Articial Hemodialysis Versus Natural Hemoltration

Related Article, p. 507

ecause the native kidney is a lter and does not engage in the process of dialysis, longheld beliefs in the superiority of blood ltration for eliminating uremic toxins have rarely been challenged. What could be better than the divine prototype? In the early 1960s, shortly after hemodialysis (HD) was rst applied as a life-sustaining therapy for patients with chronic irreversible kidney failure, it became clear that the astonishing life-saving effects of HD could not be extended to restore a normal quality of life. Patients continued to suffer from lethargy, poor appetite, occasional nausea and vomiting, and inability to concentrate and function on a par with coworkers. Mortality rates were, and continue to be, much higher than in the general population. The logical answer to the why question was that the therapy was incomplete. However, attempts during the late 1960s and early 1970s to increase the intensity or dose of dialysis with higher blood and dialysate ow rates, larger membranes, and longer treatment times failed to bring about the desired improvement in outcome. Although early work with dialysis was hampered by adverse effects of the dialysis itself, the original pioneers (as well as some present-day dialysis clinicians) concluded that inadequate removal of toxic large molecules was responsible at least in part for these disappointing results.1 Early reports of new highly permeable membranes made from synthetic polyacrylonitrile that could cure uremic neuropathy, a uremic complication previously thought to be reversed only by renal transplantation, spurred efforts to develop membranes and delivery systems aimed at removing larger molecules.2 Hollow ber membranes are now available across a spectrum of porosities that range from a tight low-ux conguration that excludes ltration of 2-microglobulin (molecular weight, 11,800 Da) and all solutes heavier than 10,000 Da, to membranes used for plasmapheresis that offer little or no resistance to ltration of albumin (molecular weight, 66,000 Da). Typical high-

ux membranes that are increasingly used for HD in developed countries have hydraulic permeabilities 20 to 40 times that of previously used low-ux membranes and consequently require ultraltration control devices to protect the patient from sudden gains and losses of uid during treatments. The permeability of high-ux membranes to larger molecules is also markedly enhanced, allowing nite clearances of 2-microglobulin in the 30- to 40-mL/min range compared to near 0 for conventional low-ux membranes. Despite this advance in membrane construction, a randomized controlled trial (RCT) published in 2002 from the Hemodialysis (HEMO) Study group failed to detect a signicant clinical advantage of high-ux membranes.3 The HEMO Study, which was designed to detect improvements in several outcome measures, including survival, remains the most denitive RCT conducted to date. It showed that HD with high-ux membranes conferred only a small and insignicant survival advantage over standard-ux membranes in a large cohort of patients followed for an average of 2.8 years in 72 dialysis clinics scattered across the United States. A more recent smaller RCT of high-ux HD in Europe also failed to show a signicant benet after a minimum of 3 years of follow-up.4 However all of the above were studies of dialysis, not ltration. Filtration has an intrinsic capacity to remove larger molecular species even when the membrane is identical to that used for HD.5 Hydraulic pressure applied across the membrane forces larger molecules to traverse membrane pores at a more rapid rate than is possible by simple diffusion. This understanding and the above-described yearning to mimic the natural glomerular lter encouraged the dialysis industry to develop and manufacture hemoltration (HF) equipment with more porous membranes that could replace the dialysis machines and membranes that currently dominate the market. However, the thought of
Address correspondence to Thomas A. Depner, MD, University of California Davis Medical Center, Division of Nephrology, 4150 V St, Ste 3500, Patient Support Services Bldg, Sacramento, CA 95817. E-mail: tadepner@ucdavis.edu 2008 by the National Kidney Foundation, Inc. 0272-6386/08/5203-0005$34.00/0 doi:10.1053/j.ajkd.2008.07.007
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infusing many gallons of sterile uid directly into the bloodstream during each treatment and, conversely, directly removing by ltration an equal amount of uid from the body and sending it down the drain, might have caused early investigators to pause, even if they had in hand the highly permeable membranes and control devices necessary to make therapeutic HF work. Early attempts to show a clinical advantage of HF were hampered by an excessive focus on large-molecule clearance; inadequate smallmolecule clearance probably accounted for worse HF outcomes in some of the studies.6 Clearly, one must rst assure small-molecule clearance before attempting to improve outcomes by removing larger solutes.7 Later observational studies of HF that provided adequate small-molecule clearance, measured as Kt/Vurea, suggested a benet of HF when compared to HD.8 However, a recent review published in the American Journal of Kidney Diseases of 18 RCTs comparing ltration with dialysis concluded that the trials were not adequately powered to recommend one modality over the other.9 Hemodialtration (HDF), a modality that combines diffusion and ltration within the same hollow ber device, was associated with a signicantly higher mortality among 4 clinical trials totaling 336 patients. The authors stated that for HF, HDF, and HD, signicant differences in the clinically important outcomes have not been shown. . . . 9 In a related area, a large US study published this year failed to show a survival advantage of continuous HDF compared to intermittent HD for critically ill patients with acute kidney injury.10 The collective effect of these reports showing no benet of HF or HDF have dampened enthusiasm and caused providers in the United States to all but abandon HF as a substitute for long-term HD, despite availability of Medicare funding. Providers were probably relieved by these negative ndings because, if mandated by clinical evidence, over 15,000 existing dialysis clinics throughout the world would require retooling to replace HD with HF, a method that has not advanced as far as dialysis in terms of ease of use, cost efciency, and patient safety. Most recently, in the current issue of AJKD, Santoro et al report improved survival and other outcome measures in a small RCT in Italy of thrice-weekly HF versus HD.11 In the HF arm, this

study used on-line generation of predilution replacement uid, which for an average-sized adult patient would amount to approximately 80 L infused intravenously per treatment, three times weekly. Both dialysate and replacement uids met ultrapure standards and were warmed to 37oC, mitigating a source of previous controversy about low temperatures stabilizing blood pressure during HF.12 Membranes for dialysis and ltration were identical in their chemical composition (polyamide), but the HD membranes were small-pore low-ux membranes that were essentially impermeable to, and therefore incapable of removing, 2-microglobulin and similar large molecules. Selection of tight membranes in the HD group allowed a maximum separation of large-molecule clearance, which is the most signicant and perhaps only difference between the 2 modalities, but it did not allow a comparison of HF to high-ux HD. The patient numbers were small, starting with 32 and ending with 11 patients after 3 years in each arm of the study, so the seemingly signicant improvement in survival with HF is hazardous to interpret and runs the risk of misleading the clinician.13 Although the natural kidney is a lter, it wasnt always that way. On the evolutionary scale, primitive organisms relied on the innite dialysate of the primordial sea to dispose of their wastes or end products of metabolism. They also developed highly specialized membrane transporters to gather and keep substances vital to their existence. For example, existing bacteria and fungi have specialized transporters with high afnity for environmental iron, which is vital to energy transfer within the organism.14 As animals left the expanse of the sea, they were challenged to develop a substitute system to allow immediate disposal of metabolites and to quickly remove unwanted xenobiotics that might be ingested with their food and drink. Some students of evolution believe that glomerular ltration was developed to satisfy that need.15 Analogous to the function of cell membranes, the purpose of the glomerular lter is to separate large from small particles, including soluble molecules. The tremendous ltration rate of metanephric kidneys allowed immediate disposal of unknown and unwanted solutes while specialized transporters, previously developed for vital solute recovery and retention, were utilized by the tubular cell membranes.16,17 From this point of view, diffu-

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sion is the original purgative mechanism and ltration is a wannabe compromise for terrestrial organisms designed to mimic the effectiveness of the innite dialysate enjoyed previously by simpler ancestral organisms. Perhaps this explains the success of HD, a purgative mechanism similar to that enjoyed by ancestral organisms, and sometimes touted as the most successful therapy to be introduced during the last century.18 Living forms are accustomed to removing solutes by diffusion, and continue to transport solutes internally by diffusion. Recent successes with slow, more prolonged HD have underscored the importance of diffusion within the patient that limits extracorporeal removal of uremic toxins, whether by HD or by HF.19,20 If the major goal is to preserve the more complex molecular structures (often synthesized at no small expense within the organism) by separating them from simpler compounds (often byproducts of metabolism that have no function or salvage value), then which separation method is best: diffusion, or its terrestrial substitute, ltration? Current minimum standards for small-molecule clearance appear to optimize outcomes but do not restore health to most patients. Efforts should therefore continue to improve dialysis treatments globally, seeking to lower the mortality rate by novel treatments. Improved clearance of higher-molecularweight solutes is one reasonable direction to pursue and the few available positive studies are encouraging, but the long-sought reduction in mortality promised by advocates of HF has not been realized. Santoro et al agree that more studies are needed, and the positive results of their admittedly underpowered single-center study provide a strong impetus to continue searching in a larger controlled trial such as the ongoing Dutch Convective Transport Study (CONTRAST) targeted for completion in December, 2009.21 This more ambitious comparison of HDF to low-ux HD began in 2004 and aims to enroll 800 incident and prevalent patients from 20 or more centers in the Netherlands. With primary end points of cardiovascular morbidity and all-cause mortality, this study is likely to shed more light on both the potential toxicity of large molecules and the true relative merits of ltration versus dialysis. Thomas A. Depner, MD University of California, Davis School of Medicine Sacramento, California

ACKNOWLEDGEMENTS
Support: None. Financial Disclosure: None.

REFERENCES
1. Scribner BH, Farrell PC, Milutinovic J, et al: Evolution of the middle molecule hypothesis, in Villarreal H (ed): Proceedings of the Fifth International Congress of Nephrology, Basel, Karger, 1974, pp 190-199 2. Funck-Brentano JL, Man NK, Sausse A: Effect of more porous dialysis membranes on neuropathic toxins. Kidney Int 7:52-57, 1975 3. Eknoyan G, Beck GJ, Cheung AK, et al: Effect of dialysis dose and membrane ux in maintenance hemodialysis. N Engl J Med 347:2010-2019, 2002 4. Locatelli F, Gauly A, Czekalski S, et al: The MPO Study: just a European HEMO Study or something very different? Blood Purif 26:100-104, 2008 5. Henderson LW, Leypoldt JK: Quantitation and prescription of therapy, in Henderson LW, Quellhorst EA, Baldamus CA, Lysaght MJ (eds): Hemoltration, Berlin, SpringerVerlag, 1986, pp 129-145 6. Wizemann V, Rawer P, Schtterle G: Ultrashort haemodialtration: long term efciency and haemodynamic tolerance. Proc Eur Dial Transplant Assoc 19:175-181, 1983 7. Lowrie EG, Laird NM, Parker TF, et al: Effect of the hemodialysis prescription on patient morbidity: report from the National Cooperative Dialysis Study. N Engl J Med 305:1176-1181, 1981 8. Canaud B, Bragg-Gresham JL, Marshall MR, et al: Mortality risk for patients receiving hemodialtration versus hemodialysis: European results from the DOPPS. Kidney Int 69:2087-2093, 2006 9. Rabindranath KS, Strippoli GF, Roderick P, et al: Comparison of hemodialysis, hemoltration, and acetatefree bioltration for ESRD: systematic review. Am J Kidney Dis 45:437-447, 2005 10. Palevsky PM, Zhang JH, OConnor TZ, et al: Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 359:7-20, 2008 11. Santoro A, Mancini E, Bolzani R, et al: The effect of online high-ux hemoltration versus low-ux hemodialysis on mortality in chronic kidney failure: A small randomized controlled trial. Am J Kidney Dis 52:507-518, 2008 12. Karamperis N, Sloth E, Jensen JD: Predilution hemodialtration displays no hemodynamic advantage over lowux hemodialysis under matched conditions. Kidney Int 67:1601-1608, 2005 13. Chertow GM, Palevsky PM, Greene T: Studying the prevention of acute kidney injury: Lessons from an 18thcentury mathematician. Clin J Am Soc Nephrol 1:11241127, 2006 14. Neilands JB: Microbial iron compounds. Annu Rev Biochem 50:715-731, 1981 15. Smith HW: From sh to philosopher: the story of our internal environment. Boston, Little, Brown, & Co, 1953 16. Grantham JJ, Wallace DP: Return of the secretory kidney. Am J Physiol Renal Physiol 282:F1-F9, 2002 17. Launay-Vacher V, Izzedine H, Karie S, et al: Renal tubular drug transporters. Nephron Physiol 103:97-106, 2006

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18. Eggers PW: Medicares end stage renal disease program. Health Care Financing Review 22:55-60, 2000 19. Culleton BF, Walsh M, Klarenbach SW, et al: Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial. JAMA 298:1291-1299, 2007

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20. Pierratos A: Daily nocturnal home hemodialysis. Kidney Int 65:1975-1986, 2004 21. Penne EL, Blankestijn PJ, Bots ML, et al: Resolving controversies regarding hemodialtration versus hemodialysis: the Dutch Convective Transport Study. Semin Dial 18:47-51, 2005