albumin concentration greater than 4.0 g/dL; there was also a fivefold increase in the relative risk of death for patients whose albumin concentration was less than 3.0 g/dL compared with the reference group (albumin ~ 4.0 g/dL).13.45 Teschan et al showed that a decrease in the dose of dialysis led to a decrease in albumin concentration, interdialytic weight gain, and, presumably, food intake. 46 Our findings of increased protein catabolic rate (a measure of protein intake) as Kt/V increases support the concept that increasing the dose of dialysis may improve appetite and food intake. 47 This is also supported by our analysis of subpopulations of patients with consistently high and consistently low Kt/V, which shows that those who receive higher doses of dialysis have improved nutritional parameters. However, it is important to note that the relationship between the dose of dialysis and albumin concentration requires a long-term exposure of the patients to an adequate or optimal dose of dialysis. Another potential factor in the improvement of morbidity and mortality in the use of erythropoietin during the same time period of the study. Although there are several studies that have shown a beneficial effect of erythropoietin on cardiac function,48 studies reporting the overall clinical effects of erythropoietin have shown no clear benefit of erythropoietin in reducing hospital admissions or mortality.49.50 Finally, it is important to add that the increased dose of dialysis was also achieved by use of membranes that are more biocompatible and with greater permeability to larger "middle" molecules compared with the cuprophane membranes used
668
HAKIM ET AL
earlierY-53 Cuprophane membranes have wellknown propensities for activating complement, cytokines, and neutrophils, and recent evidence suggests that biocompatible membranes are associated with a significantly reduced risk of infectious mortality and overall mortality. 53 However, the relative importance that the dose of dialysis and biocompatibility play in the observed reduction of mortality remains speculative at present. In summary, we have shown that the dose of dialysis is an important prescription parameter that can influence the morbidity and mortality of dialysis patients. A potential link between these two parameters may be the improved appetite and nutritional parameters of patients who are well-dialyzed with biocompatible membranes. Further studies are needed to unravel the relationship between these two issues. ACKNOWLEDGMENT The authors acknowledge the contribution of the patientcare staff of the DCI unit at 1600 Hayes St, Nashville, TN, as well as the patients who, at times reluctantly. agreed to an increase in the dose of dialysis. The secretarial assistance of Donna Richards and Valerie McSterling is also gratefully acknowledged.
REFERENCES I. US Renal Data System: 1990 Annual Data Report. Bethesda, MD. National Institutes ofHeaIth, National Institute of Diabetes and Digestive and Kidney Diseases. 1990 2. Gotch FA. Uehlinger DE: Mortality rate in U.S. dialysis patients. Dial Transplant 205:255-257. 1991 3. Lowrie EG. Laird NM, Parker TF, Sargent JA: Effect of the hemodialysis prescription on patient morbidity. Report from the National Cooperative Dialysis StUdy. N Engl J Med 305: 1176-1181. 1981 4. Lowrie EG, Laird NM: Cooperative Dialysis StUdy. Kidney Int 23:SI-SI22. 1983 (suppl 13) 5. Gotch FA, Sargent JA: A mechanistic analysis of the national cooperative dialysis study (NCDS). Kidney Int 28: 526-534, 1985 6. Hull AR, Parker TF: Proceedings from the Morbidity, Mortality and Prescription of Dialysis Symposium, Dallas, Texas, September 15 to 17, 1989. Am J Kidney Dis 15:375383, 1990 (editorial) 7. Held PJ, Brunner F. Odaka M, Garcia JR. Port FK, Gaylin DS: Five-year survival for end stage renal disease patients in the United States, Europe and Japan, 1982 to 1987. Am J Kidney Dis 15:451-457, 1990 8. Odaka M: Mortality in chronic dialysis patients in Japan. Am J Kidney Dis 15:410-413, 1990 9. Held PJ, Blagg CR. Liska DW. Port FK. Hakim RM, Levin N: The dose of hemodialysis according to dialysis prescription in Europe and the United States. Kidney Int 42:1621.1992
10. Parker TF. Laird NM. Lowrie EG: Comparison of the study groups in the National Cooperative Dialysis Study and a description of morbidity, mortality and patient withdrawal. Kidney Int 23:S42-S49, 1983 (suppl 13) II. Hakim RM. Depner TA, Parker TF: Adequacy of hemodialysis. Am J Kidney Dis 20:107-123, 1992 12. Held PJ. Levin NW, Bovbierg RR, Pauly MV, Diamond LH: Mortality and duration of hemodialysis treatment. JAMA 265:871-875,1991 13. Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15:458-482, 1990 14. Lowrie E, Lew N. Liu Y: The effect of difference in urea reduction ratio (URR) on death risk in hemodialysis patients: A preliminary analysis. Memorandum to Medical Directors, November 1991 15. Shen F-H, Hsu K-T: Lower mortality and morbidity associated with higher KtjV in hemodialysis patients. J Am Soc Nephrol 1:377, 1990 (abstr) 16. Charra B. Calemard E, Chazot C, Ruffet M, Terrat JC, Vanel T, Laurent G: Survival as an index of adequacy of dialysis. Kidney Int 41:1286-1291, 1992 17. Ahmed S, Cole JJ: Lower morbidity associated with higher KtjV in stable hemodialysis patients. J Am Soc Nephrol 1:346, 1990 (abstr) 18. Collins AJ, Hanson G, Umen A, Kjellstrand C. Keshaviah P: Changing risk factor demographics in end-stage renal disease patients entering hemodialysis and the impact on long-term mortality. Am J Kidney Dis 15:422-432, 1990 19. Wolfe RA, Gaylin DS, Port FK, Held PJ, Wood CL: Using USRDS generated mortality tables to compare local ESRD mortality rates to national rates. Kidney Int 42:991996, 1992 20. Sargent JA: Control of dialysis by single-pool urea model: The National Cooperative Dialysis Study. Kidney Int 23:S19-S25, 1983 (suppI13) 21. Gotch FA: Kinetic modeling in hemodialysis, in Nissensson AR, Gentile DE, Fine RN (eds): Clinical Dialysis (ed 2). Norwalk, CT. Appleton and Lange, 1989, pp 118-146 22. Daugirdas JT: The post:pre dialysis plasma urea nitrogen ratio to estimate KtjV and NPCR: Mathematical modeling. Int J ArtifOrgans 12:411-419.1989 23. Goldstein MB. Jindal KK: Urea kinetic modeling. Semin Dial 1:82-85. 1988 24. Kjellstrand C, Ulan R, Cederliif 10, Ericsson F, Skroder R, Jacobson S: All derived KtjV overestimate and increasingly deviate from true KtjV as dialysis speed is increased and dialysis time shortened. J Am Soc NephroI2:332, 1991 (abstr) 25. Pedrini LA, Zereik S. Rasmy S: Causes, kinetics and clinical implications of post hemodialysis urea rebound. Kidney Int 34:817-825. 1988 26. Tsang MK. Leonard FL. Williams S: Urea dynamics during and immediately after dialysis. ASAIO Trans 8:251260, 1985 27. Degoulet p. Legrain M, Reach I, Aime F, Devries C. Rojas p. Jacobs C: Mortality risk factors in patients treated by chronic hemodialysis. Nephron 31: I 03-110. 1982 28. McClellan WM, Flanders D, Gutman RA: Variable mortality rates among dialysis treatment centers. Ann Intern Med 117:332-336. 1992
DOSE OF DIALYSIS AND MORTALITY
29. Laird NM, Berkey CS. Lowrie EG: Modeling success or failure of dialysis therapy: The National Cooperative Dialysis Study. Kidney Int 23:SIOI-SI06. 1983 (suppI13) 30. Wineman RJ: Rationale of the National Cooperative Dialysis Study. Kidney Int 23:8·11 , 1983 31. Harter H: Review of significant findings from the Na· tional Cooperative Dialysis Study and recommendations. Kidney Int 23:SI07·SI12, 1983 (suppl 13) 32. Delmez J, Windus D, and the Saint Louis Nephrology Study Group: Hemodialysis prescription and deli very in a metropolitan community. Kidney Int 41 : 1023-1028. 1992 33. Windus DW, Audrain J, Vanderson R, Jendrisak MD, Picus D, Delmez JA: Optimization of high-efficiency hemodialysis by detection and correction of fistula dysfunction. Kidney lnt 38:337-341, 1990 34. Gotch FA. Yarian S. Keen M: Akinetic survey of US hemodialysis prescriptions. Am J Kidney Dis 15:511-515, 1990 35. Lindsay RM. Heidenheim AP. Spanner E, Baird J. Simpson K, Allison ME: Urea monitoring during dialysis: The wave of the future. Atale of two cities. ASAIO Trans 37: 49-53, 1991 36. LeFebvre J. Spanner E, Heidenheim A, Lindsay R: Kt/V: Patients do not get what the physician prescribes. ASAIO Trans 37:mI32-mI33, 1991 37. Sargent JA: Shortfalls in the delivery of dialysis. Am J Kidney Dis 15:500·510. 1990 38. Held PJ, Port FK. Garcia J. Gaylu DS, Levin NW. Agadoa L: Hemodialysis prescription and delivery in the US: Results from USRDS case mix. J Am Soc Nephrol 2:328. 1991 (abstr) 39. Held P, Blagg C, Liska D, Port F. Hakim R, Levin N: The dose of hemodialysis according to dialysis prescription in Europe and the United States. Kidney Int 42:sI6·s21 , 1992 (suppI38) 40. De Oreo P: Analysis of time, nutrition and Kt/V as risk factors for mortality in dialysis patients. J Am Soc Nephrol 2:321, 1991 (abstr) 41. Collins A, Keshaviah P. Ma J, Umen A: Comparison
669 of hemodialysis survival in USRDS patients vs. regional kidney disease program pts. J Am Soc Nephrol 3:359. 1992 (abstr) 42. Collins A, Liao M. Umen A, Hanson G, Kesheviah P: Diabetic hemodialysis patients treated with a high Kt/V have a lower risk of death than standard Kt/V. J Am Soc Nephrol 2:318, 1991 (abstr) 43. Schleifer CR, Snyder S, Jones K: The influence of urea kinetic modeling on gross mortality in hemodialysis. J Am Soc Nephrol 2:349, 1991 (abstr) 44. Schoenfeld PY, Henry RR. Laird NM. Roxe DM: Assessment of nutritional status of the National Cooperative Dialysis study population. Kidney lnt 23 :80-88, 1983 (suppl 13) 45. Hakim RM, Levin M: Malnutrition in hemodialysis patients. Am J Kidney Dis 21:125·137, 1993 46. Teschan PE. Ginn HE. Bourne JR. Ward JM, Hamel B, Nunally JC, Musso M, Voughn WK: Quantitative indices of clinical uremia. Kidney Int 15:676·697.1979 47. Lindsay R. Spanner E. Heidenheim p. leFebure JM. Hodsman A. Baird J. Allisson M: Which come first, Kt/V or PCR-Chicken or egg? Kidney 1m 42:S32o$37. 1992 (suppl 38) 48. Wizemann V, Kaufmann J. Kramer W: Effect of erythropoietin on ischemia tolerance in anemic hemodialysis patients with confirmed coronary artery disease. Nephron 62: 161·165.1992 49. Paganini EP, Latham D. Abdulhadi M: Practical considerations of recombinant human erythropoietin therapy. Am J Kidney Dis 14:19-25, 1989 (suppll) 50. Parfrey PS: Cardiac and cerebrovascular disease in chronic uremia. Am J Kidney Dis 21:77·80. 1993 51. Chenoweth DE, Cheung AK, Henderson LW: Anaphylatoxin formation during hemodialysis: Effect of different dialyzer membranes. Kidney Int 24:764-769, 1983 52. Gutierrez A. Alverstrand A, Wahren J, Bergstrom J: Effect of in vivo contact between blood and dialysis membranes on protein catabolism in humans. Kidney Int 38:487494, 1990 53. Hakim RM: Clinical implications of hemodialysis membrane biocompatibility. Kidney Int 44:484·494, 1993
T
HE mortality rate of end-stage renal disease (ESRD) patients on hemodialysis in the United States remains high. Data compiled by the Health Care Financing Administration (HCFA) and analyzed by the US Renal Data System (USRDS) show that in 1988, the annual mortality rate reached approximately 24.3% per year, an increase from 20.1 % in 1983. 1,2 This is probably an underestimate since the HCFA does not place patients in their registry until 90 days after the start of chronic hemodialysis. During these first 90 days, 10% to 15% of the patients, depending on their age, may die and may not be included in these mortality calculations. I This disturbing trend has taken place despite several technologic improvements in the delivery of dialysis and after publication of the results of the National Cooperative Dialysis Study (NCDS), which suggested a target dose of dialysis for delivery of adequate therapy.3-5 Studies comparing survival for new ESRD patients accepted for hemodialysis between 1982 and 1987 have found striking geographic differences. 6 Five-year survival rates for patients beginning renal replacement therapy in 1982 were 61%,59%, and 40% for Japan, Europe, and the United States, respectively. These geographic differences in survival are particularly marked for patients who are 60 years or older, and do not appear to be based solely on differences in acceptance or transplantation rates for these populations or on higher proportions of elderly or diabetic patients in the United States. 7 ,8
Several lines of evidence suggest that the high mortality rate in the United States may be influenced by the dose of delivered dialysis. A recent analysis of dialysis prescriptions in the United States and Europe found a substantially lower prescribed level of dialysis in the United States for the period from 1986 to 1987. 9 In the NCDS, which prospectively assessed the influence of the dose of dialysis on patient morbidity and mortality, there was a dramatic increase in hospitalizations and drop-outs for those patients whose dose of dialysis was significantly less than the conventional therapy at that time. 3,10 Although there were more deaths in the groups that received less dialysis, in the short period of the study (12 months), differences in mortality were not statistically significant. 1O Most other studies of the relationship between dose of dialysis and morbidity and mortality have been retrospective. I I Mortality was negatively associated with length of hemodialysis session in a national random sample of600 hemodialysis patients from 36 dialysis units treated between 1984 From the Division a/Nephrology, Department a/Medicine, Vanderbilt University Medical Center, Nashville, TN. Received September ]3, 1993: accepted in revised/arm December 21, 1993, This study is partially funded by National Institutes 0/ Health Grant No, HL-36015-7, Address reprint requests to Raymond M. Hakim, MD, PhD, Vanderbilt University Medical Center, S-3307 MCN, 1161 21st Ave S and Garland, Nashville, TN 37232-2372. © 1994 by the National Kidney Foundation, Inc. 0272-6386/94/2305-0005$3.00/0
American Journal of Kidney Diseases, Vol 23, No 5 (May), 1994: pp 661-669
661
HAKIM ET AL
662
and 1985. 12 However, the dose of dialysis could not be calculated in this retrospective study. In addition, in a retrospective analysis of more than 12,000 hemodialysis patients in the United States, dialysis treatment time and the intradialytic urea reduction rate (an index of dialysis dose) inversely correlated with increased mortality. I 1,13.14 Similarly, Shen and Hsu found an 89% 2-year survival rate and a lower hospitalization rate in patients receiving a higher dose of dialysis, 15 while Charra et al reported the best survival data in ESRD patients (75% at 10 years) in patients who were dialyzed overnight. 16 Finally, Ahmed and Cole analyzed hospitalized and nonhospitalized patients over a 34-month period and found the dose of dialysis to be higher in the nonhospitalized patients. 17 Because these studies have been retrospective and inferential, and do not take into account changes in patient comorbid conditions, 18 they suggest, but do not conclusively demonstrate, that the dose of dialysis may have an important impact on morbidity and mortality. In this study, the effect of increasing the dose of dialysis was examined in a prospective fashion in a large urban university-affiliated dialysis facility. Changes in patient mix and comorbid conditions were also taken into account using a newly developed method by the USRDS, which calculates expected mortality based on the etiology of the patient's renal disease and demographic characteristics. 19 MATERIALS AND METHODS
Dialysis Unit The dialysis unit used in this study is an open-staffing facility for chronic dialysis operated by Dialysis Clinic, Inc. However. the medical management of the unit has been determined by Vanderbilt-affiliated nephrologists. The dialysis facility accepts all patients referred to the facility. Patients receiving dialysis in the facility are followed by nephrologists affiliated with different hospitals in Nashville, TN; however, since 1988, the majority of patients have been referred from Vanderbilt University-affiliated hospitals. The dialysis unit is situated in an urban, low-income neighborhood and the majority of the patients dialyzed in the facility reside in surrounding communities. This is reflected by the characteristics of the patient population in 1991; the mean age of the patients was 57.1 ± 14.6 years (age range, 19.8 to 82 years), with males representing 30% of the patients. The percentage of patients whose primary renal diagnosis was diabetes was 23.6%. Reflecting the racial mix of the surrounding communities and the patient population of the referring hospitals, 81 % of the patients dialyzed at the facility are black, 18% are white, and less than I % are Oriental. Also reflecting
the economic status of the surrounding communities, 25% of the patients have only Medicare insurance and 48% have combined Medicare and Medicaid insurance. These patient characteristics have not changed substantially throughout the study period (Table I). For example, the percentage of Medicare- and Medicaid-dependent patients was 52% in 1988,48% in 1989,54% in 1990, and 52% in 1991.
Dialysis Modalities All patients were dialyzed with bicarbonate dialysate using reverse osmosis-treated water and a dialysate flow rate of 500 mL/min. The composition ofthe dialysate is sodium 140 mEq/ L, potassium 2 mEq/L, bicarbonate 39 mEq/L, calcium 3.0 mEq/L, chloride 107 mEq/L, magnesium 1.0 mEq/L, acetate 4 mEq/L, and dextrose 150 mg/dL. In 1991, the concentration of calcium in the dialysate was reduced to 2.7 mEq/L to reduce the incidence of hypercalcemia in patients taking calciumcontaining compounds for control of the serum phosphorus. All treatments were performed with volumetric control machines. Medical rounding was consistently maintained throughout the period by Vanderbilt-affiliated staff nephrologists. The general guidelines include physical rounding by a staff physician at every treatment episode (by shifts) and monthly review oflaboratory results (complete blood cell count, sequential multichannel analyzer-I 8) of all patients on that shift. In general, therefore, the medical care of the patients for each shift was determined by the principal rounding physician. Patients who required hospital admissions were admitted to their referring hospital, predominantly to Vanderbilt University Medical Center. A single dietitian is assigned to the dialysis unit and encounters each patient at least monthly. During the study period, there were no changes in the frequency of the visits of either the nephrologist or the dietitian. Automated reuse of the dialyzers has been practiced using sequential rinsing with reverse osmosis water, 2.5% hypochlorite (bleach) solution, and 4% formaldehyde for sterilization (Seratronics, CA). The average number of reuses was 14 per dialyzer. The same quality control and rejection criteria (decrease of fiber bundle volume to <85% of initial volume) have been maintained throughout the study period. Table 1. Patient Demographics and Primary Renal Diagnoses for Each Year
Age (yr) 20-29 30-39 40-49 50-59 60-69 70-79 >80 Diagnosis (%) Hypertension Diabetes Glomerulonephritis Other
1988
1989
1990
1991
9 8 15 23 24 11 2
12 10 23 26 26 13 4
12 9 25 30 32 15 5
12 9 26 29 33 16 5
42 28 14 16
43 25 12 20
48 23 12 17
46 24 14 16
DOSE OF DIALYSIS AND MORTALITY
663
Determination of Dose of Dialysis
method of measurement was instituted in mid-1989, as the use of high-flux dialyzers and rapid blood flow became prevalent. Under these conditions, as the dialytic clearance increases, there is disequilibrium in the rate of urea diffusion from the intracellular to the vascular space and urea levels "rebound" immediately postdialysis, until they achieve equimolar concentration across all body spaces. This exponential rebound is typically 15% to 20% of urea level immediately postdialysis, and equilibration generally requires several minutes. 24. 26
Prior to 1988, the dose of dialysis was determined by calculating the minimum time required to provide the patient with a dose of dialysis equivalent to Kt/V = 1.0, where K = urea clearance of the dialyzer (determined from the manufacturer's specification prior to 1988), t = dialysis time, and V = volume of distribution of urea (taken as equivalent to total body water and approximated as 60% of body weight). Kt/V is a dimensionless number and represents the fraction of body water cleared of urea during each dialysis. There was no attempt to verify the dose of dialysis delivered to the patient. Since 1988, the dose of delivered dialysis has been determined quarterly by a three-point single compartment, variable volume urea kinetic modeling program (predialysis, postdialysis, and pre-next dialysis urea levels), taking into account any residual renal function. 20•21 The intradialytic exponential decrease in blood urea nitrogen (BUN) concentration provides an estimate of the dose of delivered dialysis, expressed as Kt/ v. The interdialytic change in BUN (postdialysis to pre-next dialysis) allows calculation of net urea nitrogen appearance. Assuming neutral nitrogen balance, urea appearance is a reflection of dietary protein intake: this is often termed the "protein catabolic rate" (PCR) and is actually the protein catabolic rate normalized to a body composition of 58% water. It is expressed as grams of dietary protein per kilogram per day. 17.22 Patients with residual urine output greater than 300 mL/d were asked to collect their urine for an interdialytic period at the time the urea kinetic modeling was determined. This endogenous clearance was included in the calculation of the dose of delivered dialysis and PCR. 2 ) However, less than 5% of patients had residual renal function exceeding 2 to 3 mL/min. For prevalent patients, a minimum target for the delivered dose of dialysis was Kt/V of ~ 1.0. 5 This was achieved by increasing the dialyzer surface area and maximizing blood flow (up to a blood flow of 400 to 450 mL/min) to increase dialytic clearance (K). In general, the increase in dialyzer surface area necessitated the use of large surface area dialyzers, made of biocompatible high flux membranes such as the polysulfone membrane (F-60; Fresenius, Concord, CAl. When necessary, dialysis time (t) was also increased to arrive at the target Kt/V. However, because of the general resistance to increasing dialysis time by most patients, achievement of target Kt/V in prevalent patients was slow and incremental. For all patients starting dialysis after January 1988, the dialysis prescription included dialysis time to be fixed initially at 4 hours. Unless the patients were on a specific clinical study, new patients were dialyzed with a biocompatible, high-flux polysulfone membrane (F-60; Fresenius) at a blood flow rate of ~350 mL/min. For these new patients, dialysis time was maintained at 4 hours until two successive kinetic modeling (over 6 months) demonstrated that Kt/V was 1.4 or higher. If the measured Kt/V was substantially higher than 1.4, dialysis time was reduced by 15-minute decrements and urea kinetic modeling was remeasured to ensure that delivered Kt/V was not less than 1.4. It is important to emphasize that these doses of dialysis were measured from "equilibrated" values of urea concentration determined at least 25 minutes postdialysis. This
Calculations of Mortality Gross mortality was calculated for each year by determining the number of deaths and dividing by the average number of patients in the unit (the mean of the number of patients on January I and the number of patients on December 31 of the same year). This is the method used by the local ESRD Network and the HCFA for all dialysis units. This method may underestimate the mortality rate of a facility if the denominator (ie, the total number of patients dialyzed in the unit) is increasing and may be biased by changes in the distribution of comorbid conditions of the patients, such as the proportion of patients with diabetes, or of older patients. To avoid the confounding influence of patient selection, changing comorbid conditions and demographics, and the possibility that the decrease in gross mortality is biased by the increasing patient population (ie, larger denominator), we compared the observed patient deaths to the table of expected deaths recently published by the USRDS. '9 This analysis assigns a risk of mortality to prevalent patients present on January I at a facility. The assignment of a risk of expected deaths to each patient is based on the age, race, and ESRD diagnosis (diabetes, hypertension, glomerulonephritis, and "other," which includes all patients with a missing diagnosis). Using this table, a ratio of observed to expected mortality can be calculated. '9 This is called the "standardized mortality ratio" (SMR). A value of 1.0 indicates that the observed mortality in a specific dialysis unit is similar to the mortality expected in the United States based on the patient's age, race, gender, and underlying diagnosis. A value lower than 1.0 indicates that the observed mortality in the dialysis unit is less than the expected mortality in the United States. A chi-squared statistic and a probability value can be calculated. '9
Hospitalization Days Hospital records of all Vanderbilt University-affiliated patients were analyzed for the total number of hospital days, and a mean of hospital days per patient per year was calculated for each year since 1988. Causes of hospitalizations were not analyzed separately for each year, but the criteria for hospitalization, including criteria for access related events, have remained the same throughout this period.
RESULTS
The average dose of dialysis, defined as Kt/V and determined for all patients during each year, is shown in Table 2 as mean (± SD) and median values, As can be seen, the median dose of dialysis increased by 25% from 1988 to 1991, All patients
664
HAKIM ET AL Table 2. Average Dialysis Time, Kt/V, and Dialyzer Clearance and Distribution of Doses of Dialysis From 1988 to 1991 Kt/V' Average Dialysis Time (min)
1988 1989 1990 1991
195 196 202 212
Mean ± SD
0.82 0.955 1.012 1.18
± ± ± ±
0.32 0.28 0.40 0.41
Median
< 0.8(%)
0.8-1.0 (%)
> 1.0 (%)
> 1.4 (%)t
0.89 0.91 0.965 1.125
33 28 20 17
42 39 32 18
25 33 48 65
4 8 13 27
In Vivo, Whole Blood Dialyzer Clearance (mL/min)
170 184 196 220
± ± ± ±
27 17 14 20
• Derived from equilibrated values of postdialysis. The percentage of patients with Kt/V > 1.4 is also included in the percentage of patients with Kt/V > 1.0.
t
with a low Kt/V had their dialyzer surface area and blood flow maximized and attempts were made to lengthen their dialysis time. However, in some patients, because of intractable problems with access and consequent limitations of blood flow or because of chronic noncompliance, resistance to increasing their dialysis time, or difficulty in transportation from and to the dialysis unit, Kt/V was less than 1.0. The distribution of patients on different doses of dialysis is also shown in Table 2. Whereas in 1988, 33% of patients had a mean Kt/V of less than 0.8 and only 4% had a Kt/V greater than 1.4, in 1991, 17% of patients had a Kt/V of less than 0.8 and 27% had a Kt/V of greater than 1.4. The average length of dialysis session and the average urea clearance of all dialyzers in use during that time are also shown. Both dialysis time and dialyzer clearance (using higher surface area dia1yzers) increased from 1988 to 1991. All urea kinetic modelling in 1990 and 1991 was calculated using postdialysis equilibrated values of urea. However, because this method involves requesting patients to remain in the dialysis unit at least 25 minutes after termination of dialysis, most dialysis units determine the delivered dose of dialysis from BUN values immediately postdialysis (ie, unequilibrated BUN). To determine the relationship between the dose
of dialysis calculated from BUN values immediately postdialysis to ones calculated from equilibrated BUN values, we measured in 32 patients the rebound in the BUN values from termination of dialysis to 25 minutes following termination of dialysis. The Kt/V calculated from values immediately postdialysis was 18% ± 4% higher than that calculated from equilibrated BUN values. If such a factor is applied to all determinations in patients using rapid dialysis, the equivalent median Kt/V in our unit would be 1.14 for 1990 and 1.33 for 1991. The mortality rates for the years 1988 to 1991 are shown in Table 3. As the median dose of dialysis increased, gross mortality declined from 22.8% to 9.1%. Also shown in Table 3 are the SMRs, which were derived from actual and expected deaths. The SMR gradually decreased from 1.03 in 1988 to 0.611 in 1991 , ie, in 1991 , the observed number of deaths was 61 % of the expected mortality based on the patients' demographic characteristics and renal diagnoses. Because of the small number of observations, the year-by-year comparison did not yield statistical significance. Nevertheless, the chi-squared value of 3.46 calculated for 1991 when the mean Kt/ V was 1.2 is close to the value of 3.84, which would have resulted in a statistically significant probability value of 0.05 . In addition, by com-
Table 3. Gross Mortality and Standardized Mortality Ratio of Dialysis Patients
1988 1989 1990 1991
No. of Patients
Mortality (% )
Observed
Expected
SMR
X2
Probability Value
92 114 128 130
22.8 17.8 15.6 9.1
17 14 17 14
16.5 19.9 21.6 22.9
1.030 0.703 0.785 0.611
0.01 1.76 1.00 3.46
~~:~~~}p > 0.100 :~:~~~}p < 0.050
665
DOSE OF DIALYSIS AND MORTALITY
bining the data for the years 1988 and 1989 and separately for the years 1990 and 1991 (a method suggested by the USRDS), it can be seen that the expected number of deaths for the years 1990 and 1991 was statistically significantly less than observed, whereas the expected and observed numbers of deaths for the years 1988 and 1989 were not significantly different (Table 3). Data obtained during urea kinetic modeling were used to calculate Kt/V and PCR from intradialytic and interdialytic urea appearance, respectively. These parameters were plotted against each other as shown in Fig 1. A strong correlation between the dose of dialysis and protein intake is evident (r = 0.838, P < 0.001), and the leastsquare regression line is represented by the equation PCR = 0.12 + 0.73* (Kt/V). Thus, as the dose of delivered dialysis increased, daily protein intake, as judged by net urea appearance, increased. Recent evidence has suggested that indices of malnutrition, and specifically albumin concentration, inversely correlate with mortality.13.27 To explain the possible relationship between the decreased mortality and increased dose of dialysis, we further analyzed the distribution ofKt/V and
the serum albumin concentration determined predialysis. We averaged the dose of dialysis (Kt/ V) achieved by each patient over a period of 1 year (1990-1991; ie, typically four determinations) and determined the distribution of these "time-averaged Kt/V." Next, we identified the patients who had a time-averaged Kt/V of ~ 1.21 (upper quartile of the distribution) and patients whose average Kt/V over the same time period was sO.86 (lower quartile of the distribution). Biochemical parameters of nutrition (albumin, transferrin concentration, and PCR) of all patients identified in these two subgroups are shown in Table 4. As can be seen in this table, patients with a mean Kt/V of~1.21, averaged over a period of 1 year, had a statistically significant higher albumin level, transferrin concentration, and PCR than patients whose average Kt/V was less than 0.86. These findings are also consistent with the observations, shown in Fig 1, that as the dose of dialysis increases, the protein catabolic rate, a surrogate for protein intake in the stable dialysis patient, also increases. We also investigated the morbidity of these patients by counting the total number of hospital days at Vanderbilt University Medical Center in
>. 0
~
01
~
1.8
.!?)
W
I
a:: u
1.5
1
1.2
-1
0
CD
Fig 1. The relationship of the dose of dialysis (Kt/V) and interdialytic urea appearance (PCR) in hemodialysis patients. The numbers inside the figure refer to the number of data points at each point. The least square fit is best described by the equation PCR = 0.12 + 0.73 • (Kt/V). The relationship is statistically significant (P < 0.001) with a correlation coefficient of 0.838.
tiU Z
.90 .60
W
I0 .30
1 1 1 1 1 1111111 1 1 1 1 2 12 11 1315113311143 1 2 13111 1 111 1 11 2 2 1 1 1 2122 1 3141 1211 211 2 1 2 1 1 121 1 1 1 1 21111314 1121 133 1 221 311311122321 1 1 2 1 2 2 1232233112 3 111211 1 2 1131 21121 1 1 11 4 343221 1 1 1 1 34222353 3241 21 211 1 1 21 1112311 1331 111 21 13 1 1 1 24 1121 1 31112113 341 1 111 11 2123 4111332213121 1 1 1 2 1 22 22 1121 1 1 1 11 1 11 112 1 11 1 11 l' 111 1 1
'1
,
1
l' 1
1
1 11
1
11
1
1 31 1 1 1 11 2 1 1 11 1 1 1 1 1 1 1 1 11 1 1 1
1
1
1
1
0:
£l..
0
0
0.5
1.0
1.5 Kt / V
2.0
2.5
HAKIM ET AL
666 Table 4. Nutritional Parameters and Yearly Average Kt/V
No. of Patients
Yearly Average Kt/V (g/kg/d)
Albumin (g/dL)
Transferrin (mg/dL)
peR
32 32
<0.86 > 1.21
3.5 ± 0.3 3.9 ± 0.2*
220 ± 34 257 ± 64*
0.83 ± 0.19 1.00 ± 0.19*
*
P < 0.05.
a given year and dividing by the number of Vanderbilt-affiliated patients for that year. This is shown in Table 5, which summarizes the total number of hospital days for these patients and the average number of hospital days per patient per year. In general, the criteria for hospitalization of dialysis patients, including the criteria for admissions for access surgery, have not changed over the time period of observation. The average number of hospital days per patient per year decreased from a mean of 15.2 days in 1988 to 11.6 days in 1990 and 10.3 days in 1991 (P < 0.0 I compared with 1988). At the same time, the average length of stay for other patients has remained approximately the same (7 d/patient/ stay) throughout this period of time. DISCUSSION
In this prospective study, it was demonstrated that an increase in the delivered dose of dialysis by an average of25% correlated with a significant decrease in the annual morbidity and mortality rates of hemodialysis-dependent ESRD patients in a large urban facility. This decrease in morbidity and mortality is not related to differences in patient selection since it was also evident in the standardized mortality rate, which takes into account the patients' major comorbid characteristics (age, diagnosis ofESRD, gender, and race). IS A recent study has also concluded that adjustments for patient attributes did not substantially Table 5. Morbidity of Vanderbilt University Medical Center Dialysis Patients
1988 1989 1990 1991
No. of Patients
No. of Hospital Days
Hospital Days/ Patient/Yr
92 114 128 130
1,399 1,319 1,379 1,345
15.2 14.7 11.6 10.3
change the degree of variation of mortality among dialysis centers. 28 The estimation of an adequate dose of dialysis for ESRD patients has been derived from studies such as the NCDS, which was completed in 1982. 3.29 The NCDS study was intended "to develop techniques by which dialysis could be prescribed on an individual and quantitated basis, and by which it would improve the minimum exposure that would keep patients free from dialysis-related complications. ,,30 In that study, the participating patients were dialyzed with less than the "standard dose" of dialysis and their dialysisrelated morbidity was monitored. 1O While the original study used a time-averaged concentration of urea as the parameter of adequacy, further analysis of the results indicated that a delivered dose of dialysis defined by KtjV of approximately 0.9 is sufficient to maintain the morbidity of these patients at an acceptable level. 5 Although there were more deaths in the groups with Kt/V lower than 0.9, this was not statistically significant in the short period of the study (I year). 10,31 It must be recalled, however, that the general applicability of the NCDS may be limited since the randomized patients participating in the study were approximately 10 years younger than the median age of the US ESRD population, were free of major comorbid conditions (such as cardiovascular disease), and were selected for their compliance. In addition, none of the patients in the NCDS study were diabetic, in contrast to the 33% of ESRD patients in the United States who are currently diabetic and to the 23% in our patient population, II More importantly, the dose of dialysis judged to be adequate by the NCDS was determined from predialysis and postdialysis BUN levels (ie, was a delivered dose of dialysis). Subsequently, nephrologists have used these target doses to prescribe dialysis. However, rather than measuring
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actual in vivo clearances (K) and volumes of distribution (V) and access recirculation, nephrologists have relied on the manufacturers' derived in vitro urea clearances of dialyzers and have used standard formulas for the calculation of the volume of distribution. 32 .33 From these, the minimum amount of time (t) to achieve a Kt/V of 0.9 to 1.0 is then prescribed. 34.35 This has led to a significant difference between prescribed and delivered dose of dialysis. 36 Indeed, recent studies suggested that more than 50% of the treatments had a delivered dose of dialysis less than prescribed. 35 .37 In an analysis of a random sample of 3,000 patients, Held et al recently showed that while the median prescribed Kt/V was 1.0, there was a wide distribution of prescriptions; 50% of the patients had prescriptions of Kt/V less than 1.0 and 24% had prescriptions of Kt/V less than 0.8. 38 Because of this relatively inadequate prescription and of the potential factors mentioned above, the median delivered Kt/V was 0.72, again pointing to the large discrepancy between prescribed and delivered dose of dialysis as possibly accounting for the increased mortality in ESRD patients treated by hemodialysis. Thus, prescribed doses of dialysis are often less than that considered adequate by NCDS criteria, and the delivered dose is substantially less than prescribed. 11 It is therefore likely that one of the factors contributing to the high mortality rate of the hemodialysis-dependent population in the United States is inadequate dialysis. 39 ,40 Our study suggests that increasing the dose of delivered dialysis is associated with decreasing mortality and morbidity. Our data are consistent with those recently reported by Collins et aI, who presented retrospective data to show that in a large dialysis program, the relative risk of mortality (adjusted for comorbid conditions, age, and diabetes) was significantly less for patients dialyzed with a calculated Kt/V of greater than 1.2 than for patients with a calculated Kt/V of ~ 1.0 or less. 41 These investigators also showed that it is possible to reduce the high mortality rate in diabetic patients if the dose of dialysis is increased to a mean Kt/V of ~ 1.4.42 In a smaller population, Schleifer et al recently examined retrospectively the influence of increasing dialysis dose from a Kt/V of 1.0 ± 0.2 to a Kt/V of 1.3 ± 0.23 and found that gross yearly mortality decreased from 28% to 11%.43
667
Our study prospectively confirms these findings in a large urban patient population. The relationship between the dose of dialysis and mortality may not be simple. However, the relationship between the dose of dialysis and nutritional parameters may be one of the potential links between increasing the dose of dialysis and improved survival. 10.44 The importance of nutritional parameters in the mortality of dialysis-dependent patients has been recently highlighted by studies by Lowrie and LewY In that study patients with serum albumin concentrations between 3.5 and 4.0 g/dL, considered to be within the range of "normal" in most laboratories, had a relative risk of death twice that for the reference group of patients with albumin concentration greater than 4.0 g/dL; there was also a fivefold increase in the relative risk of death for patients whose albumin concentration was less than 3.0 g/dL compared with the reference group (albumin ~ 4.0 g/dL).13.45 Teschan et al showed that a decrease in the dose of dialysis led to a decrease in albumin concentration, interdialytic weight gain, and, presumably, food intake. 46 Our findings of increased protein catabolic rate (a measure of protein intake) as Kt/V increases support the concept that increasing the dose of dialysis may improve appetite and food intake. 47 This is also supported by our analysis of subpopulations of patients with consistently high and consistently low Kt/V, which shows that those who receive higher doses of dialysis have improved nutritional parameters. However, it is important to note that the relationship between the dose of dialysis and albumin concentration requires a long-term exposure of the patients to an adequate or optimal dose of dialysis. Another potential factor in the improvement of morbidity and mortality in the use of erythropoietin during the same time period of the study. Although there are several studies that have shown a beneficial effect of erythropoietin on cardiac function,48 studies reporting the overall clinical effects of erythropoietin have shown no clear benefit of erythropoietin in reducing hospital admissions or mortality.49.50 Finally, it is important to add that the increased dose of dialysis was also achieved by use of membranes that are more biocompatible and with greater permeability to larger "middle" molecules compared with the cuprophane membranes used
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earlierY-53 Cuprophane membranes have wellknown propensities for activating complement, cytokines, and neutrophils, and recent evidence suggests that biocompatible membranes are associated with a significantly reduced risk of infectious mortality and overall mortality. 53 However, the relative importance that the dose of dialysis and biocompatibility play in the observed reduction of mortality remains speculative at present. In summary, we have shown that the dose of dialysis is an important prescription parameter that can influence the morbidity and mortality of dialysis patients. A potential link between these two parameters may be the improved appetite and nutritional parameters of patients who are well-dialyzed with biocompatible membranes. Further studies are needed to unravel the relationship between these two issues. ACKNOWLEDGMENT The authors acknowledge the contribution of the patientcare staff of the DCI unit at 1600 Hayes St, Nashville, TN, as well as the patients who, at times reluctantly. agreed to an increase in the dose of dialysis. The secretarial assistance of Donna Richards and Valerie McSterling is also gratefully acknowledged.
REFERENCES I. US Renal Data System: 1990 Annual Data Report. Bethesda, MD. National Institutes ofHeaIth, National Institute of Diabetes and Digestive and Kidney Diseases. 1990 2. Gotch FA. Uehlinger DE: Mortality rate in U.S. dialysis patients. Dial Transplant 205:255-257. 1991 3. Lowrie EG. Laird NM, Parker TF, Sargent JA: Effect of the hemodialysis prescription on patient morbidity. Report from the National Cooperative Dialysis StUdy. N Engl J Med 305: 1176-1181. 1981 4. Lowrie EG, Laird NM: Cooperative Dialysis StUdy. Kidney Int 23:SI-SI22. 1983 (suppl 13) 5. Gotch FA, Sargent JA: A mechanistic analysis of the national cooperative dialysis study (NCDS). Kidney Int 28: 526-534, 1985 6. Hull AR, Parker TF: Proceedings from the Morbidity, Mortality and Prescription of Dialysis Symposium, Dallas, Texas, September 15 to 17, 1989. Am J Kidney Dis 15:375383, 1990 (editorial) 7. Held PJ, Brunner F. Odaka M, Garcia JR. Port FK, Gaylin DS: Five-year survival for end stage renal disease patients in the United States, Europe and Japan, 1982 to 1987. Am J Kidney Dis 15:451-457, 1990 8. Odaka M: Mortality in chronic dialysis patients in Japan. Am J Kidney Dis 15:410-413, 1990 9. Held PJ, Blagg CR. Liska DW. Port FK. Hakim RM, Levin N: The dose of hemodialysis according to dialysis prescription in Europe and the United States. Kidney Int 42:1621.1992
10. Parker TF. Laird NM. Lowrie EG: Comparison of the study groups in the National Cooperative Dialysis Study and a description of morbidity, mortality and patient withdrawal. Kidney Int 23:S42-S49, 1983 (suppl 13) II. Hakim RM. Depner TA, Parker TF: Adequacy of hemodialysis. Am J Kidney Dis 20:107-123, 1992 12. Held PJ. Levin NW, Bovbierg RR, Pauly MV, Diamond LH: Mortality and duration of hemodialysis treatment. JAMA 265:871-875,1991 13. Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15:458-482, 1990 14. Lowrie E, Lew N. Liu Y: The effect of difference in urea reduction ratio (URR) on death risk in hemodialysis patients: A preliminary analysis. Memorandum to Medical Directors, November 1991 15. Shen F-H, Hsu K-T: Lower mortality and morbidity associated with higher KtjV in hemodialysis patients. J Am Soc Nephrol 1:377, 1990 (abstr) 16. Charra B. Calemard E, Chazot C, Ruffet M, Terrat JC, Vanel T, Laurent G: Survival as an index of adequacy of dialysis. Kidney Int 41:1286-1291, 1992 17. Ahmed S, Cole JJ: Lower morbidity associated with higher KtjV in stable hemodialysis patients. J Am Soc Nephrol 1:346, 1990 (abstr) 18. Collins AJ, Hanson G, Umen A, Kjellstrand C. Keshaviah P: Changing risk factor demographics in end-stage renal disease patients entering hemodialysis and the impact on long-term mortality. Am J Kidney Dis 15:422-432, 1990 19. Wolfe RA, Gaylin DS, Port FK, Held PJ, Wood CL: Using USRDS generated mortality tables to compare local ESRD mortality rates to national rates. Kidney Int 42:991996, 1992 20. Sargent JA: Control of dialysis by single-pool urea model: The National Cooperative Dialysis Study. Kidney Int 23:S19-S25, 1983 (suppI13) 21. Gotch FA: Kinetic modeling in hemodialysis, in Nissensson AR, Gentile DE, Fine RN (eds): Clinical Dialysis (ed 2). Norwalk, CT. Appleton and Lange, 1989, pp 118-146 22. Daugirdas JT: The post:pre dialysis plasma urea nitrogen ratio to estimate KtjV and NPCR: Mathematical modeling. Int J ArtifOrgans 12:411-419.1989 23. Goldstein MB. Jindal KK: Urea kinetic modeling. Semin Dial 1:82-85. 1988 24. Kjellstrand C, Ulan R, Cederliif 10, Ericsson F, Skroder R, Jacobson S: All derived KtjV overestimate and increasingly deviate from true KtjV as dialysis speed is increased and dialysis time shortened. J Am Soc NephroI2:332, 1991 (abstr) 25. Pedrini LA, Zereik S. Rasmy S: Causes, kinetics and clinical implications of post hemodialysis urea rebound. Kidney Int 34:817-825. 1988 26. Tsang MK. Leonard FL. Williams S: Urea dynamics during and immediately after dialysis. ASAIO Trans 8:251260, 1985 27. Degoulet p. Legrain M, Reach I, Aime F, Devries C. Rojas p. Jacobs C: Mortality risk factors in patients treated by chronic hemodialysis. Nephron 31: I 03-110. 1982 28. McClellan WM, Flanders D, Gutman RA: Variable mortality rates among dialysis treatment centers. Ann Intern Med 117:332-336. 1992
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29. Laird NM, Berkey CS. Lowrie EG: Modeling success or failure of dialysis therapy: The National Cooperative Dialysis Study. Kidney Int 23:SIOI-SI06. 1983 (suppI13) 30. Wineman RJ: Rationale of the National Cooperative Dialysis Study. Kidney Int 23:8·11 , 1983 31. Harter H: Review of significant findings from the Na· tional Cooperative Dialysis Study and recommendations. Kidney Int 23:SI07·SI12, 1983 (suppl 13) 32. Delmez J, Windus D, and the Saint Louis Nephrology Study Group: Hemodialysis prescription and deli very in a metropolitan community. Kidney Int 41 : 1023-1028. 1992 33. Windus DW, Audrain J, Vanderson R, Jendrisak MD, Picus D, Delmez JA: Optimization of high-efficiency hemodialysis by detection and correction of fistula dysfunction. Kidney lnt 38:337-341, 1990 34. Gotch FA. Yarian S. Keen M: Akinetic survey of US hemodialysis prescriptions. Am J Kidney Dis 15:511-515, 1990 35. Lindsay RM. Heidenheim AP. Spanner E, Baird J. Simpson K, Allison ME: Urea monitoring during dialysis: The wave of the future. Atale of two cities. ASAIO Trans 37: 49-53, 1991 36. LeFebvre J. Spanner E, Heidenheim A, Lindsay R: Kt/V: Patients do not get what the physician prescribes. ASAIO Trans 37:mI32-mI33, 1991 37. Sargent JA: Shortfalls in the delivery of dialysis. Am J Kidney Dis 15:500·510. 1990 38. Held PJ, Port FK. Garcia J. Gaylu DS, Levin NW. Agadoa L: Hemodialysis prescription and delivery in the US: Results from USRDS case mix. J Am Soc Nephrol 2:328. 1991 (abstr) 39. Held P, Blagg C, Liska D, Port F. Hakim R, Levin N: The dose of hemodialysis according to dialysis prescription in Europe and the United States. Kidney Int 42:sI6·s21 , 1992 (suppI38) 40. De Oreo P: Analysis of time, nutrition and Kt/V as risk factors for mortality in dialysis patients. J Am Soc Nephrol 2:321, 1991 (abstr) 41. Collins A, Keshaviah P. Ma J, Umen A: Comparison
669 of hemodialysis survival in USRDS patients vs. regional kidney disease program pts. J Am Soc Nephrol 3:359. 1992 (abstr) 42. Collins A, Liao M. Umen A, Hanson G, Kesheviah P: Diabetic hemodialysis patients treated with a high Kt/V have a lower risk of death than standard Kt/V. J Am Soc Nephrol 2:318, 1991 (abstr) 43. Schleifer CR, Snyder S, Jones K: The influence of urea kinetic modeling on gross mortality in hemodialysis. J Am Soc Nephrol 2:349, 1991 (abstr) 44. Schoenfeld PY, Henry RR. Laird NM. Roxe DM: Assessment of nutritional status of the National Cooperative Dialysis study population. Kidney lnt 23 :80-88, 1983 (suppl 13) 45. Hakim RM, Levin M: Malnutrition in hemodialysis patients. Am J Kidney Dis 21:125·137, 1993 46. Teschan PE. Ginn HE. Bourne JR. Ward JM, Hamel B, Nunally JC, Musso M, Voughn WK: Quantitative indices of clinical uremia. Kidney Int 15:676·697.1979 47. Lindsay R. Spanner E. Heidenheim p. leFebure JM. Hodsman A. Baird J. Allisson M: Which come first, Kt/V or PCR-Chicken or egg? Kidney 1m 42:S32o$37. 1992 (suppl 38) 48. Wizemann V, Kaufmann J. Kramer W: Effect of erythropoietin on ischemia tolerance in anemic hemodialysis patients with confirmed coronary artery disease. Nephron 62: 161·165.1992 49. Paganini EP, Latham D. Abdulhadi M: Practical considerations of recombinant human erythropoietin therapy. Am J Kidney Dis 14:19-25, 1989 (suppll) 50. Parfrey PS: Cardiac and cerebrovascular disease in chronic uremia. Am J Kidney Dis 21:77·80. 1993 51. Chenoweth DE, Cheung AK, Henderson LW: Anaphylatoxin formation during hemodialysis: Effect of different dialyzer membranes. Kidney Int 24:764-769, 1983 52. Gutierrez A. Alverstrand A, Wahren J, Bergstrom J: Effect of in vivo contact between blood and dialysis membranes on protein catabolism in humans. Kidney Int 38:487494, 1990 53. Hakim RM: Clinical implications of hemodialysis membrane biocompatibility. Kidney Int 44:484·494, 1993