Toxic Fluid Flux?
2010; Elsevier BV; Volume: 56; Issue: 1 Linguagem: Inglês
10.1053/j.ajkd.2010.04.003
ISSN1523-6838
AutoresThomas A. Depner, Todd S. Ing,
Tópico(s)Neurological and metabolic disorders
ResumoRelated Article, p. 69 Those seeking a better treatment for uremic toxicity usually do not consider accumulation of fluid as a toxic threat, but there is little in nature that allows us to conclude that frequent expansion and contraction of the extracellular space is harmless. We know that therapeutic dialysis confers its benefit by removing solute. Diuresis alone does not reverse uremia, but dialysis with or without fluid removal does. Although fluid accumulation is an important feature of kidney failure in most patients and excessive fluid can be life threatening in itself, it is not a necessary part of the uremic syndrome. Full-blown life-threatening uremia, reversible using dialysis, can occur without edema; thus, efforts to measure and deliver adequate dialysis appropriately have focused primarily on solute clearance.1National Kidney FoundationK/DOQI Clinical Practice Guidelines and Clinical Practice Recommendations for 2006 updates: hemodialysis adequacy, peritoneal dialysis adequacy, and vascular access.Am J Kidney Dis. 2006; 48: S1-S322PubMed Google Scholar Small-solute clearance targeted at or above threshold guidelines and administered 3 times weekly appears to be sufficient to control average levels of commonly measured uremic toxins and allow a reasonable quality of life. However, marked fluctuations in extracellular fluid volume (ECV) 3 times weekly in anuric patients theoretically could generate an adverse state of health, which is without precedent in the animal kingdom. Even for pathologic states, intermittent expansion coupled with rapid contraction 3 times weekly is unknown. Hemodialysis may be the only setting in which this phenomenon occurs and to a degree that causes a spectrum of symptoms, 1 or more of which most patients experience with each treatment. Is it possible that maintaining adequate solute control while inducing a rhythmic state of fluid expansion and contraction reverses uremia, but generates an adverse environment for cardiovascular health? The near-miraculous cure of uremia using dialysis perhaps has blinded us from seeing the adverse effect of fluid fluctuations. This theoretical construct could help explain the lack of benefit seen with high-dose and high-flux dialysis in the National Institutes of Health (NIH)-sponsored Hemodialysis (HEMO) Study and could explain the benefits that have been observed in patients dialyzed more frequently.2Eknoyan G. Beck G.J. Cheung A.K. et al.Effect of dialysis dose and membrane flux in maintenance hemodialysis.N Engl J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1571) Google Scholar, 3Pierratos A. Daily nocturnal home hemodialysis.Kidney Int. 2004; 65: 1975-1986Crossref PubMed Scopus (90) Google Scholar The well-demonstrated survival advantage of residual native kidney function also could be explained in part by attenuation of fluid fluctuations.4Termorshuizen F. Dekker F.W. van Manen J.G. Korevaar J.C. Boeschoten E.W. Krediet R.T. Relative contribution of residual renal function and different measures of adequacy to survival in hemodialysis patients: an analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2.J Am Soc Nephrol. 2004; 15: 1061-1070Crossref PubMed Scopus (278) Google Scholar, 5Bargman J.M. Golper T.A. The importance of residual renal function for patients on dialysis.Nephrol Dial Transplant. 2005; 20: 671-673Crossref PubMed Scopus (44) Google Scholar Reversal of anorexia using dialysis obligates more fluid intake; therefore, the present schedule of treatments 3 times weekly, while reversing uremia, could present a cardiovascular risk due to fluid fluxes that attenuate the otherwise beneficial effect of improved nutrition. Some have argued that we place too much emphasis on solute control at the expense of fluid control, although more recent guidelines address fluid issues (see Guideline 5, Control of Volume and Blood Pressure, in1National Kidney FoundationK/DOQI Clinical Practice Guidelines and Clinical Practice Recommendations for 2006 updates: hemodialysis adequacy, peritoneal dialysis adequacy, and vascular access.Am J Kidney Dis. 2006; 48: S1-S322PubMed Google Scholar). Nephrologists recognize that interdialysis fluid accumulation is harmful, but patients gain as much or more fluid between dialyses now as they did 30 years ago. Historically, high-flux dialysis likely contributed indirectly to fluid gains between dialyses and may have helped generate a subtle vicious cycle. When high-flux dialysis became available, concern was raised about the risk of acute volume depletion during treatments with membranes that had much higher hydraulic permeability, 20-40 times higher than conventional cellulosic dialyzers.6Kunas G.A. Burke R.A. Brierton M.A. Ofsthun N.J. The effect of blood contact and reuse on the transport properties of high-flux dialysis membranes.ASAIO J. 1996; 42: 288-294PubMed Google Scholar, 7Locatelli F. Mastrangelo F. Redaelli B. et al.Effects of different membranes and dialysis technologies on patient treatment tolerance and nutritional parameters The Italian Cooperative Dialysis Study Group.Kidney Int Suppl. 1997; 30: S15-S19Google Scholar Initially, the risk of inadvertent volume depletion limited its application until volumetric control devices became available.8Roy T. Ahrenholz P. Falkenhagen D. Klinkmann H. Volumetrically controlled ultrafiltration Current experiences and future prospects.Int J Artif Organs. 1982; 5: 131-135PubMed Google Scholar The zeal to shorten dialysis treatments, fueled by patient desires and cost control, further increased the need for methods to stabilize blood pressure (BP) while removing fluid at a more rapid rate. Clinicians quickly recognized that acetate dialysate, because of its vasodilating properties, could not be tolerated and had to be abandoned in favor of bicarbonate.9Vreman H.J. Assomull V.M. Kaiser B.A. Blaschke T.F. Weiner M.W. Acetate metabolism and acid-base homeostasis during hemodialysis: influence of dialyzer efficiency and rate of acetate metabolism.Kidney Int. 1980; 18: 62-74Google Scholar, 10Pagel M.D. Ahmad S. Vizzo J.E. Scribner B.H. Acetate and bicarbonate fluctuations and acetate intolerance during dialysis.Kidney Int. 1982; 21: 513-518Crossref PubMed Scopus (46) Google Scholar Any effort to support BP during dialysis was encouraged because it allowed the patient to benefit from high-flux dialysis, presumably from removal of larger toxic solutes. Increasing the dialysate sodium concentration and sodium modeling were encouraged and became popular methods for preventing hypotension.11Van Stone J.C. Bauer J. Carey J. The effect of dialysate sodium concentration on body fluid compartment volume, plasma renin activity and plasma aldosterone concentration in chronic hemodialysis patients.Am J Kidney Dis. 1982; 2: 58-64Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 12Acchiardo S.R. Hayden A.J. Is Na+ modeling necessary in high flux dialysis?.ASAIO Trans. 1991; 37: M135-M137PubMed Google Scholar, 13Dheenan S. Henrich W.L. Preventing dialysis hypotension: a comparison of usual protective maneuvers.Kidney Int. 2001; 59: 1175-1181Crossref PubMed Scopus (100) Google Scholar High sodium concentrations served as a buffer to prevent volume depletion, resulting in fewer alarms during the treatment. The consequent increased weight gain between treatments was considered a reasonable trade-off. The patient was admonished about fluid and salt intake between treatments and often was blamed when efforts to remove fluid failed. After nearly 30 years of experience with high-flux dialysis, continued high mortality rates compel us to go back in time and re-examine the rationale for manipulating dialysate sodium concentrations to support BP during dialysis. High dialysate sodium concentrations have the potential for initiating and sustaining a vicious cycle. Both fluid removal during dialysis, which stimulates volume receptors, and high postdialysis serum osmolality stimulate the thirst mechanism, a powerful craving that is difficult, if not impossible, for patients to ignore. The consequent high fluid intake between treatments mandates a higher ultrafiltration rate during the next dialysis session, when staff find it necessary to support BP with higher dialysate sodium concentrations, often with sodium modeling. These maneuvers further increase thirst and fluid intake between treatments. Decreasing the dialysate sodium concentration during dialysis can help break the cycle, but how does staff deal with the decrease in BP, which may be accentuated by this maneuver? Decreasing salt intake between dialyses also can help break this cycle; however, salt restriction has limited potential because of dietary preferences. The method described by Manlucu et al14Manlucu J. Gallo K. Heidenheim P.A. Lindsay R.M. Lowering postdialysis plasma sodium (conductivity) to increase sodium removal in volume-expanded hemodialysis patients: a pilot study using a biofeedback software system.Am J Kidney Dis. 2010; 56: 69-76Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar in the present issue of the American Journal of Kidney Diseases is designed to help solve this dilemma; in other words, to decrease the dialysate sodium concentration while avoiding hypotension. The key is a slow stepwise reduction, assisted in their clinic by proprietary biofeedback software. Although most clinics do not have the biofeedback technology used by Manlucu et al,14Manlucu J. Gallo K. Heidenheim P.A. Lindsay R.M. Lowering postdialysis plasma sodium (conductivity) to increase sodium removal in volume-expanded hemodialysis patients: a pilot study using a biofeedback software system.Am J Kidney Dis. 2010; 56: 69-76Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar the principles set forth in their article can be applied in general to eventually achieve an average decrease in dialysate sodium. The investigators note that a decrease in dialysate sodium concentration removes more salt from the patient, compensating in part for dietary indiscretion, analogous to giving a diuretic to allow salt intake in patients with hypertension and normal kidney function. If removal of solute is the primary purpose of dialysis, one might conclude that thirst would be decreased after dialysis due to decreased serum osmolality. Unfortunately, the most abundant and quantitatively the only significant osmole removed is urea, which, like alcohol, is ineffective for stimulating or inhibiting thirst and causing intracellular shifts of water.15Rose B.D. New approach to disturbances in the plasma sodium concentration.Am J Med. 1986; 81: 1033-1040Abstract Full Text PDF PubMed Scopus (206) Google Scholar In contrast, sodium is an effective osmole; thus, manipulation of dialysate concentrations can have significant effects on ECV, as well as on intracellular trafficking of water. Decreasing the dialysate sodium concentration without removing fluid from the patient creates a potential gradient across the dialysis membrane for sodium movement out of the patient, but because sodium is the principal osmole in both blood and dialysate, it creates an osmolal gradient that favors movement of water in the opposite direction, into the patient.11Van Stone J.C. Bauer J. Carey J. The effect of dialysate sodium concentration on body fluid compartment volume, plasma renin activity and plasma aldosterone concentration in chronic hemodialysis patients.Am J Kidney Dis. 1982; 2: 58-64Abstract Full Text PDF PubMed Scopus (33) Google Scholar This osmolal gradient in volumetrically controlled systems is opposed by hydraulic pressure across the membrane, preventing excessive water movement into the patient while maintaining a net ultrafiltration rate independent of osmoles. This independent (volumetric) control of fluid removal allows manipulation of the dialysate sodium concentration downward to effectively remove sodium from the patient without concern about movement of the more easily diffusible water molecule in the opposite direction. At the other end of the vascular compartment, where the freshly dialyzed blood equilibrates with body tissues, no volumetric control exists; therefore, water moves down its concentration gradient very quickly into the cellular compartment, further potentiating the hypotension caused by pressure-induced ultrafiltration at the dialysis membrane. In the absence of ultrafiltration, if the patient's serum sodium concentration is 140 mEq/L and body water volume is 33 L, complete equilibration with dialysate containing sodium at 135 mEq/L (ignoring serum water and Gibbs-Donnan correction factors because these tend to cancel each other) theoretically would remove 33 L × 5 mEq/L = 165 mEq or 3.8 g of sodium, the equivalent of approximately 1 L of normal saline solution or 2 days of sodium intake in a patient on a moderately salt-restricted diet. However, ECV would decrease even if no fluid was removed from the patient because water moves into the intracellular compartment to maintain osmotic equilibrium. The magnitude of this decrease is approximately 800 mL as calculated from the initial and final concentrations, the amount removed, and the relative intracellular fluid volume to ECV ratio (which we will assume is 2:1), and assuming no role of osmotically inactive sodium.16Titze J. Water-free sodium accumulation.Semin Dial. 2009; 22: 253-255Crossref PubMed Scopus (51) Google Scholar This theoretical quantitative exercise shows the potential power of dialysate sodium or conductivity manipulations and provides incentive to make changes slowly. The benefits of the initial dialysate sodium reduction will not be appreciated fully until subsequent dialyses when, because of decreased thirst, the need for fluid removal will be lessened. In addition, the BP-reducing effect may not appear for several months because of the “lag” phenomenon.17Charra B. Bergstrom J. Scribner B.H. Blood pressure control in dialysis patients: importance of the lag phenomenon.Am J Kidney Dis. 1998; 32: 720-724Abstract Full Text PDF PubMed Scopus (157) Google Scholar, 18Twardowski Z.J. Sodium, hypertension, and an explanation of the “lag phenomenon” in hemodialysis patients.Hemodial Int. 2008; 12: 412-425Crossref PubMed Scopus (40) Google Scholar This “pay forward” approach requires a stepwise gradual decrease over several weeks. In our zeal to blame the patient for excessive interdialysis weight gain, we usually ignore simple mass balance considerations that might help reassure the patient. Similar to caloric restriction in obese individuals, achievement of a negative balance in volume-expanded patients is required only transiently. When a new steady state of ECV is achieved, the patient theoretically could return to the previous level of salt and water intake provided the dialysis providers are able to continue removing fluid at the same rate. The dialysis clinic would not necessarily need to step up the rate of fluid removal during the negative-balance phase if intake was curtailed. Ideally, the dialysis clinic would remove fluid at a fixed rate during each treatment while the patient controls ECV by altering the diet. One could argue that the place to control salt and water balance is in the home, not in the dialysis clinic. Unfortunately, this ideal interface between the patient and provider rarely is achieved. Instead, after periods of dietary indiscretion, the dialysis clinic steps up the rate of fluid removal, creating hemodynamic stress for the patient that could be avoided using salt restriction. In severe cases, hospitalization is required to return the patient to an optimal steady state of fluid balance. Doubling the frequency of dialysis without other changes should decrease the fluid gain between dialyses by half. The few controlled and nearly all uncontrolled studies of frequent dialysis show decreases in BP and/or a decrease in need for BP medications.19Suri R.S. Nesrallah G.E. Mainra R. et al.Daily hemodialysis: a systematic review.Clin J Am Soc Nephrol. 2006; 1: 33-42Crossref PubMed Scopus (168) Google Scholar If the ongoing NIH Frequent Hemodialysis Network clinical trial shows a similar benefit, the question about the relative benefits of solute versus volume/BP control will remain unanswered.19Suri R.S. Nesrallah G.E. Mainra R. et al.Daily hemodialysis: a systematic review.Clin J Am Soc Nephrol. 2006; 1: 33-42Crossref PubMed Scopus (168) Google Scholar, 20Kliger A.S. High-frequency hemodialysis: rationale for randomized clinical trials.Clin J Am Soc Nephrol. 2007; 2: 390-392Crossref PubMed Scopus (29) Google Scholar Further studies should be considered to examine this question, perhaps by randomly assigning pure ultrafiltration versus hemodialysis on alternate days of a 6-day per week schedule. Such a study could be partially blinded because the same equipment and blood flow would be used for both treatments. In the interim, clinicians can add a fourth dialysis treatment transiently to achieve the new steady state described. Experience has shown that this simple maneuver can have significant benefits for “difficult” patients who experience dialysis intolerance or are unable to control interdialysis fluid accumulation using the method described by Manlucu et al.14Manlucu J. Gallo K. Heidenheim P.A. Lindsay R.M. Lowering postdialysis plasma sodium (conductivity) to increase sodium removal in volume-expanded hemodialysis patients: a pilot study using a biofeedback software system.Am J Kidney Dis. 2010; 56: 69-76Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar With regard to cardiovascular disease, fluctuations in ECV and BP constitute only part of the risk because patients managed using continuous peritoneal dialysis and during the period preceding the initiation of dialysis therapy are not free of cardiovascular complications. It is noteworthy that setting the dialysate sodium level (in mEq/L) slightly lower than that of the corresponding serum level during therapeutic dialysis is not new. The idea behind this approach, very much in vogue during the early years of dialysis, was (and is) “to effect a removal of this ion into the bath and to compensate for the negative electrical charge of the serum proteins” (the latter aim in recognition of the Gibbs-Donnan effect).21Eschbach Jr, J.W. Cole J.J. Dialyzers currently in use.in: Hampers C.L. Schupak E. Long-term Hemodialysis. Grune & Stratton, New York, NY1967: 23-41Google Scholar Decreasing the dialysate sodium concentration ultimately should benefit the patient by attenuating thirst, decreasing interdialysis weight gain, and decreasing BP. Achieving this goal slowly using the method outlined by Manlucu et al14Manlucu J. Gallo K. Heidenheim P.A. Lindsay R.M. Lowering postdialysis plasma sodium (conductivity) to increase sodium removal in volume-expanded hemodialysis patients: a pilot study using a biofeedback software system.Am J Kidney Dis. 2010; 56: 69-76Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar has potential for minimizing the adverse effects of decreasing serum sodium levels abruptly while achieving the full benefit. Financial Disclosure: The authors declare that they have no relevant financial interests. Lowering Postdialysis Plasma Sodium (Conductivity) to Increase Sodium Removal in Volume-Expanded Hemodialysis Patients: A Pilot Study Using a Biofeedback Software SystemAmerican Journal of Kidney DiseasesVol. 56Issue 1PreviewExtracellular fluid expansion is common in hemodialysis patients. Aggressive fluid removal may lead to intradialytic complications. High dialysate sodium concentrations may lessen complications, but may increase extracellular volume. We hypothesized that decreasing plasma sodium concentration during dialysis will increase sodium removal and decrease extracellular volume. Full-Text PDF
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