04. FROM ADEQUATE 27/5/05 13:06 Página 19 NEFROLOGÍA. Vol. 25. Suplemento 2. 2005 From adequate to optimal dialysis Long 3 x 8 hr dialysis: a reasonable compromise B. Charra Centre de Rein Artificiel de Tassin. France. SUMMARY Long dialysis (3 × 8 hours/week) has been used in Tassin for three decades now, without method modifications. Results have been excellent considering both morbidity and mortality. Best survival compared to short dialysis is mainly due to low cardiovascular mortality. It is probably due to a good control of arterial hypertension, without antihypertensive medication, and the low rate of intradialytic hypotension. Slow ultrafiltration, allowed by the extended dialysis session, associated with a lowsalt diet and a moderate interdialysis weight gain, tend to normalize extracellular volume and ensure normotension. Long hemodialysis assure a good dialysis dose in terms of small and even middle molecules, with good nutrition, anemia correction, phosphate and potassium control with few drugs. Optimal dialysis needs several conditions, each of them necessary. Time seems a central factor, providing a high treatment safety margin. While it is quite difficult to achieve excellent dialysis results with short sessions, long-dialysis is easy to perform with high reliability. Key words: Long hemodialysis. Optimal dialysis. Cardiovascular mortality. DE LA HEMODIÁLISIS ADECUADA A LA ÓPTIMA. DIÁLISIS LARGA 3 × 8 H: UN COMPROMISO RAZONABLE RESUMEN La diálisis prolongada de 3 × 8 horas/semana ha sido usada en Tassin durante tres décadas sin modificaciones en el método. Los resultados han sido excelentes en términos de morbilidad y mortalidad. La mejor supervivencia respecto de la referida en la diálisis corta es debida principalmente a una mortalidad cardiovascular baja. Esta a su vez se debe al buen control de la tensión arterial, sin necesidad de medicación antihipertensiva, y a la baja incidencia de hipotensiones intradiálisis. La ultrafiltración suave gracias a la duración prolongada de la sesión, asociada a una dieta baja en sal y a una ganancia de peso interdiálisis moderada tienden a normalizar el volumen extracelular y aseguran la normotensión. La diálisis prolongada asegura una buena dosis de diálisis en términos de pequeñas e incluso medianas moléculas, con una buena nutrición, la corrección de la anemia, el control de fosfato y el control de potasio con pocas dosis de medicación. La diálisis óptima necesita de varias condiciones, todas ellas obligatorias. El tiempo parece un factor clave, aportando un alto margen de seguridad para el desarrollo del tratamiento; mientras que es bastante difícil realizar una diálisis corta excelente, la diálisis prolongada es fácil de llevar a cabo con gran fiabilidad. Palabras clave: Hemodiálisis prolongada. Diálisis óptima. Mortalidad cardiovascular. Correspondence: Dr. Bernard Charra Centre de Rein Artificiel de Tassin 69160 Tassin (France) 19 04. FROM ADEQUATE 6/2/40 04:59 Página 20 B. CHARRA INTRODUCTION Long hemodialysis (HD) 3 × 8 to12 hours per week on 1 square-meter flat plate cuprophan dialyzers- was in the 70's the empirical most achieved form of dialysis, the «gold standard»1. Technical advances, changing scientific views on uremia pathophysiology, but even more social and economical pressure to make a better use of the scarce HD stations led to the apparition and development of shorter dialysis sessions. In Tassin the 3 × 8 hr/wk dialysis has remained the unique treatment method for all patients for three decades. Since 1995, a «short» dialysis schedule (3 × 5-6hr/wk) has been set up. About one third of the patients are using this shortened schedule. The overall Tassin experience represents about 8,200 patient-years. PATIENTS AND METHODS Three sessions of 7-8 hours per week are performed overnight during the sleep or in the daytime according to the patient's possibility and preference. Home dialysis has been used in more than half of the patients up to the 80's. But the increasing number of dialysis units, the higher transplantation rate and the worsening patients case-mix have led to a steady decrease of the proportion of patients treated at home. Only 5% of Tassin patients are now treated at home and 10% in limited care facilities. Until 1995 the technical setting was poorly biocompatible, using cuprophan® membranes, acetate buffer and plain softened water. A 220 to 250 ml/min blood flow has been used throughout the experience (300 ml/min for the patients on the 5-6 hr/wk schedule). Since 1996 bicarbonate buffer has been substituted to acetate. In 1998 low-flux polysulfone dialyzers have replaced cellulosic ones. For «short» HD patients large area size dialyzers (1.7 to 2.5 sqmeter) are used. Since 2001 reverse osmosis completed by ultrafiltration has replaced the simple water softening system. Whatever the session duration the dose provided is large: the mean delivered spKt/V (2nd generation Daugirdas method) is over 2.0 per session. The mean normalized PCR is over 1.2. The mean protein and calories intakes are 1.2 g/kg and 32 kgcal/kg/day respectively. The patients are requested to maintain a low salt diet. No salt is added to the food and processed food is avoided. The average sodium chloride intake is 5 g per day. The mean interdialytic weight gain is 1.7 kg (2.5% of mean dry weight). The dialysate sodium is set at 138 mmol/L. The patients are not requested to restrain from drinking. Du20 Table I. Demographic and Comorbid factors vs. Survival at 5, 10, 15 and 20 yrs of Dialysis % patients surviving Initial age: < 35 y.o. 35-44 y.o. 45-54 y.o. 55-64 y.o. 65-74 y.o. 75 y.o. Etiology: Chronic Glomerulonephritis Intersticial nephritis Polycystic kidney disease Nephrosclerosis Diabetes Systemic disease/ cancer Others Unknown Atheroma: 2 cardiovascular antecedents 1 cardiovascular antecedent no antecedent Gender: Females Males TOTAL patient # 186 176 269 257 263 197 5 yr 91 85 81 70 47 24 10 yrs 85 76 67 40 24 2 15 yrs 79 60 45 16 5 ­ 20 yrs 71 34 19 5 3 ­ < 0.001 p 290 183 129 236 233 85 64 128 80 83 87 51 36 48 67 78 69 65 70 28 10 30 59 56 51 49 36 13 2 15 49 33 37 27 31 8 ­ 9 32 12 < 0.001 222 281 650 453 895 1,348 32 55 84 73 63 69 14 27 69 56 46 46 3 10 52 38 29 34 3 35 27 19 20 0.005 < 0.001 ring the initial few weeks of dialysis each patient undergoes a systematic antihypertensive treatment withdrawal in conjunction with the lowering of his extracellular volume to achieve «dry weight» and normotension2. Altogether 1,380 patients have been treated by maintenance HD since 1968 in Tassin. As elsewhere the incident population has changed drastically with calendar years. The mean age at start has steadily increased from 35.1 in 1968 to 61.9 years in 2003. During the same period diabetes mellitus and nephrosclerosis prevalence in the incident population crept up from 2 to 40% and from 3 to 20% respectively. In the same time the proportion of patients starting dialysis with cardiovascular (CV) comorbidity increased from 6 to 61%. 04. FROM ADEQUATE 6/2/40 04:59 Página 21 FROM ADEQUATE TO OPTIMAL DIALYSIS Table II. Evolution of age and cause of renal failure in 6 Tassin calendar cohorts Calendar years Age at dialysis start Diabetes mellitus (%) Nephrosclerosis (%) Glomerulonephritis Other causes (%) 68-'73 39.2 3.2 6.1 39.2 51.5 74-'79 45.0 4 10.4 33.5 52.1 80-'85 46.4 4.9 17.2 23.1 54.8 86-'91 56.8 31 23.1 20.6 25.3 92-'97 62.0 36.5 21.3 16.9 25.3 98-'03 62.8 36.7 20 11.9 31.4 Table IV. Standardized Mortality (SMR) vs USRD Calendar year 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 O/E* death 23/43,7 14/42,4 18/44,7 15/46,1 23/47,7 20/50,3 23/57 27/56,4 25/48,5 26/47,6 27/67,5 38/71,1 27/74,1 32/75,33 35/70,6 SMR 0,53 0,33 0,40 0,33 0,48 0,40 0,40 0,51 0,52 0,55 0,41 0,53 0,36 0,42 0,50 p value < < < < < < < < < < < < < < < 0,005 0,001 0,001 0,001 0,001 0,001 0,001 0,001 0,001 0,005 0,001 0,001 0,001 0,001 0,001 RESULTS 1/Mortality Due to the increased risk factors, crude mortality has steadily increased along calendar years. On table I the proportion of patients surviving after 5 to 20 years of treatment is reported as a function of age, cause of renal failure, cardiovascular story and gender. Females tend to survive better than males. Age, cause of renal failure and CV story have a strong impact on survival. These risk factors prevalence has changed over years as shown on table II. The mean age at dialysis start has crept up by about 25 years between the first and the sixth calendar cohorts. In the same cohorts the proportion of diabetic patients has been multiplied by a factor of 10. The important change in the case mix has a crucial influence on mortality (table III). Although all patients received the same unchanged treatment, due to the change in risk factors, survival has steadily decreased. To adjust for patients' risk factor the Standardized Mortality Ratio (SMR)3 adjusts for age, race, sex and cause of renal failure using USRDS standard mortality table as the reference. The average observed mortality in Tassin is about 45% of the expected value for US patients similar in age, race and cause of renal failure (table IV). It has remained quite stable over the last 15 calendar years in spite of the impressive worsening of the patients case-mix. Table III. Demographic and Comorbid factors and Patient Survival at 5, 10, 15 and 20 years Percentage of Patients Surviving Calendar cohort < 1975 1975-1979 1980-1984 1985-1989 1990-1994 1995-1999 2000 patients number 165 168 141 234 275 165 212 5 yr 88 82 82 69 52 49 ­ 10 yrs 75 71 62 47 27 ­ ­ 15 yrs 58 50 36 25 ­ ­ ­ 20 yrs 40 36 13 ­ ­ ­ ­ * O/E = observed/expected deaths. A comparison of Tassin mortality to the only available long-term French series of 4-5 hr HD reported several years ago4 shows that long HD mortality was lower (52.4 vs. 99 deaths per 1,000 pt-yrs, p < 0.001). There was no difference in specific (infection, cancer, or others) causes of death between the 2 series out of CV mortality which was much lower on long HD (19.8 vs. 44.6 CV deaths per 1,000 ptyrs, p < 0.001). We splitted the Tassin long dialysis population in 2 equal number cohorts according to the integrated pre-dialysis mean arterial pressure (MAP) and analyzed their survival. The cohort with the lowest MAP (MAP = 89 mmHg) had a significantly lower mortality (p = 0.003) than the one with a slightly elevated MAP (MAP = 107 mmHg). The difference was mainly explained by the lower CV mortality in the Table V. Tassin patients mortality using Cox proportional hazard mode Regresion coefficient Age at start Diabetes CV1 MM2 index kt/V urea Mean MAP3 Serum Albumin 1 95% Confidenc. e interval (0,033, 0,067) (0,131, 1,081) (0,204, 1,057) (-0,681,(-0,348, 0,675) (0,011, 0,056) (-0,064, 0,007) Relativ. e risk 1,05 1,833 1,879 0,668 1,165 1,034 0,971 95% Confidenc. e interval (1,033, (1,139, (1,226, (0,506, (0,706, 1,069) 2,947) 2,878) 0,880) 1,964) 0,049 0,606 0,631 -0,404 0,153 0,033 -0,029 (1,011, 1,057) (0,938, 0,993) : CV = Cardiovascular antecedent (Myocardial infarction, angina, cerebrovascular transient ischemic attack, peripheral iscemia). 2 : MM = Middle Molecule. 3 : MAP = Mean Arterial Pressure. 21 04. FROM ADEQUATE 6/2/40 04:59 Página 22 B. CHARRA 67 66 65 64 AntiHT medications: 89% < 5% 125 120 115 110 105 Post HD weight PreHD MAP 63 62 61 0 1 2 3 Dialysis months 6 9 12 100 95 90 Fig. 1.--Evolution of post-dialysis weight (kg) and pre-dialysis mean arterial pressure (mmHg) in 712 patients 12 first months of long hemodialysis. lower MAP subgroup, 12.7 vs. 28.1 CV deaths per 1,000 pt-yrs (p < 0,01)5. The Cox proportional hazard model shows that age, cause of renal failure and CV antecedents are very powerful predictors of mortality6 (table V). These factors are not amenable to medical action. Among treatment-related factors urea Kt/V does not significantly predict survival, while time-dependent middle molecule (MM) index7 does (the higher the MM removal rate, the longer the survival). But the strongest predictors of mortality are serum albumin and pre-dialysis MAP. 2/Morbidity An essential feature of long HD is that it regularly achieves a good control of blood pressure (BP). The mean observed casual pre-dialysis BP (128/79 mmHg) is within normal range. Ambulatory BP monitoring values are also within normal. Intradialytic hypotensive episodes are more scarce on long than on shorter HD: 49 events per 1,000 sessions on 8 hr HD vs. 129 events on 5 hr HD (p < 0.005). The relationship between extracellular volume (ECV) and BP is illustrated by the first month of long HD treatment displayed on figure 1. The initial sharp ECV drop contrasts with the more progressive predialysis MAP decrease over months. This lag time between changes in ECV and BP8 is an important practical point that must be explained to patients. After 2 months of dialysis (fig. 1) BP continues to decrease but weight increases due to a gain in lean and fat body mass (improved appetite and anabolism at start of maintenance HD). One of the main difficulties in 22 assessing clinically the dry weight in HD patients is to distinguish the respective part of weight change due to ECV and to lean and fat body mass change9. Tassin average hematocrit is 35% with EPO being used for 55% of the patients. The initial pre-dialysis mean serum albumin (36,7 g/l) increases to 41.6 at 2 years and remains stable after 20 years. Due to its intracellular repartition and slow intercompartimental transfer rate, PO4 can be assimilated to a MM. Hence PO4 control is rather easy in long dialysis. The mean overall pre-dialysis serum PO4 is 1.44 ± 0.33 mmol/l. Only 30% of the long HD patients need to take a PO4 binder. 3/Switching the same group of patients from short to long HD and conversely We had some years ago the opportunity to switch the same groups of patients from short to long HD and conversely10. Among 124 unselected patients dialyzed in Tassin while waiting for a kidney transplantation (all treated for 6 months or more on a 3 x 5 hr/wk HD) half were on antihypertensive treatment. After 3 months of 3 x 8 hr HD antihypertensive medications had been stopped in all but one patient, the average post-dialysis weight was reduced by 0.5 kg and pre-dialysis MAP was back to normal (mean = 101 mmHg). Thereafter MAP continued to decrease slowly but, due to anabolism, patients' weight increased progressively to plateau after one year. In the same time the mean pre-dialysis hematocrit level increased from 24 to 29% without EPO and after stopping all blood transfusions in the 27 patients who needed them while on short HD (his- 04. FROM ADEQUATE 6/2/40 04:59 Página 23 FROM ADEQUATE TO OPTIMAL DIALYSIS torical group). Pre-dialysis urea increased by 10% and pre-dialysis creatinine by 25%. Conversely, 49 patients who had been dialyzed 3 x 8-hr for more than 6 months (all normotensive without antihypertensive medication) were switched to 3 x 5 hr HD10. Dialyzer area and blood flow were increased to maintain an unchanged Kt/V. After one year the pre-dialysis MAP was significantly increased (10 mmHg) in spite of a mean 2.5 kg post-dialysis weight reduction. Pre-dialysis urea and creatinine dropped by 8 and 19% respectively. The mean hematocrit decreased from 31.5 to 27.5%. Shortening the session time without decreasing the dialysis dose was therefore associated with an impaired BP and nutrition. DISCUSSION Is survival better on long HD? In 2003 in Tassin the mean age at start was 61.9 years, 51% of patients had diabetes or renal vascular disease and a significant CV story was found in 59% of incident patients. The very slight favorable population selection bias in favor of Tassin does not account for the large mortality discrepancy with US results. One cannot exclude some «center effect» in the achieved results. But other units using long dialysis11 report the same good survival and low morbidity. Normotension is probably a major factor in reducing mortality12. On top of achieving an excellent control of volume and of BP, a long dialysis allows for a satisfactory control of nutrition, anemia, and phosphoremia13. The effect of PO4 control on HD patients survival (more specifically on CV mortality) initially reported by Block and cols.14 has been now widely confirmed. What is the role of the large urea Kt/V? Is survival better on long dialysis because the delivered urea Kt/V is higher than in the conventional short HD? When the delivered urea Kt/V is increased --in limited but well controlled groups of patients-- the mortality decreases15,16. But Kt is a better outcome-based measure of HD dose than Kt/V17. Indexing the delivered dose Kt to V which has independent outcome effect of its own confuses the issue. The clearance term K depends of several factors (blood flow, recirculation, urea rebound...) These factors reduce the system performance when shortening the HD time pushes up the necessary dialysis «efficiency». Therefore operational conditions of HD make it is very difficult to substantially increase the urea Kt/V (e.g. over 1.8) without increasing the session time t over the conventional 3 or 4 hours. Other time-related issues The effect of increasing the session time is not limited to increasing small molecules epuration. It increases proportionally more the clearance of larger solutes such as MM and of solutes which, due to their body distribution, behave as MM. We have already pointed at the importance of PO4 control to prevent CV calcifications. Identified MM have also been shown to influence strongly nutrition, immunology and infection, BP and vascular disease and to have many other implications18. The good ECV and BP control achieved are probably the most clinically relevant features of long HD. The development of shortened dialysis has led to an increased incidence of hypertension19 and most probably to the epidemics of CV disease in the HD population. Shortened session time and higher ultrafiltration rates lead to a vicious circle20 amplifying BP variations and driving to both intradialytic hypotension and interdialytic hypertension. Optimal dialysis needs several conditions not just one. All these conditions are mandatory. Each of them is necessary. Any of them if lacking suffices to sink the whole ship. Time allows not only to provide a good dose of dialysis in term of small and even more middle molecules, but also to provide a satisfactory nutrition, ECV and BP control. This last point is essential: CV morbidity is by far the first cause of death in HD patients. So time appears a key factor to achieve an optimal dialysis treatment. Besides it does not push every operational aspect of dialysis to its maximum, so that it leaves a great margin of safety for treatment for treatment delivery. Practically speaking, while it is rather difficult to perform an excellent very short dialysis, the long slow thrice weekly dialysis is easy to perform with a great liability. REFERENCES 1. Barber S, Appleton DR, Kerr DNS: Adequate dialysis. Nephron 14, 209-227, 1975. 2. Charra B: How important is volume excess in the etiology of hypertension in dialysis patients? Seminars in Dialysis 12(5), 297-299, 1999. 3. Wolfe RA: The standardized mortality ratio revisited: improvements, innovations and limitations. American Journal of Kidney Diseases 24(2), 290-297, 1994. 4. Degoulet P, Legrain M, Reach I, Aimé F, Devriès C, Rojas P y cols.: Mortality risk factors in patients treated by chronic hemodialysis. Nephron 31, 103-110, 1982. 23 04. FROM ADEQUATE 6/2/40 04:59 Página 24 B. CHARRA 5. Charra B, Calemard E, Laurent G: Importance of treatment time and blood pressure control in achieving long-term survival on dialysis. American Journal of Nephrology 16, 35-44, 1996. 6. Charra B, Chazot C, Jean G, Laurent G: Long, slow dialysis. Mineral and Elecrolyte metabolism 25, 391-396, 1999. 7. Babb AL, Strand MJ, Uvelli DA, Scribner BH: The dialysis index: a practical guide to dialysis treatment. Dialysis & Transplantation 6, 9-12, 1977. 8. Charra B, Bergström J, Scribner BH: Blood Pressure control in dialysis patients. The importance of the lag phenomenon. American Journal of Kidney Diseases 32(5), 720-724, 1998. 9. Chazot C, Charra B, Vo Van C, Jean G, Vanel T, Calemard E y cols.: The Janus-faced aspect of «dry weight». Nephrology Dialysis Transplantation 14(1), 121-124, 1999. 10. Charra B, Laurent G: Long hemodialysis: the key to survival? En: Brown EA, Parfrey PS, editors. Complications of long-term dialysis. Oxford, New York, Tokyo: Oxford University Press; p. 228-256, 1999. 11. Ackrill P, Goldsmith DJA, Covic AA, Venning MC, Ralston AJ: Outcome of long hours self-care haemodialysis in a single unit from 1969 through 1994. Nephrology 3 (Supl. 1), S536, 1997. 12. Lynn KL, McGregor DO, Moesbergen T, Buttimore AL, Inkster JA, Wells JE: Hypertension as a determinant of survival for patients treated with home dialysis. Kidney International 62(6), 2281-2287, 2002. 13. Alloatti S, Molino A, Manes M, Bonfant G, Pellu V: Long nocturnal dialysis. Blood Purification 21(1), 131-136, 2002. 14. Block GA, Hulbert-Shearon TE, Levin NW, Port FK: Association of serum Phosphorus and Calcium x Phosphate product with mortality risk in chronic hemodialysis patients: a national study. American Journal of Kidney Diseases 31(4), 607617, 1998. 15. Parker TF, Husni L, Huang W, Lew M, Lowrie EG, and the Dallas Nephrology Associates: survival of hemodialysis patients in United States is improved with a greater quantity of dialysis. American Journal of Kidney Diseases 23(5), 670-680, 1994. 16. Collins AJ, Ma J, Umen A, Keshaviah PR: Urea index and other predictors of hemodialysis patient survival. American Journal of Kidney Diseases 23(2), 272-282, 1994. 17. Lowrie EG, Chertow GM, Lew NL, Lazarus JM, Owen WFJ: The urea (clearance x dialysis time) product (Kt) as an outcome-based measure of hemodialysis dose. Kidney International 56, 729-737, 1999. 18. Vanholder R: Middle molecules as uremic toxins: still a viable hypothesis? Seminars in Dialysis 7(1), 65-68, 1998. 19. Sellars L, Robson V, Wilkinson R: Sodium retention and hypertension with short dialysis. British Medical Journal 1, 520521, 1979. 20. Charra B: Does empirical long slow dialysis result in better survival? If so, How and Why? American Society for Artificial Internal Organs Journal 47, 819-822, 1993. 24