Artificial Organs 10(3):201-201. Raven Press, New York 0 1986 International Society for Artificial Organs

Clinical Estimates of Treatment Adequacy

Paul E. Teschan

Division of Nephrology, Vnnder-bilt University School of Medicine, Nasliville, Tennessee, U . S . A .

Abstract: Adequacy of rapid, high-efficiency therapies (RHET) in patients with end-stage renal failure involves comparisons with hemodialysis, the primary reference standard. However, the latter’s adequacy is also inse- curely rendered in descriptive, subjective terms that often embrace outcomes beyond legitimate expectations of the dialysis process. Many measurable abnormalities in renal failure contribute little to patients’ clinical illness and respond poorly to dialysis. It is therefore proposed that adequacy for all proposed clinical treatment modali- ties, including RHET, be based on objective, quantitative measures of what such treatments actually do: control

volume and dialyzable solute composition of the body fluids, and suppress the uremic illness. Recognition of the dialysis-responsive-and also disabling-uremic ill- ness as an encephalopathic, neurobehavioral (NB) dis- order logically led to objective documentation of quanti- tative N B impairments that varied inversely with the amount of hemodialysis and improved following renal transplantation. Similar objective documentations of RHET are needed. Key Words: Adequacy of dialysis therapy-Rapid high-efficiency therapies-Quantitative measures of uremia- Uremia treatment.

Rapid, high-efficiency therapies (RHET) for end- stage renal disease (ESRD) are gaining attention as the requisite technology is more widely applied. Needless to say, the “quick fix” is always attrac- tive. Authors are not slow to make comparisons with more precedented treatments in attempting to win acceptance for each new treatment as a plau- sible alternative to the “gold standard,” hemodial- ysis. Examples virtually constitute the literature on hemofiltration, diafiltration, continuous arteriove- nous hemofiltration (CAVH), intermittent perito- neal dialysis (IPD), continuous ambulatory PD, (CAPD), continuous cyclic PD (CCPD), and now RHET.

Unfortunately, the reference standard is also in- securely defined in verbal generalities. Thus, there is some consensus that adequate dialysis is that which permits the patient to be rehabilitated, to eat a reasonable diet, t o make blood, to maintain a normal blood pressure, and to prevent progressive polyneuropathy. Other authors talk about maxi- mizing patient well-being, functional and emotional

Received October 1985. Address correspondence and reprint requests to P. E. Teschan

at Division cif Nephrology, Vanderbilt University School of Med- icine, B-22 14 Medical Center North, Nashville, TN 37232. U.S.A.

This work was presented in part at the ISAO ’85, Fifth World Congress of the International Society for Artificial Organs, Oc- tober 5-8, 1985, Chicago, IL, U.S.A.

health, “not be uremic,” maintaining weight, a normal serum albumin, hematocrit over 26%, BUN and creatinine within certain limits, maintain normal volume and composition of the body fluids, and freedom from complications such as pericar- ditis, pathological bone fractures, GI bleeding, en- ervating pruritus, apathy, anasarca, and suicide (1). Recommended choices of dialysis modality and prescription are further confused by the fact that the favorable treatment outcomes usually cited to support each a re also influenced by patients’ health; genetic makeup; age; level of cooperative self-discipline with respect to diet, medicines, exer- cise, and habits of constructive self-maintenance; level of life satisfaction in current circumstances; and degree of affirmative rapport with family and wider social environments. The author proposes that such multifaceted outcomes in patients’ com- plex life-support systems and settings are not legiti- mate criteria of adequate o r effective dialysis treat- ment. Indeed, they may well exceed the real influ- ence and legitimate expectations of total medical management. Instead, the author proposes that le- gitimate criteria of adequate dialysis be limited to what dialysis actually does: It helps control the volume and composition of the body fluids, and it suppresses the “uremic illness.” Thus, a few initial dialyses a n d adequa te ma in tenance dialysis schedules thereafter suppress much of the disabling

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lassitude and easy fatigue, and virtually all of the central nervous system (CNS)-mediated cognitive and affective impairments, e.g., the disabling drow- siness, sleep disturbances, restlessness, asterixis, anorexia, nausea, and vomiting of the “uremic ill- ness.”

Therefore, if indeed the effects of dialysis are to be assessed by what dialysis affects, then it is rea- sonable to attend not only to quantitative markers of volume and solute composition and flux, but also to quantitative indices of the disabling and dialysis- responsive, CNS-mediated uremic illness. Lord Kelvin helps to sharpen these issues: as he put it, “I often say that when you can measure what you are speaking about and express it in numbers, you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meager and unsatisfactory kind” (2). Indeed, when 45 normal persons and 132 patients (azotemic, dialyzed, and transplanted) were examined, by means of psychometric and electroencephalographic (EEG) neurobehavioral probes, the measures were abnormal in renal failure and were improved by treatment (3). When maintenance dialysis time was reduced in a pro- spective study of 10 patients (4) the measures be- came abnormal, then returned to control levels when dialysis time was again lengthened. When the deviation from baseline of one index-the EEG- discriminant score- was plotted against the actual reduced levels of dialysis in each patient, the slope

was 1 in e a r and intersected ‘ ‘ z e r o - E I: Ci - a b n o r - mality” at an amount of small-molecule dialysis that requires 4.5 h (not 3 h, not 2 h) of dialysis (i.e., -3,000 ml/week/L of patient’s body water volume) thrice weekly, if the dialyzer urea clearaxe is 160 ml/min and the patient weighs 70 kg, has 42 L body water, and has no residua1 renal function In stable maintenance hemodialysis patients, EEC‘ I measures during individual dialyses using a mobile test unit revealed abnormal EEG scores in patients who de- veloped the postdialysis syndrome (the postdialysis “blahs”) but much smaller perturbations even in those patients who did not have such com- plaints (5).

What about dialysis and the other orgm systems in chronic renal failure? The author has repeatedly stated that the other organ systems rErely con- tribute to symptoms, are not much influenced by dialysis, and so are not reasonable indicators of di- alysis adequacy. Most participants in the 1974 Monterey Conference on Adequacy of Dialysis (6) did not share this view. As outlined i n Table L, major categories of independent and dependent variables were identified. Relevant me.isures for each found their way into the protocol of the Na- tional Cooperative Dialysis Study (NCDS), and the results were reported in 1983 (7). A 2 x 2 factorial design examined the effects of two levels of time- averaged blood urea nitrogen (BUN) concentra- tions [small molecule (M) clearance marker] versus two levels of treatment time [and thus two levels of

TABLE 1. Indicatot-s of adequacy of dialysis

Adequacy of dialysis NCDS Variables (Kidney International 1975) (Kidney International 1983) _ _

Independent Quantified dialysis prescrip- Urea kinetics: TAC-BUN 50, 100 mg/dl tion-small M

tion-MM Quantified dialysis prescrip- Time: t, 2.5-3.5 vs. 4.5-5 h

f BUN: AK + 1 mEq/L; ApH 0.02 to -0.03 Dependent Chemistry

Nutrition

Osteodystrophy

Hematology

DPI vs. PCR, r = +0.44, p < 0.01. n = 118 1 skin fold thickness; male subjects: 1 arm muscle circumference; no ASP

BUN: APTH +75 U/ml (C = 150-350) t BUN: APO, + 1.2 mg/dl (noACa)

t BUN: ATXF +0.3 unitsipatientimo t BUN: AHCT - 1.1%

Cardiovascular (CV) T BUN: f CV illness, hospitalization Neurological t BUN: Quantified-EEG: 21/21 normals worse

1 worse; I noA

5 f , 5.1 3/10 1 Group IV , within normal limits.

(Group IV) 517 abnormals better

CRT: noA Symptom questionnaire:

Peripheral nerve function:

BUN, blood urea nitrogen; PO,, serum inorganic phosphate; K . serum potassium concentration. See text for defirii-ion of other abbreviations.

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CLINICAL TREATMENT ADEQUACY 203

middle molecule (MM) clearance] and their pos- sible interactions. Table 1 reveals the several prob- ably trivial outcomes in potassium, pH, parathyroid hormone (PTH), and phosphate concentrations in relation to the clinical uremic illnesses, while the many other chemical measures did not vary. A loose association was found between prescribed di- etary protein intake (DPI) and measured protein catabolic rate (PCR): Fat stores indexed by skin fold thickness were diminished in all patients; men had less than normal muscle mass as measured by arm muscle circumference; serum albumin and transferrin (serum protein) levels were generally normal; and the four experimental phase treatments incited no changes. A decline in hematocrit values was doubtless blunted by increased numbers of transfusions in the high-BUN groups. The patients with high BUN also withdrew from the study more frequently for reasons of illness or hospitalization, most often related to cardiovascular events or com- plaints. Neurologically, encephalopathy was in- dexed by the quantified EEG measure (the EEG discriminant score) and by a psychometric mea- sure, the cioice reaction time (CRT). The latter showed no differing responses to the four treat- ments, in contrast to the original group data (3) but consistent with the prospective study of reduced di- alysis (4). However, if the control-phase EEG score was in the normal range, it deteriorated in 21 of 21 patients during the Group IV-high-BUN, short- time-treatment, for example. Striking inhomo- geneity in this group was also revealed by the large range of coritrol phase values ( - 2.94 to + 2.07) and by the opFosite-improving-trend in five of seven abnormal control phase scores, while an- other deteriorated and the remaining score re- mained stable for a year despite a treatment that damaged the other patients. The usually elevated last recorded values for each patient clearly demon- strated why a deteriorating EEG score was recog- nized as a predictor of exit from the study.

In Group IV patients, the symptoms question- naire gave equivocal results but revealed significant average scored abnormalities in patients’ sleep; three of 10 peripheral nerve functions displayed de- terioration lwer time, but the average values re- mained within normal ranges.

Finally, the NCDS report emphasizes the impor- tance of concurrent levels of time-averaged BUN concentration (TAC-BUN) and normalized PCR in predicting probabilities of significant illness events and hospitalization, the risk of which is enhanced by clearly shorter dialysis.

Thus, treatments imposing high BUN levels (re- duced small-molecule clearance) were associated in

the NCDS primarily in relatively prompt encepha- lopathic effects in the quantified EEG, increased transfusion requirements over time, and increased rates of significant -especially cardiovascular- illness during the year of treatment, a tiny minority of all of the systemic measurements that were con- sidered so essential as the protocol was being de- veloped. In general, it may again be concluded that underdialysis is bad for ESRD patients, especially when its consequent anorexia reduces intakes of protein and, presumably, calories. Also, the sad fact remains that there is still no rational basis for connecting solute levels with encephalopathic clin- ical illness, anemia, or the other significant clinical illnesses that often required hospitalization.

Against this background, what can be said about the adequacy of therapies other than hemodialysis? The answer appears to be “very little.”

A multicenter study conducted during the past 4 years in several dialysis units of the Dialysis Clinics, Inc. (DCI) provides some relevant data (J. VanStone and S. Singh, unpublished observations). When amounts of hemodialysis were reduced from even higher levels than the 3,000 mllweekil level already indicated, EEG discriminant scores deteri- orated in parallel to those of the present author’s earlier study (4). However, the zero intercept was even higher than the 3,000 level, suggesting that not less but more dialysis is needed to optimize uremic- illness-related abnormalities. However, when 26 patients were changed from hemodialysis to CAPD, despite the fact that their average urea clearance was cut in half, essentially no average change oc- curred in the quantified EEG, consistent with the apparent clinical stability of these CAPD patients. The implications of these findings are discordant with those of the NCDS and of our prior studies (4).

However, in the same DCI multicenter study, the relationship was also investigated between the amount of total urea clearance per week and the net appearance rate of urea nitrogen as an index of steady-state daily protein intake and thus of appe- tite/anorexia, at differing levels of hemodialysis and peritoneal dialysis. In contrast to the response of the EEG, the direct relationship between rates of urea generation and rates of urea removal appeared to hold, whether urea removal was reduced by re- ducing the amount of hemodialysis or by changing from hemodialysis to CAPD, or whether urea re- moval by IPD was increased by changing to mainte- nance hemodialysis therapy. Finally, with this in- formation, what can we say about the validity, via- bility, o r promise of RHET in the treatment of ESRD patients, per se, and as compared with other therapies? On the principle that effects of dialysis

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204 P . E. TESCHAN

should be assessed by what dialysis affects, avail- able data suggest that body fluid volume and com- position can be controlled; but in the absence of relevant studies we have no objective information whatever concerning RHET and the suppression of the uremic illness in general, or the possible induc- tion by RHET of encephalic disequilibrium during such treatment.

In conclusion, perhaps attempts to define ade- quacy of dialysis continue to be unsatisfactory be- cause the question has been asked in the wrong way, that is, by imputing to dialysis treatment influ- ences upon integrated, whole-organism lifestyle ef- fects that are perhaps only remotely related to what the dialysis-filtration process really does. Given reasonable control of the body fluid volume and composition, it is suppression of the uremic illness that is the necessary-but insufficient-condition for the desirable, more general outcomes. That

suppression of illness, as a response to 'each pro- posed therapy, can and should be studied in objec- tive terms. Sadly, the backlog of candidate ther- apies for such studies is still large and growing.

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REFERENCES Blagg CR. Adequacy of dialysis. A m J Kidney Dis l984;4:2 18-23. Buchanan WW, Smytheha HA. Can clinicians and statisti- cians be friends? [Editorial]. Am J Med 1979;66:653-4. Teschan PE, Ginn HE, Bourne J R , Ward JA', Harnel B, Nunnally JC, Muss M, Vaughn WK. Quantita,.ive indices of clinical uremia. Kidney Inr 1979;15:676-97. Teschan PE. A prospective study of reduc'zd dialysis. ASIA0 J 1983;6:108-22. Teschan PE, Arieff AI. Uremic and dialysis encephalop- athies. In: McCandless DW, ed. Cerebral rr'ergy merabo- / ism and metabolic encephaloparhy. New 'fork: Plenum Press, 1985. Gotch FA, Krueger KK, eds. Conference or1 adequacy of dialysis. Kidney In! 1975;7(suppl 2):s 1-266. Lowrie EG, Laird NM, eds. National cooper>-tive dialysis study. Kidney Inr 1983;23(suppl 13):Sl-I 12.

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