Recombinant Human Erythropoietin Treatment May Improve Quality of Life and Cognitive Function in Chronic Hemodialysis Patients

Recombinant Human Erythropoietin Treatment May Improve Quality of Life and Cognitive Function in Chronic Hemodialysis Patients Deane L. Wolcott, MD, James T. Marsh, PhD, Asenath La Rue, PhD, Clifford Carr, EdD, and Allen R. Nissenson, MD • Medical, psychological, and social adaptation (quality of life) as well as cognitive function were studied in 15 chronic stable hemodialysis patients before the onset of treatment with recombinant human erythropoietin (rHuEPO), 1 month after stabilization of normal hematocrit levels, and 10 to 15 months after treatment onset. After rHuEPO treatment, subjects had significantly higher hematocrlts, markedly improved energy levels, and marginally improved global health. r-HuEPO treatment was also associated with progressively decreased levels of subject mood disturbance and dialysis-related stresses. Subjects had no Increased participation in paid employment and only minimally increased participation in social and leisure activities at posttreatment data points. There was no significant improvement in cognitive function after treatment. r-HuEPO treatment appears to be associated with higher energy levels, significant psychological benefits, and minimal improvements in social adaptation. The effects on cognitive function merit further study. © 1989 by the National Kidney Foundation, Inc. INDEX WORDS: Chronic dialysis; r-HuEPO; quality of life; cognitive function; psychosocial; neuropsychological function.

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HRONIC hemodialysis (CHD) incompletely reverses many of the physiological derangements of chronic uremia, including chronic anemia, which almost invariably develops as glomerular filtration rate decreases below 30 mLlmin. 1 The use of androgens and blood transfusions is problematic in many patients and rarely completely corrects the anemia. The risks associated with transfusions , includingdevelopment of cytotoxic antibodies and transmission of infection (hepatitis, human immunodeficiency virus) , are substantial. Anemia is thought to be a major contributing factor to chronic low energy levels, weakness, and fatigue induced by minimal exertion which CHD patients often experience. The multiple problems in medical, psychological, and social adaptation experienced by chronic dialysis patients have been extensively documented. 2-7 Likewise the incomplete reversal of chronic uremic encephalopathy by chronic dialysis is well known. 8- 12 The potential role of chronic anemia in poor psychological adaptation, social From the Departments of Medicine and of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, and the Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA. Supported by a grant from the Amgen Corporation. Address reprint requests to Allen R. Nissenson, MD, UCLA Medical Center, #57-143, 10833 Le Conte Ave, Los Angeles , CA 90024. © 1989 by the National Kidney Foundation , Inc. 0272-6386/89/ 1406--0006$3.00/0 478

adaptation, and impaired cognitive function has not been well studied. Recombinant human erythropoietin (r-HuEPO) has become available for clinical trials through the application of genetic engineering technology. The safety and efficacy of r-HuEPO treatment in patients with renal failure have been documented. 13 Anemic hemodialysis patients given r-HuEPO have had a rise in hematocrit as well as a dramatic improvement in subjective symptoms, enhanced exercise tolerance ,14 and improved brain function.l~ Side effects have been minimal; the most serious, hypertension and seizures, occur very infrequently. 16 We studied the effects of treatment with rHuEPO on longitudinal medical, psychological, and social adaptation (quality of life) as well as cognitive function in 15 stable chronic hemodialysis patients. METHODS

Subjects All UCLA chronic hemodialysis patients who were enrolled in the multicenter clinical trial of r-HuEPO treatment (sponsored by Amgen Inc, Thousand Oaks, CA) were potentially eligible to participate in our study of quality of life and cognitive function effects of r-HuEPO treatment. Study exclusionary criteria were active major acute psychiatric disorder, severe visual and/or hearing impairment, and lack of fluency in English . Eligible potential study subjects who gave written informed consent were enrolled and tested three limes: TO, before rHuEPO treatment initiation; TI , I month after stabilization of

American Journal of Kidney Diseases, Vol XIV, No 6 (December), 1989: pp 478-485

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EPO AND PSYCHOLOGICAL ADAPTATION IN DIALYSIS hematocrit in a normal range (3 to 4 months after TO); and T2, 10 to 15 months after TO.

Measures Study data included information from six domains: medical history and demographics, physiological and biochemical measurements, medical adaptation, psychological adaptation, social adaptation, and cognitive function. The demographic and medical history data included information about subject age, sex, ethnicity, years of education, marital status, presence and duration of diabetes, and time since dialysis onset. The physiological and biochemical measurement data included predialysis systolic and diastolic blood pressure, and hematocrit (Hct), blood urea nitrogen (BUN), creatinine Na + + ++ ' , K ,Ca ,PO., CO 2, protein, albumin, aluminum, and parathyroid hormone levels. The medical adaptation variables were all self-report variables included in the investigator-constructed "Current Health and Activities" questionnaire. This questionnaire includes single-item or multiple-item current health status variables reported for either "current" or "past month" time periods. The specific variables included global health, current activity of daily living abilities, pain, health-related activity of daily living restrictions-days past month, health-related vocational function restrictions-days past month, health-related household task restriction-days past month, and current vocational function ability. The psychological adaptation variables assessed included self-esteem, mood state, quality of life, general dialysis treatment stresses, modality-specific treatment stresses, and general illness stresses on self and others. Self-esteem was assessed using the nine-item Simmons scale scored with higher scores indicating higher self-esteem. The Simmons scale has been previously used in studies of dialysis and transplant patients.l1· 18 Mood state was assessed by the Profile of Mood States (POMS), a 65-adjective self-report checklist assessing mood in the previous 7 days. The POMS has six subscales including anxiety, depression, anger, fatigue, confusion, and (negative) vigor, with a summed total mood disturbance (TMD) score. Higher POMS scores indicate higher levels of mood disturbance. The POMS has normative population data and has been previously used in studies of mood state in chronically ill patients. 18 ,19 Quality of life was assessed by a IOO-mm visual analogue scale with written descriptor anchors previously used in studies of cancer patients and other medically ill patients. 18,2' Higher scores indicate better current quality of life. The illness/treatment stress scales included the 16-item General Dialysis Treatment Stress Scale (GDTSS), the II-item Modality-Specific Treatment Stress Scale (MSTSS), and the six-item General Illness Stress on Self and Others Scale (GISSOS). These scales have been used in previous studies of dialysis patients. 18 ,2l,22 Higher scores on each of these scales indicate higher degrees of stress in that dimension in the previous 3 months. The social adaptation variables included degree of current participation in productive (paid work, volunteer work, student, usual household) activities. The Social/Leisure Activities Index (SLAl) was used to assess past-month frequency of participation in selected active physical, sedentary, social, and com-

munity activities. The SLAI was developed by Lindsay and Burton and previously used in studies of chronic dialysis patients. 18 ,2l.22

Cognitive Function Measurement The battery of cognitive function tests was selected to measure functions that are most likely to be impaired in patients stabilized on dialysis, namely speeded perceptual-motor tasks that require flexibility of thinking, ability to shift sets, or mental manipulations, and tests of learning and memory. 8, 10 Specific measures included Number Cancellation Protocol (NCP),23 Trailmaking Test (TMT) forms A and B,24 the Controlled Oral Word Association (COWA) test," the SymbolDigit Modalities Test (SDMT),26 the Rey Auditory Verbal Learning Test (RAVLT) (six trials),27 and the arithmetic and block design subtests from the Weschler Adult Intelligence Scale (WAlS)-Revised. 28 The NCP measures cognitive accuracy and speed and is sensitive to impaired attention and concentration, visuoperceptive deficits, and slowed psychomotor speed. A larger NCP "number correct" score indicates better cognitive accuracy, and a smaller "number seconds" score indicates greater cognitive efficiency. The TMT, forms A and B, assess attention: concentration, visual scanning, psychomotor speed, and ability to sequence and efficiently shift cognitive sets (form B). A lower "number of seconds to accurate completion" score indicates better performance on trails A and B. The SDMT measures immediate visual memory, learning, eye-hand coordination, and reading-writing ability. The number of correct responses within the 90-second time limit is scored, with higher scores indicating better cognitive function. The RAVLT assesses the subject's ability to learn a list of 15 simple unrelated words over five consecutive trials, and then to recall words correctly from the first list after an intervening list of 15 different words is presented (sixth trial). This test assesses learning, immediate memory, and retrieval from longterm memory storage. Higher scores on each trial indicate better performance. The COWA test assesses verbal fluency and retrieval from semantic memory. The task is to name as many words beginning with a specific letter as possible in 1 minute. The score is the total number of words generated for three different letters adjusted for age, sex, and education. Higher COWA scores in~ dicate better verbal function. The WAIS arithmetic subtest measures selected verbal intellectual function, particularly concentration, short-term memory, and mental calculation. The block design subtest measures nonverbal intellectual function, including visuoperception, visuoconstruction, and nonverbal problem solving.

Testing and Data Analysis The subjects completed all study mesures at each of the three data points (before r-HuEPO treatment, 1 month after stable Hct normalization, and 10 to 15 months after treatment onset). I? gen~ral, they completed the self-report quality-of-life questionnaIres on their own while undergoing dialysis or at home. The biochemical and predialysis blood pressure measurements were taken at the last dialysis session before their cognitive function testing at each data point. The cognitive function testing was done about 24 hours (18 to 28 hours) after the most

480

WOLCOTT ET AL Table 1. Subject Demographic and Medical History Characteristics (n = 15) Months since dialysis onset Range 40-221 Mean 103 Years of education Range 12-18 Mean 15.7 Diabetes status Present 3 Absent 12

Sex 7 Male Female 8 Age, yr 22-66 Range 43.9 Mean Ethnicity White 11 Hispanic 2 Black Other Relationship status Married 5 Divorced 1 Single/committed relationship 2 Single/not committed relationship 7

Table 1 shows the demographic and medical history characteristics of the subject population. The subjects were predominantly white (73.3 %, 11 of 15), nondiabetic (80%, 12 of 15), and well-educated (mean years = 15.7). About half were male (46.7%, 7 of 15), half were married or in a committed relationship (46.7%,7 of 15), and the mean interval since dialysis onset was about 8.5 years. Table 2 shows the average blood pressure and biochemical data for the subjects at each data point, with the TO to T2 change scores and significance levels. The posttreatment increase in Hct levels was highly statistically significant (P < 0.0001, paired t test), with nonsignificant trends noted for changes in other biochemical and blood pressure values possibly relevant to cognitive function. Table 3 shows the changes in subject medical

recent hemodialysis, the time when cognitive function is optimal during the interdialytic interval. 10,29 Frequencies and group mean scores for each dependent variable were calculated for each data point. The study dependent variables were all continuous, and the significance of change scores between each pair of data points was tested by means of dependent t tests.

RESULTS

Fifteen subjects were eligible, and all were enrolled in the study. All subjects completed the quality-of-life measures at TO and T1, but three dropped out before T2 (one became blind, one declined, and one had other significant medical deterioration). Because of scheduling problems, only 12 subjects received their pretreatment cognitive function testing before first receiving r-HuEPO. Eleven subjects completed cognitive function testing at the later data points. Table 2. Variable

Hematocrit, % Na, mmollL K, mmollL CO 2 , mmollL BUN, mmollL (mg/dL) Creatinine, mmollL (mg/dL) Ca, mmollL (mEq/L) P04 , mmollL (mg/dL) Protein, gIL (g/dL) Aluminum, nmollL (j,tg/L) PTH, pmollL Systolic BP, mm Hg Diastolic BP, mm Hg TO, n

=

15;T2, n

=

12.

Blood Pressure and Biochemical Variable Results TO-T2

TO-T2

TO

T1

T2

Change

PValue

22.8 138.0 5.3 22.5 32 1,051 2.6 1.7 68 934 2,156 144 77

36.1 138.2 5.4 19.7 35 1,157 2.5 1.8 65 1,108 1,684 146 84

34.0 139.7 5.2 22.7 26.9 910 2.5 2.1 68 1,897 1,362 137 83

13.8 1.7 -0.1 0.3 -11.9 -1.3 -0.3 0.9 -0.1 26.0 -794 -8.3 6.5

<0.0001 >0.30 >0.30 >0.30 0.10 0.20 >0.30 0.09 >0.30 0.17 0.07 >0.30 0.11

(88.2) (11.9) (10.4) (5.1) (6.8) (25.2)

(96.5) (13.1) (10.1) (5.3) (6.5) (29.9)

(74.3) (10.3) (10.1) (6.4) (6.8) (51.2)

481

EPO AND PSYCHOLOGICAL ADAPTATION IN DIALYSIS

Table 3.

Medical Adaptation Variable Scores: Past Month

Variable Global health (1-4 excel) Current ADL ability (0-16 good) Pain (0-3 more) Health-related ' ADL restrictions Vigorous Moderate Free time Need travel assistance Indoors mostly Bed/chair mostly Vocational function restrictions' House task restrictions' Current vocational function ability (0-6) TO, n = 15; T2, n = 12. Work: full-time = 2, part-time = 1, none = 1, none = O. 'No. of days in past month (0-30).

Variable Simmons Quality of life General TX stress Modality specific stress General illness stress, self + others POMS anxiety POMS depression POMS anger POMS confusion POMS fatigue POMS negative vigor POMS-TMD TO, n

= 15; T2, n = 12.

TO-T2

PValue

2.7 12.4 1.6

0.5 0.5 0.1

0.14 >0.30 >0.30

49.9 15.4 10.9 10.1 2.8 7.2 4.6 11.2 4.9

69.0 22.5 12.3 13.1 7.1 8.5 7.9 11.8 7.9

24.5

0.19

9.3 2.2

>0.30 >0.30

3.5

3.0

-0.4

>0.30

T1

T2

2.3 11 .3 1.5

2.6 13.0 1.8

41.7 15.7 7.7 9.0 5.4 2.9 4.1 6.4 4.7 3.1

= 0; work: regular = 2, irregular = 1, none = 0; home: full-time = 2, part-time

variables showing significant improvement. Significantly improved variable scores included the GISSOS , POMS-anxiety, POMS-fatigue, and POMS-TMD scores (P < 0 .04, P < 0.01, P < 0.07 , P < 0.04, respectively, all by paired ttest). It should be noted that the subjects' TO POMS scores were not unusually high for chronically ill patients, and their POMS scores at study termination were unusually low, indicating a remarkable improvement in their mood states during the course of the study. As shown in Table 5, subjects had little change in social adaptation over the course ofthe study on the measures used. There was no change in sub-

adaptation over the study interval. After r-HuEPO treatment initiation, subjects showed no significant improvements in any of the medical adaptation variables studied. They reported an increased number of past-month days of activity restrictions from TO to T2, but these results were skewed by two subjects. The subject group did not report an increased capacity for current vocational functioning after r-HuEPO treatment. Table 4 shows the changes in psychological adaptation with r-HuEPO treatment. The subjects' group mean scores on all psychological measures indicated improved psychological adaptation from the TO to T2 data points, with scores on 4 of 12 Table 4.

TO-T2

Change

TO

Psychological Adaptation Variable Scores Change

TO-T2

TO-T2 P Value

6.1 82.5 37.8 25.3

1.1 1.0 -6.1 -1.1

0.08 >0.30 0.06 >0.30

3.1 5.7 5.6 6.7 4.4 5.0 12.4 39.8

-0.8 -5.2 -6.3 -2.7 -2.5 -7.2 -3.5 -27.3

TO

T1

T2

4.7 79.5 45.1 28.5

5.6 73.7 44.9 25.2

3.9 11 .7 13.3 9.6 6.6 11 .7 17.2 70.1

3.0 8.3 10.1 9.1 5.2 7.4 14.3 54.4

0.04 0.01 0.11 >0.30 0.07 0.007 0.15 0.04

482

WOLCOTT ET AL

Table 5.

Social Function Variables TO-T2

TO·T2

Variable

TO

Tl

T2

Change

PValue

Active physical activities Sedentary Community Social/leisure No. paid full-time work No. paid part-time work No. students No. volunteer work

3.9 8.3 4.1 4.8

4.9 8.3 4.9 5.9

4.4 8.3 4.4 6.0

0.3 -0.7 0.6 0.8

>0.30 >0.30 >0.30 >0.30

TO, n

2 1 2 2

2 1 2 2

= 15; T2, n = 12.

jects' reported participation in productive activities outside the home and no pattern of increased participation in social or leisure activities. Table 6 shows the changes over time in the cognitive function measures. There was a trend of progressive, but nonsignificant, improvement in cognitive function scores from TO to Tl to T2, which reached statistical significance only for the Symbol Digit Modalities Test results (P < 0.05 , paired t test).

creases in antihypertensive medications, many of which may worsen fatigue. Except for increased Hct values, blood chemistries changed only slightly following r-HuEPO, and these changes are unlikely to be of clinical significance. r-HuEPO treatment was associated with marked and progressive psychological benefits including improved mood state, decreased illnessand dialysis-related stresses, and a strong trend toward improved self-esteem. The magnitude of these benefits was surprising given the many physiological and psychological problems associated with end-stage renal disease (ESRD) and chronic dialysis still remaining, even after normalization of Hct. Although the placebo effect may be a partial explanation for the psychological improvements found, we believe it is not a complete explanation for the observed treatment effects. Any psychological benefits from being selected for an exciting new treatment would probably have been manifested at the initial data point. Placebo effects are

DISCUSSION

These findings indicate that treatment with rHuEPO is associated with markedly decreased levels of fatigue, with at most modest and insignificant improvement in self-assessed global health and minimal benefits related to performance of daily living activities or participation in productive/vocational activities. The energy level improvement seems particularly significant because increases in blood pressure often necessitated inTable 6.

Cognitive Function Variable Scores TO-T2

TO-T2

Variable

TO

Tl

T2

Change

PValue

COWA test SDMT TMT A, no. of seconds TMT B, no. of seconds RAVLT, 1st trial RAVLT, 2nd trial RAVLT, 3rd trial RAVLT, 4th trial RAVLT, 5th trial RAVLT, 6th trial NCP, no. correct NCp, no. of seconds WAIS-arithmetic WAIS-block design

46.1 41 .9 51.5 108.9 7.3 9.0 10.7 10.8 11.5 10.3 66.7 86.0 11 .9 30.7

50.3 46.5 31 .6 98.8 7.0 9.9 11 .6 12.6 12.8 11.8 64.6 80.8 12.1 33.9

51.6 47.8 30.3 86.5 7.5 10.0 11 .5 12.0 12.5 10.9 64.5 81.9 10.9 32.5

3.2 4.3 -21.5 -15.2 -0.4 0.5 0.4 1.0 0.7 0.4 -2.7 -1.5 -1.4 0.7

>0.30 0.05 0.08 0.08 >0.30 >0.30 >0.30 0.12 >0.30 >0.30 >0.30 >0.30 0.10 >0.30

TO, n = 12; T2, n = 11 .

EPO AND PSYCHOLOGICAL ADAPTATION IN DIALYSIS

often nonprogressive, whereas the psychological improvement seen in the study population was progressive through the 3-month and 12-month data points. Furthermore, our findings are consistent with two additional studies, one in predialysis30 and one in hemodialysis patients,31 which used double-blind, placebo-controlled protocols. Finally, significant correlations were found between improvements in objective brain function as measured by brain event-related potentials 32 and some of the quality of life and cognitive function results reported in this study. Studies using more sophisticated longitudinal designs are needed to more definitively rule out placebo effects as the explanation of improved psychological adaptation in CHD patients treated with r-HuEPO. The psychological benefits did not result from increased vocational participation because this did not occur. They potentially could have resulted from increased social and leisure activity participation, but we could not document increased participation in such activities. Better energy levels alone may have been psychologically beneficial. It is also possible that r-HuEPO treatment may have direct central nervous system (CNS) effects which result in biologically based positive mood changes. Our subjects showed no pattern of improved social adaptation during the course of r-HuEPO treatment. We do not know if this resulted from insensitivity of the instruments we used or from assessment of the "wrong" social adaptation variables or if it may truly reflect the difficulty of improving social adaptation in such chronically ill patients. The failure to demonstrate any increased participaton in paid employment or other productive activities was not surprising given the chronicity of ESRD and dialysis in these subjects and the multiple factors that adversely affect vocational function among chronic dialysis patients. More dramatic benefits for patient social adaptation and vocational function might be seen if anemia were corrected earlier in the course of chronic renal failure. Overall these findings are consistent with the hypothesis that r-HuEPO treatment, which results in normalization of hematocrit in anemic CHD patients, is associated with improvement in at least some aspects of medical and psychological adaptation. The medical adaptation benefits were lesser and the psychological adaptation benefits were greater than anticipated. The effects of r-HuEPO

483

treatment on social adaptation and vocational function remain unclear. These findings provide further support for the proposition that medical, psychological, and social dimensions of patient adaptation to chronic illness are independent and may respond in different ways and at different rates to treatment interventions designed to improve patients' quality of life. The improvements we found in cognitive function are consistent with, and reinforced by, our findings of improved CNS electrophysiological function with r-HuEPO treatment in the same population. 15 Although improvements with treatment were relatively small for most of the cognitive function variables, the direction of intra-individual change scores was quite consistent on most cognitive measures. The findings lend modest support to the hypothesis that chronic anemia contributes to uremic encephalopathy, and normalization of Hct in chronic dialysis patients is associated with improved cognitive function. Additional studies are clearly needed to further test this hypothesis and to determine the possible role of any direct r-HuEPO treatment effects (versus those mediated by normalization of Hct) on CNS and cognitive function. Most of our subjects scored within normal limits on the cognitive tests before and after r-HuEPO treatment. On the RAVLT, mean scores for each trial were all within one standard deviation of normative levels for healthy and well-educated 40- to 49-year-olds. 33 On verbal fluency (COWA), 7 of 10 subjects with complete data initially scored at or above the 60th percentile using age- and education-adjusted norms. Even on TMT form B, where performances tended to be poorer, only three subjects' scores clearly fell within the impaired range at TO (scoring at or below the 25th percentile). Such comparatively adequate cognitive performances are consistent with several prior studies of dialysis patients tested a day after hemodialySiS,8.10 in which impairments have been observed only on selected measures, most notably speeded perceptual-motor tasks that require flexibility of thinking, ability to shift sets, mental manipulation, and optimal verbal or nonverbal memory function. The present study replicated this selective pattern of deficits on complex perceptual-motor tasks (SDMT and TMT forms A and B) but did not find impaired verbal learning and recall. In future studies of the cognitive effects of chronic anemia and its treatment, it would be desirable to examine sub-

484

jects with a more representative range of educational backgrounds and to include nonverbal as well as verbal learning and memory measures. Our subjects' improved cognitive performance at later data points could have resulted from practice effects, although the long test-retest intervals could be expected to mitigate against this possibility. Biochemical changes other than higher Hct levels may also affect cognitive function of CHD subjects. 34 BUN, serum creatinine, and parathyroid hormone levels decreased nonsignificantly, while serum aluminum levels increased nonsignificantly over the course of the study. These small changes are unlikely to have significantly affected the cognitive function results. The study sample size was every small. While formal power analysis was not performed, the consistency of the trends of improved cognitive function and psychological adaptation with rHuEPO treatment suggests that even a modestly larger sample size would have resulted in a greater number of significantly improved psychological and cognitive function variable scores. We are currently studying additional subjects using the same protocol. Larger sample size would probably not have affected the results in the other adaptation dimensions studied. Given the relatively large number of TO to T2 comparisons studied, the possibility that some of the significant findings are spurious cannot be ruled out. However, given the exploratory nature of this study and the small sample size, the use of specific tests such as the Bonferroni' s correction did not seem indicated. Certainly these findings need to be confirmed in larger populations with rigorous statistical analysis. The patterns of significant or almost significant TO to T2 change scores were largely confined to the psychological adaptation and cognitive function dimensions. This patterning of results suggests that real changes were occurring in these two studied dimensions. Our study population was small and drawn from a university hospital-based outpatient dialysis unit. Additionally, our subjects were younger, better educated, and more predominantly white than the overall United States hemodialysis population. These factors may limit the generalizability of our results. Studies of EPO treatment effects on subject groups more representative of the United States hemodialysis population with respect to

WOLCOTT ET AL

educational history and cultural background are needed. Our subjects had been receiving ESRD treatment for 3 to 18+ years. They had almost certainly achieved a stable level of psychological and social adaptation, which may have been much less responsive to the effects of r-HuEPO treatment than would be the adaptation of newer CHD patients. This long dialysis treatment duration may have lessened the possibility of demonstrating quality-of-life benefits with r-HuEPO treatment. Clear medical indications for r-HuEPO treatment of chronic dialysis patients will likely emerge over the next few years, as will a clearer picture of the significance of medical side effects of treatment. If high r-HuEPO treatment cost prohibits its routine use in chronic dialysis patients, further studies will be needed to clarify the psychosocial indications for r-HuEPO treatment. Studies assessing the role of r-HuEPO treatment in favorably affecting vocational function, other aspects of quality of life, and cognitive function will certainly be needed to detennine which chronic dialysis patient groups will most benefit from this treatment breakthrough.

REFERENCES 1. Eschbach Jw, Adamson JW: Anemia of end-stage renal disease (ESRD). Kidney Int 28: 1-5, 1985 2. Evans RW, Manninen DL, Garrison LP, et al: The quality of life of patients with end-stage renal disease. N Engl J Med 312:553-559, 1985 3. Fragola JA, Grube S, Von Bloch L, et al: Multicentre study of physical activity and employment status of continuous ambulatory peritoneal dialysis (CAPD) patients in the United States. Proc Eur Dial Transplant Assoc 20:243-249, 1983 4. Gutman RA, Stead ww, Robinson RR: Physical activity and employment status of patients on maintenance dialysis. N Engl J Med 304:309-313, 1981 5. Kaplan DA: An overview of psychological problems in hemodialysis patients, in Levy NB (ed): Psychonephrology 2: Psychological Problems in Kidney Failure and Their Treatment. New York, NY, Plenum, 1983, pp 3-14 6. Maher BA, Lamping DL, Dickinson CA, et al: Psychosocial aspects of chronic hemodialysis: The national cooperative dialysis study. Kidney Int 23:S50-S57, 1983 (suppl 13) 7. Kutner NG, Brogan D, Kutner MH: End-stage renal disease treatment modality and patients' quality of life. Am J Nephrol 6:396-402, 1986 8. Southeaver GT, Ryan JJ, DeWolfe AS: Neuropsychological patterns in uremia. J Clin Psychol 38:490-496, 1982 9. Osberg nv, Meares GJ, McKee DC, et al: Intellectual functioning in renal failure and chronic dialysis. J Chronic Dis 35:445-457, 1982 10. Ratner DP, Adams KM, Levin Nw, et al: Effects of hemodialysis on the cognitive and sensory-motor functioning of

EPO AND PSYCHOLOGICAL ADAPTATION IN DIALYSIS

the adult chronic hemodialysis patient. I Behav Med 6:291311, 1983 11. Teschan PE, Ginn HE, Bourne IR, et al: Quantitative indices of clinical uremia. Kidney Int 15:676-697, 1979 12. Marsh IT, Brown WS, Wolcott D, et al: E1ectrophysiological indices of CNS function in hemodialysis and CAPD. Kidney Int 30:957-963, 1986 13. Eschbach IW, Egrie IC, Downing MR, et al: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: Results of a phase I and II clinical trial. N Engl I Med 316:73-78, 1987 14. Mayer G, Thurn I, Coda EM, et al: Working capacity is increased following recombinant human erythropoietin therapy. Kidney Int 34:525-528, 1988 15. Nissenson AR, Marsh JT, Brown WS, et al: Recombinant erythropoietin (r-EPO) improves brain function in chronic hemodialysis (CHD) patients (PTS). Am Soc NephroI20:85A, 1987 (abstr) 16. Eschbach IW, Adamson IW: Recombinant human erythropoietin: Implications for nephrology. Am I Kidney Dis 11:203-209, 1988 17. Simmons RG, LleinSD, Simmons RL: Gift of Life: The Social and Psychological Impact of Organ Transplantation. New York, NY, Wiley, 1977 18. Wolcott DL, Landsverk I, Nissenson AR: Quality of life in chronic dialysis patients: A critical comparison of continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis. Am I Kidney Dis 11:402-412, 1988 19. McNair DM, Lorr M, Droppleman LF: Manual for the Profile of Mood States. San Diego, CA, Educational and Industrial Testing Service, 1981 20. Spitzer WO, Dobson AJ, Hall I, et al: Measuring the quality of life of cancer patients. I Chronic Dis 34:585-597, 1980 21. Lindsay RM, Burton HJ, Kline SA: Quality of life and psychosocial aspects of chronic peritoneal dialysis, in Nolph KD (ed): Peritoneal Dialysis (ed 2). Boston, MA, Martinus Nijhoff, 1985, pp 667-684

485 22. Lindsay RM, Oreopoulos DG, Burton H, et al: Adaptation to home dialysis: A comparison of continuous ambulatory peritoneal dialysis and hemodialysis. Proc 1st Int Symp CAPD Amsterdam. Excerpta Medica, 1980, pp 120-230 23. Lezak MD: Neuropsychological Assessment (ed 4). New York, NY, Oxford University Press, 1983, pp 548-550 24. Reitan RM: Validity of the Trail Making Test as an indication of organic brain damage. Perceptual and Motor Skills 8:271-276, 1958 25. Benton AL, Hamsher K (eds): Multilingual Aphasia Examination. Iowa City, lA, University of Iowa, 1976 26. Smith A: Symbol Digit Modalities Test. Los Angeles, CA, Western Psychological Services, 1973 27. Rey A: L'examen clinique en psychologie. Paris, Presses Universitaires de France, 1964 28. Wechsler D: Wechsler Adult Intelligence Scale. New York, NY, Psychological Corporation, 1955 29. Lewis EG, O'Neill WM, Dustman RE, et al: Temporal effects of hemodialysis on measures of neural efficiency. Kidney Int 17:357-363, 1980 30. Kleinman KS, Schweitzer SU, Perdue SI, et al: The use of recombinant erythropoietin in the correction of anemia in pre-dialysis patients and its effects on renal function: A doubleblind, placebo-controlled trial. Kidney Int 35:229, 1989 (abstr) 31. Canadian Erythropoietin Study Group: The effect of recombinant human erythropoietin (EPO) upon quality of life (QL) and functional capacity (FC) of anemic patients on chronic hemodialysis. Kidney Int 35:915, 1989 (abstr) 32. Nissenson AR, Marsh IT, Brown WS, et al: Brain function improves in chronic hemodialysis (CHD) patients (PTS) after recombinant erythropoietin (r-EPO). Kidney Int 35:257, 1989 (abstr) 33. Wiens AN, McMinn MR, Crossen IR: Rey AuditoryVerbal Learning Test: Development of norms for healthy young adults. Clinical Neuropsychologist 2:67-87, 1988 34. Wolcott DL, Wellisch DK, Marsh IT, et al: Relationship of dialysis modality and other factors to cognitive function in chronic dialysis patients. Am I Kidney Dis 12:275-284, 1988