Survival of Hemodialysis Patients in the United States Is Improved With a Greater Quantity of Dialysis

Survival of Hemodialysis Patients in the United States Is Improved With a Greater Quantity of Dialysis Tom F. Parker III, MD, Leigh Husni, BS , Wei Huang, BM, MPH, Nancy Lew, SM, Edmund G. Lowrie, MD, and Dallas Nephrology Associates • The mortality rate for hemodialysis patients in the United States is higher than in other industrialized countries. Some aHribute this to insufficient quantities of prescribed and delivered dialysis. A multicenter study in Dallas dialysis centers (Dallas Nephrology Associates) was begun in 1989 to assess the impact of increasing the delivered quantity of dialysis on mortality in subsequent years. Dialysis dose was measured by urea kinetic modeling. Kt/V, reflecting the fractional volume of body water clearance of urea during a dialysis treatment, was purposefully increased from 1.18 starting in 1989 to 1.46 in 1992. Additionally, the dialysis dose measured by the urea reduction ratio, the fractional reduction of blood urea nitrogen concentration caused by a dialysis treatment, increased from 63.0% to 69.6% between 1990 and 1992. Outcome analytical methods included both crude and standardized mortality rates and mortality ratios standardized to large end-stage renal disease databases at the United States Renal Data System and at National Medical Care, Inc. Crude mortality rates at Dallas Nephrology Associates decreased from 22.5% in 1989 to 18.1% in 1992. In comparison, between 1990 and 1992 the urea reduction ration in National Medical Care facilities increased from 57.1% to 62.5%. During that time crude mortality rates decreased from 21.8% to 19.5%. Crude mortality in the United States remained essentially unchanged in the same time period. By 1992, Dallas Nephrology Associates and National Medical Care had standardized mortality ratios of 0.77 and 0.74, respectively, compared with the US dialysis population, indicating almost 30% fewer observed deaths than expected. Monitoring dialysis dose by urea kinetic modeling or urea reduction ratio are equally effective in predicting improvement in patient survival. Improved survival is possible in the US end-stage renal disease program with greater amounts of dialysis. This strategy can save an estimated 8,000 to 16,000 lives per year. © 1994 by the National Kidney Foundation, Inc. INDEX WORDS: HemodialysiS; Kt/V; adequacy; mortality; urea reduction ratio; clearance.

T

HE MORTALITY rate for patients with end-stage renal disease (ESRD) in the United States is higher than in most other industrialized nations. Crude, or "gross," mortality is above 22% per year. 1 Reasons for this cannot be explained by patient demographics or transplant acceptance rates. 2 Numerous studies and reports have suggested that a major cause of the high US mortality is underdialysis. 2. 20 Consequently, there is a compelling need to evaluate the strategies by which dialysis is prescribed and monitored. A number of studies, some reported in abstract form, have suggested that greater quantities of dialysis, or dialysis dose, improve both patient survival and morbidity.6-14 However, these were not prospective studies, they reported on very From Dallas Nephrology Associates, Dallas. TX; Section a/Nephrology, Department a/Internal AIedicine, Southwestern Medical School. Dallas, TX; and National Medical Care. Inc .. Waltham. MA. Received September 13. 1993; accepted in revised/arm December 21. 1993. Supported by Dallas Nephrology Associates. Address reprint requests to Tom F. Parker Ill. MD. Dallas Nephrology Associates, 3601 Swiss Ave, Dallas, TX 75204. © 1994 by the National Kidney Foundation, Inc. 0272-6386/94/2305-0006$3.00;0 670

small patient samples, and they did not control for variables known to also influence outcome. No study to date has shown that survival in a large hemodialysis population can be improved by increasing the delivered dialysis dose. The purpose of this study was to evaluate the effect of altering the intensity of dialysis on patient survival and to evaluate and validate monitoring techniques, urea kinetic modeling (UKM), and the urea reduction ratio (URR) as tools to influence mortality in a cluster of dialysis facilities (Dallas Nephrology Associates [DNA]) with controlled practice patterns and in a national grouping of dialysis units in which practice is not controlled (National Medical Care, Inc [NMC]). The larger NMC database was used to confirm analyses when applicable. Changes were being made simultaneously in DNA and NMC with regard to dialysis delivery using different techniques, which makes these comparisons appropriate. A secondary goal was to describe the relationship between these two measures of dialysis intensity (UKM-derived Kt/V and URR) in a clinical setting using a large cohort of patients. MATERIALS AND METHODS The DNA dialysis centers are hemodialysis facilities located in the metropolitan area of Dallas, TX. They are staffed by

American Journal of Kidney Diseases, Vol 23, No 5 (May), 1994: pp 670-680

671

QUANTITY OF HEMODIALYSIS V SURVIVAL 26 board-certified nephrologists. Facility policies, staffing ratios, procedures, and techniques are the same in all facilities. Reprocessing of dialyzers is performed using dilute « 1%)heated formaldehyde as disinfectant and dilute sodium hypochlorite as a cleaning agent. All dialyses are performed using bicarbonate-containing dialysate. Physicians and physician assistants round at least two times per week on each patient shift. The ratio of patients to physicians, dieticians, social workers, nursing personnel, or other patterns did not change during the study period. Since 1982, the prescription and monitoring of therapy uses UKM based on minor modifications of formulations developed by Gotch and colleagues. 21 -24 The equations are based on a single-pool, variable-volume pharmacokinetic model. Kt/ V is a dimensionless, exponential term that determines the predicted decrease in urea concentration during a dialysis session. K is dialyzer clearance (mL/min), t is time on dialysis (min), and V is volume of urea distribution (milliliters), which approximates total body water. KtjV has been suggested to be a useful measure of dialysis dose. 25 Prior to 1989, the target delivered KtjV at DNA was 1.0 to 1.3. Patients underwent UKM bimonthly. The time on dialysis (Td), blood flow rate, dialysate flow rate, and size of the dialyzer were adjusted to attain and maintain the desired KtjV. The range ofTd was 150 (minimum) to 240 (maximum) minutes; blood flow rate and dialysate flow rate were 300 mL/ min and 500 mL/min, respectively. Dialyzer membranes were largely cuprophane with area X urea permeability products (KoA) ranging from 381 to 498 mL/min. In addition, DNA began to monitor the URR on a monthly basis in 1990, through a service offered by NMC, obtained at different times than UKM samples. This ratio is simply the fractional decrease of blood urea nitrogen concentration caused by a dialysis treatment. 26 Dallas Nephrology Associates used UKM to determine the quantity of dialysis, protein catabolic rate, and amount of change in the dialysis prescription to attain desired goals. Urea reduction ratio was used as a quality assurance tool. In 1989, the decision was made to increase the quantity of delivered dialysis in DNA facilities. The target delivered Kt/ V for conventional dialysis was increased to a minimum of 1.3 with no maximum, and in facilities capable of high-efficiency dialysis KtjV was increased to a minimum Kt/V of 1.5 with no maximum. Practically speaking, Kt/V was limited by the constraints of the allowable Td of the facility. To facilitate the increased quantity of dialysis. the initial step was to increase the Td and blood flow rate, dialysate flow rate, and size of the dialyzer. The minimum Td was increased from 150 to 210 minutes, with the maximum remaining at 240 minutes. The blood flow rate was adjusted between 300 and 500 mL/min. The dialysate flow rate was adjusted between 500 and 800 mL/min. Dialyzers with KoAs ranging from 622 to 960 mL/min were used. The higher KoA membranes were of the high-efficiency cuprophane variety, and not the high flux, more biocompatible, synthetic membrane. The second step was to convert each of the dialysis facilities with conventional equipment to that which would be capable of highefficiency dialysis with volumetric control. This equipment has been phased into the facilities between 1989 and 1992. Some facilities had not completed the conversion by December 1992. Thus, some patients continued to receive conventional

dialysis at the conclusion of the study. No change in approach to nutrition or blood pressure was effected during this time. Demographic and UKM information for each DNA patient is maintained in the DNA Medical Information System, a computerized, privately developed database. Additional information is maintained by the NMC Patient Statistical Profile System (PSP; National Medical Care, Inc. Reservoir Place, Waltham, MA).6.12 All laboratory samples are processed through LifeChem Laboratories (Rockleigh, NJ). Data files from the years 1989 to 1992 from DNA, PSP, and LifeChem were merged by patient to construct the analytical files used in these analyses. National Medical Care is a provider of dialysis services, with 385 facilities in December 1992. These facilities provide patient clinical and demographic information to PSP. Laboratory services are provided through LifeChem. In 1990, information from NMC's PSP was provided to facilities and physicians showing the then current delivered dialysis dose using URR. Analyses were performed and distributed to medical directors at NMC facilities suggesting that low URR was associated with a high odds ratio of death and that facilities consider increasing the amount of delivered dialysis to possibly influence dialysis-related mortality. National Medical Care also maintains a library of data tapes from the Health Care Financing Administration's annual ESRD facility surveys. Those data were used to compare NMC mortality statistics to national trends. Mortality rates were estimated from Health Care Financing Administration data as the number of deaths that occurred during the year divided by the mean of the patient counts at the beginning and end of the year. Crude mortality rates estimated from PSP data were calculated as the number of deaths divided by the number of patient days of exposure divided by 365. Separate analyses have shown that there is a difference in the death rate of less than 0.1 % between the two methods of calculation. Outcome analytical methods involved calculating crude death rates; death rates standardized for age, sex, race, and diabetic condition; and standardized mortality ratios (SMRs).21.28 All prevalent patients for both DNA and NMC were included during the study interval. The SMR was adjusted to the US dialysis population using published tables and techniques. 28 To calculate the SMR, patients who had undergone prior transplantation were excluded. Patients were not categorized into type I or type II diabetes, but were assigned to diabetic or nondiabetic groups. All deaths in the NMC and DNA facilities are included, regardless of whether they underwent UKM or URR tests. or failed to receive any tests of dialysis dose. This was determined to be most representative of practice patterns and a most conservative approach to the data. For example, a death occurring within 3 weeks of admission to a facility, prior to obtaining a URR or UKM profile, would be included in the mortality calculations. Patients who died within I year of being withdrawn from dialysis were also included. Only those patients who had follow-up for I year were included in the calculation. The patients in both the NMC and DNA groups were treated as pooled samples (except that the NMC sample excluded the DNA sample). Individual facilities were not analyzed for variability in SMR.

RESULTS

Table 1 provides basic demographic information. In general, DNA patients who had UKM

672

PARKER ET AL Table 1. Demographic Characteristics of Dallas Nephrology Associates (Modeled and Non-modeled) and National Medical Care Patients: 1989 to 1992 Age (yr)

Year/patients'

N

Median

Mean

Sex(% Male)

Race (% White)

Diabetic (%)

667 260 740 20,142

57.6 58.7 57.1 59.9

55.4 56.4 55.5t 57.4t

48.3 42.8 45.3+ 50.5+

30.5 27.9 30.8+ 50.0+

37.5 35.4 38.1t 33.9t

864 296 875 24,561

56.1 60.4 56.8 60.4

54.9t 57.3t 55.6+ 57.8+

50.4t 42.9t 46.6t 50.2t

30.9 32.0 32.8:1: 49.5:1:

39.8 37.4 38.9 36.0

1,007 358 979 27,460

56.2 61.3 57.3 60.7

54.9+ 58.6+ 56.1:1: 58.2:1:

52.0+ 41.3+ 47.3 50.2

30.4 32.0 31.2:1: 49.0:1:

40.5 39.4 39.0 37.7

1,096 413 1,202 31,658

56.7 59.8 56.8 60.9

55.6t 57.5t 56.2:1: 58.5+

53.0+ 39.7+ 49.4 49.9

32.0 31.4 36.7:1: 49.8:1:

40.3 40.4 39.3 39.3

1989 DNA modeled DNA not modeled Total DNA Total NMC

1990 DNA modeled DNA not modeled Total DNA Total NMC

1991 DNA modeled DNA not modeled Total DNA Total NMC

1992 DNA modeled DNA not modeled Total DNA Total NMC

* Modeled and nonmodeled DNA patients included in the census during the year were treated by DNA for more than 90 days. Total DNA and total NMC patients were on treatment at year's end. t Modeled DNA different from non modeled DNA or total DNA different from all other NMC: P < 0.05. + Modeled DNA different from non modeled DNA or total DNA different from all other NMC: P < 0.01.

tended to be younger and were more likely to be male than those who did not. Similarly, DNA patients appeared to be younger than NMC patients. The DNA patients had greater proportions offemale and non-white patients than NMC. The prevalence of diabetes was not statistically different between the groups or between modeled

and not modeled patients. These data illustrate the necessity for adjusting mortality to case mixrelated factors, as noted below. It is unknown as to why there was a difference in those DNA patients with UKM and those without. The protocol is the same for all patients in the dialysis facilities and is not subject to interpretation by the nursing

Table 2. Descriptive Statistics on Dallas Nephrology Associates Modeled Patients: 1989 to 1992 Variable

1989

1990

1991

1992

N Body weight (kg) PCR/body weight (g/kg/d) VOlume(L) Volume/body weight (L/kg) Dialysis time (min) Clearance (mL/min) UKM-Kt/V URR(%)

809 72.16 ± 17.01 0.95 ± 0.24 38.17 ± 7.92 0.54 ± 0.09 194.7 ± 23.1 223.40 ± 36.00 1.18 ± 0.28 61.32 ± 6.98

869 71.46 ± 17.53 0.98 ± 0.28 40.16 ± 8.72 0.57 ± 0.10 200.4 ± 21.9 236.14 ± 43.57 1.21 ± 0.29 63.05 ± 7.34

884 72.50 ± 17.39 1.04 ± 0.31 39.91 ± 8.46 0.56 ± 0.10 210.9 ± 22.0 254.55 ± 49.58 1.39 ± 0.37 66.87 ± 8.08

764 73.66 ± 19.24 1.02 ± 0.26 41.50 ± 9.35 0.57 ± 0.09 220.1 ± 19.0 266.49 ± 43.01 1.46 ± 0.30 69.64 ± 7.31

NOTE: Values are given as mean ± SD.

673

QUANTITY OF HEMODIALYSIS V SURVIVAL

100 90 80

" ''""

::J

70 60 50 40 30

o

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Kt/V

Fig 1. Comparison of computer-derived UKM, Kt/V, and URR in DNA modeled patients (14,126 modeling sessions and observations).

or physician staff. The protocol attempts to model all patients. Nevertheless, case mix adjustment allows for this variance. Furthermore, the age, gender, race, and diagnosis were different from the US Renal Data System (USRDS) data sets. However, case mix adjustments again allow for these differences. Table 2 shows the effects of the change in dialysis intensity in DNA patients receiving UKM (modeled). There were no significant trends or differences in body weight, protein catabolic rate, or volume of urea distribution during the 4 years. By design, mean time on dialysis (Td), determined from the time reported by the staff during the kinetic modelling sessions, increased from 195 minutes in 1989 to 220 minutes in 1992, an increase of 13%. Kd, determined as an effective clearance from urea kinetics, increased from 222 mL/min in 1989 to 266 mL/min in 1992, an increase of 20%. Kt/V, determined by full computer-generated single pool urea kinetics, increased from 1. 18 to 1.46, an increase of 24%. The URR increased from 61 % to almost 70%, an increase of 13%. The changes in dialysis time, clearance, UKM-KtjV, and URR were statistically different from year to year. The protein catabolic rate was significantly different in 1992 compared with 1989. Body weight was not different. Figure 1 shows the relationship ofURR to Kt/ V in those patients who underwent UKM at DNA. Its curvilinear nature should be noted. For example, increasing Kt/V from 0.5 to 1.0 yielded an increase of URR from 41.5% to 58.2%, an increase of 16.7 percentage points. Further in-

creasing KtjV from 1.0 to 1.5 yielded an additional URR increase to 70.2%, an increase of 12.0 percentage points. Increasing Kt/V even more to 2.0 increased URR by only 8.7 percentage points (to 78.9%). Hence, when using URR or single pool kinetics to determine Kt/V, the maximum effect in terms of urea removal is achieved by increasing KtjV from values ofless than 1 to values over 1, and diminishing returns are evident as Kt/V is increased beyond 1.5. Figure 2 is a time trend chart showing the comparative URRs in DNA patients (modeled, nonmodeled, and all) and NMC patients as well as Kt/V for the DNA modeled patients. Some URR data are shown for 1990 through 1992 only, because data for NMC and DNA patients who were not modeled were only available for those years. There is a progressive increase in the URR and Kt/V from 1989 to 1992, except during 1990 for DNA nonmodeled patients. The URR in DNA modeled patients increased from a median value of 60.9% (first quartile = 56.2; third quartile = 65.2) during the first calendar quarter of 1989 to 70% (range, 65.5% to 75.4%) during the fourth quarter of 1992. The URR among DNA nonmodeled patients increased from 56.3% (range, 50.0% to 62.0%) during the third quarter of 1990 to 65 .3% (range, 59.1 % to 73.4%) during the fourth quarter of 1992. Thus, the URR increased progressively and substantially whether patients were modeled or not. The URR in the total DNA population increased from 62.0% (range, 56.7% to 67.1 %) during the third quarter of 1990 to 69.0% (range, 62.9% to 74.7%) during the fourth quarter of 1992. Kt/V values among DNA mod-

7S

NUC~URR

1.5

DNA TOTAL - URR

70

it

~

DNA~-UfIR

~

=~:-~

.... ..................

ONANO~~D-URR ~ .....•...*. . . DNA AVO YEARLY Kr/V

.,/

1.4

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50

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1234123412341234

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1.

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1112

YEAR - QUARTER

Fig 2. Trend analysis of delivered dialysis dose measured by KtV and URR. Data are median values or DNA and NMC for the years 1989 to 1992.

674

PARKER ET AL

26r------------------------------

24

~ 22

~

~ a:

23

~

"H'

~~

NMC DNA

1 .

•••••••••••••••••••••

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1989

1990

YEAR

1991

1992

Fig 3. Crude "gross" mortality for the US ESRD, NMC, and DNA populations using different data files for the years 1989 to 1992. •, US providers (ESRD); fJ, NMC (ESRD); D, NMC (PSP); [!!!j, DNA (PSP).

eled patients were 1.18, 1.21, 1.39, and 1.46 for the 4 years, respectively (Table 1). The URR among NMC treated patients increased from 59.6% (range, 52.4% to 66.1 %) during the second quarter of 1990 to 63.3% (range, 57.4% to 68.9%) during the fourth quarter of 1992. Figure 3 compares the crude mortality rates of the three data files. All US providers using data from the Health Care Financing Administration's ESRD facility survey are shown for each year. There has been no change in the annual mortality rate. The NMC PSP data files were validated by comparing them to the Health Care Financing Administration ESRD data files for NMC facilities only. Noteworthy is the close correlation for years 1989, 1990, and 1991. The public files for 1992 are not available. Finally, DNA data are shown. The US ESRD crude mortality rate shows only a minor or nonexistent trend of decreasing mortality over the period, but both DNA and NMC show significant improvements. In the second analysis, all DNA and NMC mortality rates were standardized to the NMC population of patients prevalent in 1989. Since death rates may vary among populations due to differences in age, sex, and the prevalence of diabetes, statistical adjustments were made for those variables. Figure 4 shows that analysis, in which statistical adjustments were made for age, sex, and diabetes. * The DNA patients experi-

* A four-factor standardization using age, sex, diabetes, and race also was done. Cell-specific rates for DNA were artificially inflated due to low patient exposure days. All three combination tests yielded results similar to those shown in Fig 4.

••••••••

..................

,~

17 .... .

.......

......

16

.......

... H.·

H •••••

;;;;;;;;;,

...... .

15~~~~~-'~~~~~-L~~~ 1992 1991 1989 1990 YEAR

Fig 4. Standardized mortality rates (%) for NMC and DNA populations for the years 1989 to 1992. The 1989 NMC population is the standard. Standard factors are age, sex, and diabetes.

enced substantially higher case mix-adjusted mortality than the NMC patients in 1989, which improved rapidly thereafter. The NMC patients also showed a progressive decrease in standardized mortality from 1989 to 1992. Comparing Fig 3 with Fig 4 suggests that the standardization process increases the estimated mortality rates for DNA patients relative to NMC patients. The DNA had more non-white and younger patients. Both of these groups have lower mortality rates than older white persons. Consequently, the statistical standardization, so that mortality rates are computed for comparable populations of patients, increases DNA mortality relative to NMC. By 1992, the adjusted rates were essentially equal.

.... ........... ............. .....

1.1

D.~~~ .

U'~'~:F.p.

P=NS

1 .. II:

:::;:

en

0.9

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•••••••••••••••~.:NS

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0.8

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~<:99.t

.

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0.7

1989

1990

1991

P <.OO1

1992

YEAR

Fig 5. Standardized mortality ratios for NMC and DNA populations. 28 The US dialysis patient population serves as the reference.

QUANTITY OF HEMODIALYSIS V SURVIVAL

Figure 5 shows the final strategy for assessing DNA and NMC mortality. Mortality is shown as a standardized ratio to the US population (SMR) as it existed in 1987 to 1989. Published tables of the USRDS were used for calculating the expected deaths.28 This technique of analysis provides a ratio of expected deaths divided by observed deaths based on a national expected death rate weighted for the noted case mix attributes. Any value less than 1.0 indicates fewer deaths than expected. The SMRs for NMC, compared with the US ESRD population for years 1989 through 1992, were 0.88, 0.84, 0.81, and 0.74, respectively. The SMRs for DNA were 1.04,0.93, 0.74, and 0.77, respectively, for the same years. Compared with a consistent and standard reference population, the mortality ratios of both DNA and NMC have improved at the same time as the amount of dialysis has increased. DISCUSSION

The quantity of dialysis was progressively increased in the patients in 11 dialysis facilities in Dallas, TX, from 1989 to 1992, under protocols developed by DNA. In an un associated simultaneous effort, NMC began increasing the delivered dialysis "dose" implemented by an information-sharing program for its medical directors. This study of those events supports the conclusion that increasing the amount of delivered dialysis is associated with improved patient survival. This is the first such observation in a study with over 1,000 patients and a separate population with in excess of 25,000 study patients. Measuring dialysis intensity, whether by formal kinetics or the less stilted URR, seems to be equally effective in encouraging improved dialysis dose. The comparison of the US population, NMC, and DNA, using the SMRs, shows that DNA and NMC mortality rates are less than those in the US population. Mortality rates among both populations have declined as dialysis dose increased. While this is not a controlled trial and one cannot prove a cause and effect, such a relationship can reasonably be inferred from the data. Figure 1 shows the strong relationship between computer-generated Kt/V and measured URR. This suggests that either measurement is appropriate for controlling and monitoring dialysis dose.

675

While DNA physicians agreed to a general policy of performing kinetic modeling on all patients, in general, modeled patients tended to be younger and were more likely to be male than patients for whom UKM was not performed. In addition, URR tends to be lower in patients not receiving UKM. That was particularly true during 1990, when the monitoring of treatment dose by URR had just started for non modeled patients at DNA. The URR increased rapidly in persons not receiving UKM during 1991 and 1992. Therefore, even the quality assurance component ofURR caused a significant increase in quantity of dialysis, although these patients did not undergo formal UKM. This latter observation shows the positive effect of monitoring dialysis intensity on a routine basis using objective measurement. It is notable that the relationship between Kt/ V and URR is not linear. Although this fact has been mentioned by others, it is not generally appreciated. Large increases in Kt/V are associated with relatively small improvements in URR when Kt/V and URR are high. Hence, there comes a point at which increasing Kt/V, at least using the technique in this study, yields disproportionately diminishing returns with respect to solute removal. The relationship ofURR to mortality suggests that there is greater improvement in mortality by improving from values less than 60% (Kt/V ~ 1.0) to measures exceeding that value than there is from improving beyond that threshold. This has previously been pointed out by Lowrie and Lew. 12 In other words, mortality is improved much more by going from a URR of 58% or 59% to 65% than it is from increasing it from 68% or 69% to 75 %. In terms of Kt/V, improvement from 0.9 to 1.4 yields more improvement than increasing from 1.5 to 2.0. One might infer further support for that concept from Figs 2 and 4. The URR for all DNA patients improved from the range of 62% in 1990 to 65% in 1991 to nearly 70% in 1992. The adjusted death rate improved during 1990 and 1991, but did not improve during 1992. The URR at NMC facilities improved slowly but progressively from 1990 through 1992, with final values in the range of 63%. Adjusted death rate improved progressively over that period so that the rates at DNA and NMC were equal during 1992. There was then no appreciable difference

676

between standardized mortality rates at DNA and NMC during 1992 even though there was a 6 percentage point difference in URR. Patients in the United States with ESRD undergoing hemodialysis are said to have the highest mortality of any of the major industrialized nations. 2,29-33 Suggested reasons have been patient demographics, the Medicare reimbursement schedule, patient preference, and inadequate quantity of dialysis. This latter reason, inadequate dialysis, is now hypothesized to be the dominant factor. Insufficient dialysis has been said to result from lack of objective measures for assessing adequacy, misinterpretation of the National Cooperative Dialysis Study (NCDS),34 lack of emphasis in the care of the dialysis patient in nephrology training programs,35 modern technology that allows rapid dialysis, cost containment,36 and patient preferences. If anyone event had to be declared responsible for quantifying the dialysis component of therapy during the past decade it would be the NCDS. The results, attributes, and shortcomings of the NCDS, completed in 1982, have been well reviewed elsewhere. 2,11,34,37-39 The NCDS established a useful, reproducible, and valid technique for the quantification of prescribed and delivered dialysis. However, patients with diabetes and other significant comorbid conditions were excluded. Diabetic patients constitute 32% of the US ESRD population today.40 The average age was almost 8 years younger than the current US ESRD population. Only 26% of patients in the DNA ESRD population for 1990 would fit NCDS inclusion criteria. Results of the NCDS showed that the quantity of dialysis delivered and adequate protein intake were both significant predictors of success in treatment. In the analysis by Gotch and Sargent, using KtjV as the marker for the delivered dialysis, there was a 13% failure rate in the NCDS study population if the KtjV was higher than 0.9. 25 The failure rate was significantly higher if the KtjV was lower than 0.8. Following this publication KtjV became the most widely accepted estimate of "adequate" dialysis, with an approximate target of 1.0. Depner has reviewed this concept of KtjV extensively.41 In 1988, it is estimated that fewer than 25% of dialysis facilities used UKM or any other direct quantification. This percentage has probably now

PARKER ET AL

increased due to the forces of quality oversight by various agencies. In the mid to late 1980s, increasing pressures to shorten dialysis became evident. In this situation, using urea as a surrogate molecule may be a problem, Within the past 4 years concern began to be expressed that the US ESRD population was, by and large, receiving insufficient dialysis. 1-JO, 13,15-20,42,43 A hallmark meeting in Dallas in 1989 awakened the nephrology community to the problem. 1 Initially, the focus was on the length of the dialysis session rather than on the quantity of dialysis. Two large epidemiologic studies show that patients receiving less time on dialysis have a significantly higher mortality risk. 12,20 However, insufficient quantity of dialysis, rather than insufficient length of a dialysis session, has been suggested to be the most probable reason for the high mortality, Held et al (USRDS), reviewing a random national sample, noted that 53% of patients had prescriptions of 0.99 or less; 24% had prescriptions of 0.8 or lessY,44 In a separate cohort, Held et al showed differences in the amount being prescribed and the amount being delivered. Using formulas derived from the URR, delivered KtjV could be calculated in 313 of the patients, and was 0.72 using one formula and 0.90 using another. Moreover, Held et al recently compared the dose of dialysis prescription and the effect on mortality in Europe (European Dialysis and Transplant Association) and the United States. 15 These investigators concluded that US hemodialysis patients receive less dialysis than European Dialysis and Transplant Association patients, at least during the study period of 1986 to 1987. In a different study, Held et al noted that in every age group of patients on renal replacement therapy, except the pediatric population, Europe has better survival. 29 In a survey of 75% of the dialysis population of a large metropolitan area, Delmez et al noted that due to a prescription of insufficient dialyzer clearance and dialysis time, nearly half of the patients had a KtjV of less than 1.0. and 20% of the patients had a KtjV ofless than 0.8. 18 Moreover, in 45% of patients the quantity of dialysis delivered was less than 80% of that predicted or prescribed. Gotch noted that nearly half of the patients visiting one facility were receiving dialysis that was inadequate by NCDS standards, 19

QUANTITY OF HEMODIALYSIS V SURVIVAL

leFebvre et al45 and Sargent 16 have shown similar shortfalls in delivered dialysis. The most fundamental and important test of any quantification of a dialysis program in 1993 is the impact on patient morbidity and survival. Ahmad and Cole, comparing hospitalization rates with KtjV, concluded that a KtjV of 1.0 may be inappropriately low. 10 In patients with an average KtjV of approximately 1.67, Charra et al noted 87% patient survival at 5 years and 43% survival at 20 years.9 These investigators concluded that blood pressure control, through optimum volume removal with longer dialysis, was the principle reason for the high survival. Shen and Hsu, in a study of an Asian population, found that patients with KtjV of 1.8 had improved morbidity and mortality over patients with KtjV of 1.5. 8 Schleifer et al stated that mortality improved as KtjV increased from 1.0 to 1.3. 7 In addition, Lowrie et al have shown that the relative risk of mortality continued to improve with URRs to 65% to 70%, equating to KtjV values of 1.3 to 1.6.6 Hull, reporting on data from Held and the USRDS, stated that patients with short dialysis (compared with those with long dialysis) have a relative risk of death of 1.17 to 2.18. 36 A very bothersome feature of the Held analysis is that the risk of death in the short dialysis group, using Cox analysis, continues to increase as the number of years on dialysis increases, whereas it does not in the long dialysis group. This suggests that exposure to "underdialysis" may not manifest as morbidity and mortality for several years. In separate studies, Keshiviah and colleagues,'4.37 Cheigh et aV Fernandez et aV and Hakim et al 3 noted enhanced survival with Ktj V beyond that currently being received by most patients in the United States. The USRDS data in the 1993 report show a slightly improving mortality in years, beginning in 1989 and continuing in 1990. 46 This is different from other reports, probably due to this being incident-based data Kaplan-Meier survival curves. This report and most of the others noted above use prevalent-based data survival data. Held et al concluded that the higher mortality in the United States is due to less dialysis. 15 It appeared that the average patient in the United States "is prescribed a substantially shorter total treatment time per week with a smaller dialyzer." Their final conclusion was that this " ... observa-

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tion may in part explain the higher mortality of hemodialysis patients in the U.S." In another analysis of NMC data, Owen et al recently have shown the effect of higher dialysis dose and albumin on mortality. Mortality improved with a higher URR and with higher albumin. There did not appear to be an improvement in mortality beyond a URR of70%.47 These investigators analyzed the adjusted risk of death and expressed it as an odds ratio. The reference group was a URR of 65% to 69% (odds ratio = 1.00). Improvement in mortality began to lessen at a URR of 65% to 69% and there was no improvement beyond 70%. This was not a longitudinal study and only the patients who were receiving dialysis in October 1990 were included. If all these studies are representative and reviewed collectively, they show that the United States, on average, is providing less dialysis than the 15-year-old NCDS and significantly less than the European Dialysis and Transplant Association. They even imply that results from NCDS data may suggest a safe KtjV that is too low. This is a critical issue. The NCDS did not study a population that is undergoing dialysis in the 1990s; the patient population studied was younger, compliant with care, nondiabetic, and had few comorbid conditions. Moreover, the studies suggest that as KtjV increases, even beyond the 1.4 range, morbidity and mortality may continue to improve. As such, KtjV does predict outcome, but good outcome is based on much higher values of KtjV than originally predicted. This report confirms that mortality improves as measured dialysis is increased beyond that noted in the NCDS and, more importantly, beyond that usually provided in the United States. The survival rates reach those of other industrialized nations. Notably, in the current analysis from DNA and NMC comparing crude mortality rates and adjusted mortality rates, there were differences. Each of NMC's adjusted rates is lower than the crude rate for the same year. This is due to the fact that in each year the pool of NMC patients was older and had proportionately more diabetic patients than the NMC population in 1989. The DNA standardized rates are higher than the DNA crude rates. This is because DNA patients were generally younger and there were more nonwhites, both groups that have lower mortality;

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therefore, the standardized rate is higher. For both NMC and DNA, the SMR display a downward trend as dialysis dose increased. These differences show the importance of standardizing the reporting of mortality, especially in the ESRD population. The data suggest that an increase in delivered dialysis beyond a Kt/V of 1.5 or a respective URR may not be associated with further large improvement in mortality. However, as pointed out above, patients who have been systematically underdialyzed may not have a significantly changed mortality risk even when optimal dialysis is delivered. Further analysis of those patients who have only received higher URR or Kt/V during their entire course of renal replacement therapy will be required to answer this question. The recent report from Owen et al confirms that when using URR or single-pool kinetics, there is a level of delivered dialysis beyond which further improvement in survival may not be noted. 47 It is unclear whether the improvement in delivered dialysis dose resulted from improved nutrition, as has been suggested by Lindsay and Spanner. 48 This present study was not designed to answer the question of whether improvement in dialysis dose was due to better nutrition, improved somatic or visceral protein indicators, lipid status, acid base balance, or other comorbid conditions known to influence dialysis outcome. Indeed, these may have improved and could possibly have been associated with the better outcome. These variables were simply not measured. In addition, it is unclear if the increase in time on dialysis or the increase in clearance caused the improved mortality. Technically, it is difficult to achieve a delivered Kt/V in the ranges noted without increasing both. This is especially true when considering the compartmentalization of potential uremic toxins. Short, very high-efficiency dialysis may give a falsely high Kt/V.41 This study used single-pool kinetics for the calculation of Kt/V and URR, which would give a higher Kt/V than double-pool models. However, since the technique for calculation remained the same throughout the study, the conclusions remain appropriate. Additionally, the study confirms the curvilinear relationship of Kt/V and URR. These are simple techniques and indeed are widely applicable until other models (total

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urea removal, double pool kinetics, determination of mass transfer coefficients, etc) are shown to further enhance survival. The effect of blood pressure control was not analyzed. Charra et al have suggested that a higher quantity of dialysis is associated with better blood pressure control and that it is the latter which improves survival. 9 In 1989, erythropoietin became available and has since been widely used. However, there have been no published data to suggest a correlation of erythropoietin usage and improved survival. The USRDS, as reported by Held, shows a tendency to improvement in survival by 8% for each increase in Kt/V of 0.1 (presented at the 1991 meeting of the American Society of Nephrology). The DNA data confirm this for each incremental increase in Kt/V of 0.1, up to 1.4. In the same report, the USRDS showed that the average delivered Kt/V is 0.78 to 0.92, depending on the formula used for estimating Kt/V from URR. Is it plausible to suggest that, given a US dialysis population of 150,000 (estimated) and an increase of delivered Kt/V to 1.4 as the US average, there may be 8,000 to 16,000 fewer annual deaths in the US dialysis population in a given year? If this is true, there needs to be a change in the minimal acceptable quantity of dialysis. Trials and pilot studies are now in the developmental stage. These are to investigate methods whereby dialysis-related morbidity and mortality may be decreased. Until those trials are complete, this study indicates that a minimum dialysis dose of 1.4 (Kt/V) or an equivalent URR be provided to patients with renal failure. ACKNOWLEDGMENT Dallas Nephrology Associates comprises Alan Hull, MD, Ronald Prati, MD. Dewey Long, MD, Steven Rinner, MD, Martin White, MD. Michael Stephens, MD. Michael Emmett, MD. Pedro Vergne, MD, Russell Silverstein, MD, Mark Lerman, MD, David Nesser, MD, Ruben Velez, MD, Karl Brinker, MD, Andrew Fenves, MD, Bruce Wall, MD, Thomas Gonwa, MD. Judson Hunt, MD, George Rojas, DO. Martin Mai, MD, Larry Melton, MD, Robert Kunau, MD, Robert Hootkins, MD, Lauren McDonald, MD. and John Schwartz, MD. The authors gratefully acknowledge and sincerely appreciate Jill Marshall and Laura Sturdivant for secretarial support, the staff of all of the DNA facilities, and especially the patients.

REFERENCES 1. Hull AR. Parker TF: Proceedings from the Morbidity, Mortality and Prescription of Dialysis Symposium: Dallas,

QUANTITY OF HEMODIALYSIS V SURVIVAL TX. September 15-17, 1989. Am J Kidney Dis 15:375-383, 1990 (editorial) 2. Hakim RM. Depner T A, Parker TF: Adequacy of hemodialysis. Am J Kidney Dis 20: 107 -123. 1992 3. Hakim RM. Lawrence P, Schulman G. Breyer 1: Increasing dose of dialysis improves mortality and nutritional parameters in hemodialysis patients. J Am Soc Nephrol 3: 367, 1992 (abstr) 4. Fernandez JM, Carbonell ME, Mazzuchi N, Petruccelle D: Simultaneous analysis of morbidity and mortality factors in chronic hemodialysis patients. Kidney Int 41: 1029-1034. 1992 5. Cheigh J, Raghavan V . Sullivan J, Tapia L. Rubin A, Stenzel HK: Is insufficient dialysis a cause for high morbidity in diabetic patients? J Am Soc Nephrol 2:317. 1991 (abstr) 6. Lowrie EG, Lew NL, 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 5, 1991 7. Schleifer CR, Snyder S. Jones K: The influence of urea kinetic modeling (UKM) on gross mortality in hemodialysis. J Am Soc NephroI2:349, 1992 (abstr) 8. Shen F, Hsu K: Lower mortality and morbidity associated with higher Kt/V in hemodialysis patients. 1 Am Soc Nephrol 1:377. 1990 (abstr) 9. Charra B. Calemard E. Ruffet M. Chazot C, Terrat lC, Variel T, Laurent G: Survival as an index of adequacy of dialysis. Kidney Int 41 : 1286-1291. 1992 10. Ahmad S, Cole Jl: Lower morbidity associated with higher KtjV in stable hemodialysis patients. J Am Soc Nephrol 1:346, 1990 (abstr) 11. Deoreo PB: Analysis of time, nutrition, and Kt/V as risk factors for mortality in dialysis patients. 1 Am Soc Nephrol 2:321, 1991 (abstr) 12. 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 13. Berger EE, Lowrie EG: Mortality and the length of dialysis. JAMA 265:909-910. 1991 14. Collins A. Liao M, Umen A. Hanson G. Keshaviah P: Diabetic patients treated with a high Kt/V have a lower risk of death than standard KtjV. J Am Soc NephroI2:318, 1991 (abstr) 15. Held PJ, Blagg CR, Liska DW. Port FK. Hakim R. Levin N: The dose of hemodialysis according to dialysis prescription in Europe and the United States. Kidney Int42:SI6S21. 1992 (suppl 38) 16. Sargent J: Shortfalls in the delivery of dialysis. Am J Kidney Dis 15:500-510. 1990 17. Held PJ. Port FK, Garcia J, Gaylin DS. Levin NW. Agodoa L: USRDS: Hemodialysis prescription and delivery in the U .S.: Results from USRDS case mix study. J Am Soc Nephrol 2: 328, 1991 (abstr) 18. Delmez JA, Windus DW: Hemodialysis prescription and delivery in a metropolitan community. Kidney lnt 41 : 1023-1028, 1992 19. Gotch FA, Varian S. Keen M: A kinetic survey of US hemodialysis prescriptions. Am J Kidney Dis 15:511-515, 1990

679 20. Held PJ. Levin NW, Bovbjerg RR, Pauly MV, Diamond LH: Mortality and duration of hemodialysis treatment. JAMA 265:871-875,1991 21. Gotch FA, Sargent JA , Keen ML, Lam M, Prowitt M, Grady M: The solute kinetics of intermittent dialysis therapy. Annual report to the Artificial Kidney-Chronic Uremia Program ofNIAMDD covering work June 30, 1974, to December 31. 1975, on contract no. NO I-AM-4-2202 (AK-2-2202). January 19, 1976, P 41 22. Gotch FA: Hemodialysis: Technique and kinetic considerations. Brenner BM. Rector FC (eds): The Kidney. Philadelphia, PA, Saunders, 1976, pp 1672-1704 23. Sargent JA, Gotch FA: Mathematical modeling of dialysis therapy. Kidney Int 18:S2-10. 1980 (suppl 10) 24. Sargent JA: Control of dialysis by a single-pool model: The National Cooperative Dialysis Study. Kidney lnt 23:S 1925. 1983 (suppl 13) 25 . Gotch F, Sargent J: A mechanistic analysis of the National Dialysis Study. Kidney lnt 28:526-537. 1985 26. Lowrie EG. Lew NL: The urea reduction ratio (URR). A simple method for evaluating hemodialysis treatment. Contemp Dial Nephrol 11-20, 1991 27. Breslow NE. Day NE: Statistical Methods in Cancer Research, vol II. The Design and Analysis of Cohort Studies. New York. NY. Oxford University Press, NY. 1987 28. Wolfe RA, Gaylin S, Port FK, Held PJ, Wood CL: Using USRDS generated mortality tables to compare local ESRD mortality rates to national rates. Kidney lnt. 42:991996, 1992 29. Held PJ, Brunner F. Odaka M, Garcia lR. 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 30. Odaka M: Mortality in chronic dialysis patients in Japan. Am J Kidney Dis 15:410-413, 1990 31 . Disney APS: Dialysis treatment in Australia, 19821988. Am J Kidney Dis 15:402-409, 1990 32. Posen GA. Jeffery lR, Fenton SSA, Arbus GS: Results from the Canadian Renal Failure Registry. Am 1 Kidney Dis 15:397-401. 1990 33. Brunner FP. Selwood NH: Results of renal replacement therapy in Europe. 1980 to 1987. Am J Kidney Dis 15:384896, 1990 34. The National Cooperative Dialysis StUdy. Kidney lnt 23:SI-SI23, 1983 (suppI13) 35. Nissenson AR: Morbidity and mortality of United States dialysis patients-The legacy of inadequate nephrologist training? Semin Dial 5:277-278, 1992 36. Hull AR: Impact of reimbursement regulations on patient management. Am J Kidney Dis 20:8-11 , 1992 (suppllJ 37. Keshaviah P, Collins A: Are-appraisal of the National Cooperative Dialysis Study. Kidney lnt 33:227 A, 1988 (abstr) 38. Hakim RM: Assessing the adequacy of dialysis. Kidney lnt 37:822-833. 1990 39. Van holder RC, Ringoir SM: Adequacy of dialysis: A critical analysis. Kidney lnt 42:540-558, 1992 40. United States Renal Data System: 1990 Annual Data Report. US Department of Health and Human Services, 1990 41. Depner T A: Prescribing Hemodialysis: AGuide to Urea Modeling. Boston, MA , Kluwer Academic, 1990

680 42. Parker TF: Optimizing survival in hemodialysis patients, in Nissenson AR, Fine RN (eds): Dialysis Therapy. Philadelphia, PA, Hanley and Belfus, 1992, pp 87-90 43. Levine J, Bernard DB: The role of urea kinetic modeling, TAC u, .., and KtjV in achieving optimal dialysis: A critical reappraisal. Am J Kidney Dis 15:285-30 I, 1990 44. United States Renal Data System: 1992 Annual Data Report. US Department of Health and Human Services, 1992 45. LeFebvre JMJ, Spanner E. Heidenheim AP, Lindsay R: KtjV: Patients do not get what the physician prescribes. ASAIO Trans 37:mI32-mI33, 1991

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46. United State Renal Data System: 1993 Annual Data Report. US Department of Health and Human Services, 1993 47. Owen WF, Lew NL, Liu Y, Lowrie EG, Lazarus JM: The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Eng! J Med 329:1001-1006, 1993 48. Lindsay RM, Spanner E: A hypothesis: The protein catabolic rate is dependent upon the type and amount of treatment in dialyzed uremic patients. Am J Kidney Dis 13: 382-389, 1989