NEFROLOGIA. Vol. XIV. Suplemento 2, 1994 The influence of dialysis prescription and nutritional status on outcome of dialysis patients R. M. Lindsay Artificial Kidney Research Centre and O n t a r i o , Canada. Medicine,Victoria Hospital, and The University of Western Ontario Adequacy of dialysis: Kt/ V (urea) and outcome The determination of the adequacy of dialysis is difficult and definitions are in constant change. In the 1960's and early 1970's, the clinical acumen of the nephrologist plus review of routine biochemical and haematological parameters, were all that was availab l e . The National Cooperative Dialysis Study (NCDS) 1 was the first attempt at providing parameters of adequacy and to this day, provides the most solid information available. The NCDS results show that the protein catabolic rate (PCR; g/kg/day) and b l o o d urea nitrogen (BUN) are important determinants of morbidity in patients undergoing haemodialysis. A PCR > 1g/kg/day and a time average conc e n t r a t i o n (TAC) of BUN of approximately 50 mg/dL w e r e shown to be determinants of low morbidity. Gotch and Sargent 2 in their mechanistic analysis of the NCDS indicate that the dose of small molecular weight toxin removal could be defined by the dimensionless parameter Kt/V (urea) where K is the dialyzer urea clearance (ml/min), t is the treatment time (min), V is the body urea distribution volume (ml) and Kt/V is the exponent determining the decrease of BUN during each dialysis treatment. Their analysis of the NCDS shows that the probability of uraemic manifestations developing was high, 57 %, and constant over the treatment range 0.4 < Kt/V < 0.8 and that over the treatment range 0.9 C. Kt/V < 1.5 there was a sharp decrease in morbidity to a constant 13 % 2. The midweek pre-dialysis BUN, PCR and Kt/V (urea) are mathematically interrelated and BUN alone provides no indication of the level of treatment or probability of u r a e m i c manifestations; all three parameters BUN, PCR, and Kt/V (urea) are required to describe the domain of adequate dialysis 2. The NCDS results suggest that removal of small molecules such as urea (BUN) controls the adequacy of the dialysis prescription1, 2. Thus, many dialysis units monitor their patients' BUN levels after prescribing a dialysis schedule that they believe delivers a Kt/V (urea) of approximately 1 and they assume that they are providing good therapy. The Kt/V (urea) can be fairly accurately approximated by examining the urea reduction rate (URR %). J i n d a l and co-workers 3 gave data that showed that the URR closely reflected the Kt/V (urea) value when the later was calculated by total dialysate collection. T h e i r data indicated that a URR of approximately 5 5 % was necessary to obtain a Kt/V (urea) = 1. D a u g i r d a s 4 argued that this URR may result in Kt/V (urea) values substantially above or below target Kt/V (urea); the main causes of error were unusual volume to weight ratios or K/Qb (blood flow, ml/min) ratios. He suggested a formula that modified the URR by factors involving the amount of ultrafiltration and the patient's weight. This formula has also showed an excellent correlation with formal urea kinetic modelling but suggests that the 55 % URR (as per Jindal et al 3) is an underestimate and that the URR should be approximately 60 % to safely achieve a Kt/V (urea) of 1. L o w r i e et al 5 had examined a large number (> 2 0 , 0 0 0 ) of patients who received regular haemodialysis therapy in the United States of America and have examined the relative risk of death against the URR. Taking a referente URR between 65-70 %, they show that URR values between 60 and 65 % and'those over 70 % do not increase or decrease the relative risk of death but values below 60 % are clearly associated with increased death risk. Indeed, patients with a URR below 45 % have a relative risk of death of over 4.0 supporting the thesis generated from the NCDS. Correspondencia: Dr. Robert M. Lindsay. V i c t o r i a Hospital. 375 South Street. London, Ontario, Canada. Malnutrition and outcome Protein and energy malnutrition is frequently present in patients undergoing haemodialysis (HD) the25 R.M. LINDSAY rapy 6-13. Evidente for this includes reduced subcutaneous fat stores and muscle mass as assessed by anthropometric methods; low total body nitrogen; low concentrations of albumin, transferrin and other visceral proteins; abnormal plasma amino acids and intracellular amino acid profiles. S e v e r a l recent studies suggest that malnutrition is an important risk factor for morbidity and mortality in HD patients. Observations, again by Lowrie 14,15. on his large population of HD patients indicate that patients with a low plasma blood urea nitrogen (BUN) and albumin levels have a higher probability of mortality and morbidity than «standard» HD patients. One easily obtainable parameter of nutrition is the protein catabolic rate (PCR; g/kg/day) obtainable by urea kinetic studies and gives an excellent approximation to dietary protein intake. The National Cooperative Dialysis Study (NCDS) 1 demonstrated that a PCR < 0.8 was associated with treatment failure. Among 120 HD patients, Acchiardo et al 16 found that a subgroup with a mean PCR of 0.63 had a mortality rate of 14 % per year while groups with higher PCRs had lessened mortality rates and the group with a PCR of 1.29 had a 0 % mortality rate. The number of hospitalizations per year was also much higher in the group of patients having the lowest intake of protein who also had higher frequencies of heart disease, pericarditis, infections and gastrointestinal manifestations than the other patient groups. The authors concluded that protein malnutrition was the main factor governing morbidity and mortality of HD patients. gether with the observation that decreasing the Kt/V (urea) was associated with decrease in appetite, indicates dependence of PCR upon the Kt/V (urea). The data otherwise might be interpreted as a reflection of the increased dose of dialysis Kt/V (urea) necessary to control the urea of patients ingesting larger quantities of protein. This observation is not entirely new. Lowrie et al in their early studies on adequacy of dialysis noted that patients spontaneously modulated their protein intake when the amount of small molecule clearance was reduced 18. Furthermore, the study of Acchiardo et al 16 also noted that in their group of patients who maintained a PCR < 0.8 they were unable to improve the nutritional status «in spit e of repeated counselling by the dietician». However, they felt that this was because those patients were black with a low socio-economic status and had eating habits that were difficult to change. We 17 felt that the direct dependence of the PCR upon the Kt/V (urea) had not been appreciated and may be of fundamental importance in any consideration of the adequacy of dialysis. Thus, we proposed that prospective studies involving the manipulation of Kt/V (urea) by different dialysis techniques and following the PCR (and other nutritional parameters), were indicated to confirm or refute this hypothesis. We subsequently carried out such a study, the results of w h i c h have recently been published 19. This was a randomized prospective study and gives clear cut evidente that the PCR is dependent upon the Kt/V (urea) in haemodialysis patients. Interrelationship of Kt/V (urea) and PCR We hypothesized that the PCR was dependent upon the Kt/V (urea): Figure 1 shows the plots of PCR VS. Kt/V (urea) for the original 322 observations we made on 55 haemodialysis patients. A significant linear relationship is demonstrated (r = 0.73; 2a < 0.001). The Kt/V (urea) values show wide range from 0.4 to 1.8 17. In 20 of these 55 patients, a deliberate change in the dialysis prescription was made involving a Kt/V (urea) change >0.2 in either a positive or negative direction. This change was followed, in 1 to 2 months, by a similar positive or negative change in the PCR. It was also observed that patients with low PCRs (and low dietary protein intakes as assessed by a dietician) who w e r e receiving inadequate dialysis by NCDS standards Kt/V (urea) < 0.8 would not increase their protein intake, in spite of extensive dietary counselling and the provision of oral protein supplements, until an adequate dose of dialysis was prescribed. This, to26 Influence of dialysis membrane upon the Kt/V; PCR relationship There does seem to be some influente of the type of dialysis membrane used upon the Kt/V, PCR relationship. The plots of PCR versus Kt/V (urea) shown in Figure 1 can be separated into those from patients dialyzed by devices containing cellulose acetate membranes and those containing the synthetic AN69S membrane (HOSPAL, Basel, Switzerland). In both cases, a significant (2a < 0.001) linear correlation between Kt/V (urea) and PCR exists. However, the slope of the line for the dialyzers containing ceI l u l o s e acetate m e m b r a n e s is significantly (2p < 0 . 0 0 5 ) less than the slope of the line for dialyzers containing the AN69S membrane (0.6 VS 1.18) 17. Thus, a second hypothesis was generated17; that different treatment methods influente the interrelationship of PCR and Kt/V (urea) in different ways. Review of the data suggests that to obtain a PCR of 1 gm/kg/day, a Kt/V (urea) of 1 must be prescribed when using a cellulose acetate dialysis membrane. DIALYSIS PRESCRIPTION AND NUTRITIONAL STATUS L." 1.8 1 . . . . .,#. ...` ;;`" .-i" 1. ..i;.,, n .f / ll* »`. .,.+a . I. ,. . .d.' . .: Y.8 8 , -c . . I , *.m, , ..*. I. ci.. / .,,. I. 1. . yiO.34+0.6X Fig. 1.-Plots of P C R versus Kt/V (urea); 322 observations on 5 5 haemodialysis patients. (Figure reprinted wirh permission of the editor of Am J Kid Dis). Fig. 3.-Plots of PCR versus Kt/V (urea); 2,107 observations on 34b haemodialysis patients. Break point analysis suggests that the l i n e a r relationship is lost after the KW (urea) exceeds 7.8 (only 1,000 data points, randomly selected, are shown). (Reprinted with the permission ofthe editor of Kidney International). This is in excellent agreement with Gotch's mechanistic analysis of the NCDS in which cellulosic membranes were used 2. Should a PCR of 1.4 gm/gk /day be felt to give added protection from morbidity (as suggested by Acchiardo) 16, then a Kt/V (urea) of 1.6 will be necessary. The use of the more permeable and biocompatible polyacrylonitrile membrane (AN69S) as found in the HOSPAL (Basel, Switzerland) series of dialyzers, should provide the patient with a PCR of 1 g/kg/day if a Kt/V (urea) of 0.85 PCR 1.0 GmlKglday 0.5 0.0 0.5 1.0 1.5 2.0 2 . 5 Kt/V(UREA) P = 0.01~ CELL Y = 0.25x = T = 0.68 P = 0.05 AN69S Y= 0.47X + r = 0.55 Fig. 2:-Regression lines of data points [PCR versus Kt/V (urea)] for 9 patients treated initially (t=O) by haemodialysis using cellulosic membrana and subsequently after 6 months of dialysis by AN69S membranes. (Reprinted with permission oi the editor of ASAIO Trans). is given; if the higher PCR of 1.4 is desired, then the Kt/V (urea) must be 1.19. In other words, a lower dose of dialysis, as modelled by urea, is necessary for the same influence on PCR. We were able to test this hypothesis by analysis of preliminary data from an ongoing prospective multicentre trial comparing short ( 3 hrs) dialysis using the AN69S membrane versus conventional (ã 4 hrs) using cellulosic dialysis membranes 20. At the time of analysis, 49 patients (28 on AN69S membrane containing dialyzers; 21 on cellulosic) had been follow e d in detail for over 6 months. At the 6 month point, the patients on AN69S had received significantly less Kt/V (urea) than those on cellulosic dialyzers (0.97 + 0.3 vs 1.2 + 0.2; p = 0.0016) yet attained s i m i l a r PCRs (1.07 f 0.2 VS 1.02 f 0 . 1 , N S ) . Significant (p = 0.002) linear relationships between PCR and Kt/V (urea) were found yet the line slopes were higher for AN69S than cellulosic. Of the 49 patients, there were 9 who were initially on cellulosic dialysis and changed to AN69S following in-centre prospective randomiration. They had significant Iinear relationships between PCR and Kt/V (urea) at baseline and after 6 months of treatment but showed an increase in the line slope when they moved from the cellulosic to AN69S (Figure 2). This preliminary data clearly indicates that patients on high flux dialysis (here by AN69S) achieve the same PCR for less Kt/V (urea) than patients on cellulosic dialyzers thus, supporting the hypothesis. The ongoing study will augment this information. 27 R.M. LINDSAY Explanations for this are possible. The most obvious relates to the different solute/clearance profiles PCR that exist with dialysis by AN69S and cellulosic m e m b r a n e s ; thus, removal of equal amounts of urea by these membranes will be associated with greater removal of higher molecular weight retention products by the more permeable AN69S membrane 21, 22. If this is the explanation then these studies support the role of «middle molecules» as uraemic toxins a n d hence, a therapeutic role in their removal. Another explanation relates to differing degrees of complement, interleukin-1 (IL-1) and tumour necrosis factor (TNF) activation produced by these membranes which may increase muscle catabolism and impair protein appetite 23 24 While, the first may transiently increase urea generation immediately postdialysis, the latter is more lasting and may reduce the measured PCR. Support for this hypothesis comes from the excellent study of Bergström and his c o l l e a g u e s in Stockholm who found that blood membrane contact within a dialyrer with cuprophan membranes elicit an enhanced release of amino acids from skeletal muscle which is abolished by Indomethacin and with the use of the biocompatible dicates the level at which dialysis adequacy is obtaiAN69S membrane 25, 26 ned. Figure 4 supports this by showing a semilog plot of PCR and Kt/V. PCR now shows a significant correlation with In Kt/V over the whole range of Kt/V vaCurvilinear relationship betwen Kt/V and pcr lues (r = 0.37; p = 0.000). We have continued our observations on the interrelationship between PCR and Kt/V (urea) by pooling data from a number of haemodialysis studies that we have carried out where good quality urea kinetic measurements were made and Figure 3 shows data taken from 346 patients from 8 countries (Canada, USA, Italy, France, Germay, Denmark, Sweden and the United Kingdom) followed serially providing 2,107 data points (the figure itself shows 1,000 data points randomly selected). The scatter gram does suggest that this relationship is not completely linear and can be described by looking at two separate linear regression lines with different slopes taken after a cut point of around Kt/V (urea) = 1.8 (the best fit of lines was chosen by multiple examinations of regression lines taken with different cut point values for Kt/V). The linear relationship of PCR and Kt/V (urea) below a Kt/V of 1 .8 are statistically significant (r = 0.312; p = 0.0000). Above the cut point, the relationship weakens and the slope of the line becomes negligible strongly suggesting that beyond a certain Kt/V (urea), no extra benefit is obtained as far as dietary protein intake is concerned. This would appear perfectly logical and it is likely that the relationship between the two parameters is curvilinear and that the Kt/V (urea) level where the maximum PCR benefit is obtained in28 Protein and energy requirements in haemodialysis patients I n normal adults, a protein intake of 0.75 g/kg body weight is considered to be a safe intake for over 95 % of the population 27. It has long been recognized that dietary requirements for protein are higher for uraemic patients being treated by intermittent HD than for normal subjects and non-dialyzed uraemic patients 28 and it has been suggested that 1.2 gm of protein of high biological value and an energy intake of 35 kcaI/kg body weight/day should be prescribed for HD patients 29. Anorexia, low protein and energy intake in haemodialysis patients It is a common experience that HD patients do not eat well because of anorexia and nausea. Nutritional surveys indicate that the mean intake of protein is < 1 gm/kg body weight/day in a large proportion of HD patients. Jacob et al 30 noted in 61 HD patients that 45 % had a protein intake of < 1 g/kg body weight/day. Furthermore, Bergström examined 117 DIALYSIS PRESCRIPTION AND NUTRITIONAL STATUS r `%l OF CASES WITH PCR > 1 .OO 120 # CASES 300 be determined an adequate protein intake and as less dialysis is provided, then the PCR progressively falls. Indeed, only 20 %, of patients receiving a Kt/V (urea) of 0.5 are ingesting satisfactory protein. On the other hand, 80 % of patients receiving a Kt/V (urea) of 1.8 seem to be nutritionally adequate by this parameter and nearly all the patients receiving Kt/V (urea) in excess of 2.5. Conclusion: the interrelationships between Kt/V (urea), PCR, dialysis membrane and outcome These correlations are summarized in Figure 6. A g i v e n dialysis membrane will allow a given Kt/V (urea) and hence, influence urea removal. The balance between urea removal and urea generation will determine the urea pool and the urea concentration for a given volume of distribution. It is postulated that this urea concentration in some way causes «biofeedback» determining the protein intake of a given pat i e n t which, of course, will influence the PCR and hence, the urea generation. The PCR may be adversely influenced by the use of bio-incompatible membranes which produce activated complement, IL 1 , TNF, etc. In addition, the membrane will determine the Kt/V (other toxins; «middle molecules» which may also influence protein intake. The protein intake will affect the overall nutritional status which, in turn, has a major impact on morbidity and mortality. We suggest that the most effective way to influence morbidity and mortality is to insure that a Kt/V (urea) well Fig. 5.-Percentage of cases with a PCR2 for given Kt/V (urea) values. Data obtained f r o m 2 1 0 7 observations on 1 4 6 haemodialysis patients (Reprinted with the permission of the editor of Kidney International. unselected HD patients and observed that the protein intake, calculated from urea kinetic modelling (PCR), was < 1 gm/kg body weight/day in about 25 % of the p a t i e n t s and < 0.8 g/kg body weight/day in 12 % ie. clearly insufficient to meet their daily requirements 29. Bergström also found that the energy intake was low in HD patients with a mean intake of 26-29 kcal/kg b o d y weight/day which is much less than the 35 kcal/kg body weight/day generally recommended. This may explain why such high proportion of HD patients show signs of energy depletion 31. There are innumerable factors that can contribute to low intake of protein and energy such as unpalatable or inadequate diets, gastropathy (in diabetic patients with autonomic neuropathy), medications, psycho-social and socio-economic factors such as loneliness, depression, ignorance and poverty. In addition, nausea and vomiting during and immediately after HD which are frequently associated with cardiovascular instability and post-dialysis fatigue, may lead to the reduction of food intake during the dialysis days. Also, as has been suggested earlier in this paper, the persistence of uraemic toxicity by underdialysis is a very important and correctable cause of anorexia and hence, protein and energy malnutrition. W e have further examined the pooled data previously mentioned (2,107 data points on 346 patients) to discern the percentage of cases who indeed have a satisfactory dietary protein intake as judged by a PCR > 1 .00. This information is shown in Figure 5 w h i c h clearly demonstrates that only 60 % of patients receiving a Kt/V (urea) of 1.5 have what would Fig, 6.-Suggested interrelationships between PCR, Kt/V and dialysis membrane used .(Reprinted with pennission of the editor of Kidney International). 29 R.M. LINDSAY over 1 (perhaps 1.8) is delivered to the patient if a ceIlulosic membrane is used. It may be possible to deliver less than this value using a biocompatible membrane which has increased Kt/V (middle molecules) for a given Kt/V (urea). Whatever the method of dialysis or Kt/V (urea) applied, attention should also be given to nutritional assessment of the patient and amongst the tools available to the clinician is the estim a t i o n of the PCR by urea kinetic modelling. It is strongly recommended that if this is less than 1 for a patient undergoing haemodialysis and no other obvious cause is found (eg. peptic ulceration, malignancy, etc.) then empirically the Kt/V (urea) delivered shou Id be i'ncreased. Acknowledgements The information given in this manuscript was presented as a «State-of-the-Art» lecture at the XIIth I n t e r n a t i o n a l Congress of Nephrology (Jerusalem, I s r a e l , June 1993) and will be published in Kidney InternationaI (suppl 44, January 1994). This manuscript including the figures are presented with the permission of the Editor of Kidney Infernational. The authors wish to thank MS. J. Elphee for the preparation of the manuscript. References 1. Laird N, Berkey CS and Lowrie EG: Modelling success or failure on dialysis therapy. The National Cooperative Dialysis Study. Kidney Int (suppl 13):S101 -S106, 1983. 2. Gotch FA and Sargent JA: A mechanistic analysis of the N a t i o n a l Cooperative Dialysis Study (NCDS). 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