I 0- Should Hernodialysis Fluid Be Sterile?

Lee Henderson Baxter Healthcare CorDoration, Round Lake, Illinois

There is no question in my mind that hemodialysis fluid should be sterile. This reaches beyond the en- culturating forces brought to bear both by genera- tions of grandmothers and the subtly crafted adver- tising campaigns of such moguls of clean as Lever Brothers and Proctor and Gamble. Unquestionably, in the United States “cleanliness is next to godliness.” My concerns reach even beyond the medical preju- dice that we are constantly at war with our micro- environment, whether that battlefield happens to be epidermal, endothelial, or anywhere in between and that anything we as physicians do to tilt the scale in favor of the human organism (as contrasted with its monocelluar invader) is indeed a virtuous act.

Rather, I should like to tie this to a chain of scientific and clinical concerns that sterile pyrogen- free dialysis fluid is a logical evolution in upgrading the quality of therapy, as we render it with the artificial kidney.

Let me point to several recent publications and the implications thereof. Held et al. ( I ) point to a significantly higher mortality in the U.S. dialysis population when the registry data for the United States are contrasted with those from Europe or Japan. This “statistically robust” observation cannot be easily accepted on the basis of case mix and in the minds of these authors is best explained by a reduction of treatment time causing inadequate di- alysis in the United State (2). Many [including Held et al. ( 3 ) ] consider the reduction in treatment time to be driven by a systematic cutback in federal reimbursement for hemodialysis, i.e., economic con- siderations taking a primary role in the prescription of therapy.

We consider urea to be a metabolic waste product with relatively low toxicity that is a surrogate for other more toxic substances that we do no? measure and may not yet be identified. The number of hours spent in treating patients with hemodialysis in a given week may also be considered a surrogate for Dr. Scribner’s “middle molecules.” I recognize that many of you regard middle molecules as nephrol- ogical flying saucers (in large measure because their clear-cut biochemical identification is only now be- ginning to occur). This skepticism does not, however, vitiate the rigorous engineering logic that underlies this kinetic relationship.

How then may we reconcile saving personnel time by shortening treatment schedules and the need to

Address correspondence to: Lee Henderson, MD, Executive Director, Extramural Grant Program, Baxter Healthcare Cor- poration, Route 120 and Wilson Road, Round Lake, IL 60073- 0490. Seminars in Dialysis-Vol 6, No 1 (Jan-Feb) 1993 pp 26-27

provide adequate medical therapy? Large surface area dialysis with conventional membranes will cer- tainly reduce treatment time while sustaining a suit- able amount of urea mass removed to qualify for adequate therapy using National Cooperative Di- alysis Study (NCDS) standards. Clinical experiments of this sort, however, reach beyond the reasonable limits of extrapolation from the NCDS data. Taken to its logical extreme, a 4 m2 cuprophane membrane area will ensure that the limiting mass transfer/area resistance will be at the cell membrane rather than at the dialyzer and as such, the single pool urea kinetic model used by the NCDS is no longer valid. In parallel with this event, the orderly relationship that urea bears to other more slowly moving meta- bolic toxins (i.e., its surrogate status) breaks down as well.

It is this line of reasoning that requires that atten- tion be paid to the full spectrum of solutes that is being removed during hemodialysis rather than sim- ply focusing on urea. This is especially true for physicians employing high-efficiency and/or high- flux techniques used to deliver shorter treatment times. They must pay attention to the time surrogate and remove larger-molecular-weight species with at least the efficiency seen in conventional dialysis prac- tice, i.e., 20.9 m2 cuprophane for 4.5-5 hours, three times a week (NCDS Group I).

To accomplish this goal of short treatment (<3 hours three times a week/75 kg body weight) will require membranes with more open structure, from the standpoint of both diffusive permeability and the degree of openness to water transport, with its at- tendant convective elimination of middle molecules.

A second line of reasoning stems from the work by Cutierrez et al. (4) from Stockholm, who point out that in all likelihood, complement activation by extracorporeal exposure of normal whole blood to cuprophane membrane releases cytokines that result in a catabolic event at the level of skeletal muscle, i.e., catabolism of protein that is endogenous rather than dietary. This iatrogenic auto-cannibalism must factor into the dialysis prescription in an economi- cally unfavorable way, from the standpoint of both the need for more dialysis to remove the metabolic wastes and the increased morbidity and mortality in the dialysis population that may result from this protein lysis.

If economic constraints set the scene for more open membranes, the role of bacterial lipopolysac- charide in stimulating monocytes to produce cyto- kines that catabolize protein must be examined- again, iatrogenic auto-cannibalism.

Obviously, the rosy scenario that I am leading you toward relates to the use of complement-kind mem-

26

SHOULD HEMODIALYSIS FLUID BE STERILE? 27

branes that are very open to the transport of both water and solute. Our complacency with regard to the bacterial/endotoxin content of dialysis fluid needs to be cast off when shortened treatment times using either high-efficiency or high-flux techniques are to be employed safely to provide adequate di- alysis. “Safely,” in my estimate, requires sterile py- rogen-free dialysis fluid. This will serve both the taxpayer and the patient.

References Held PJ, Brunner F, Odaka M, Garcia JR, Port FK, Gaylin DS: Five year survival for end stage renal disease patients in the U.S., Europe, and Japan 1982-87. Am J Kdney Dis I5:45 1-457, 1990 Held PJ, Levin NW, Bovbjerg PR, Pauly MV, Diamond LH: Mortality and duration of hemodialysis treatment. JAMA 26537 1-875, 199 I Held PJ, Garcia JR, Pauly MV, Cahn M A Price of dialysis, unit staffing, and length of dialysis treatments. Am J Kidneji Dis 15:441- 450, 1990 Gutierrez A, Alvestrand A, Wahren J, Bergstrom J: Effective in vivo contact between blood and dialysis membranes on protein catabolism in humans. Kidney Int 38:487-494, 1990

Richard A. Ward Division of Nephrology, School of Medicine, University of Louisville, Louisville, Kentucky

Bicarbonate dialysate, highly permeable mem- branes, and ultrafiltration control systems have achieved widespread use in recent years. These ad- vances have increased patient exposure to bacterial products in the dialysate. Indeed, according to the Centers for Disease Control (CDC), 22% of dialysis facilities in the United States reported pyrogenic reactions in the absence of septicemia during 1989 (1). Furthermore, the authors of the CDC report believe that only the most severe pyrogenic reactions are detected by their surveys. Based on the CDC data, we might reasonably conclude that current standards for the microbiological purity of dialysate are not adequate for today’s practice of hemodialysis.

Prospective clinical studies, however, have failed to demonstrate a link between bacterial contamina- tion of dialysate and pyrogenic reactions (2). In addition, other studies show that dialysate, and the water used to prepare it, often fail to meet current standards for microbiological purity (3) and that clusters of pyrogenic reactions are often associated with poor reuse procedures, rather than the presence of bacteria in the dialysate (4). Advocates of the status quo have used these findings to argue against the imposition of more stringent microbiological standards for dialysate.

While debate on the association between contam- inated dialysate and pyrogenic reactions remains inconclusive, an increasing body of evidence suggests that contaminated dialysate results in more subtle molecular changes that may be considered the “bio- chemical equivalent” of pyrogenic reactions. Recent studies using sensitive and specific analytical tech- niques show an increase in serum Limulus amoe- bocyte lysate (LAL) activity during dialysis with high-permeability polysulfone membranes ( 5 ) : pas- sage of radiolabeled lipopolysaccharide across di- alysis membranes (6); and the transmembrane pas- sage of low-molecular-weight substances derived from the common dialysate contaminant Xuritho- inonas inaltophilia (7). These bacterial products

Address correspondence to:Richard A, Ward, Ph.D., Division of Nephrology. School of Medicine, University of Louisville, Louisville, K Y 40292. Seminars in Dialysis-Vol 6, No 1 (Jan-Feb) 1993 pp 27-28

stimulate monocytes to produce the cytokines tumor necrosis factor a (TNF-a) and interleukin lp (IL-

TNF-a and IL- 1 p have wide-ranging effects on the body, including the induction of fever and catabo- lism, and they are thought to play an important role in the etiology of some of the chronic complications associated with hemodialysis, including osteoarthri- tis, fibrosis, and amyloidosis (8). Because these com- plications of dialysis develop over long periods of time, it will be very difficult to obtain unequivocal epidemiological data linking them to bacterial prod- ucts in the dialysate. However, the important contri- bution these complications make to long-term pa- tient morbidity and our increased understanding of the molecular mechanisms of cytokine production and its sequelae provides a compelling rationale for more stringent microbiological standards for dialy- sate. Based on these arguments, one may conclude that “sterile” dialysate will be required if we are to reduce long-term patient morbidity. (Here the defi- nition of “sterile” is extended to include the absence of bacterial products as well as the absence of viable organisms.)

Given that small, bacterially derived products play an important role in the long-term morbidity of hemodialysis patients, is it technically and econom- ically feasible to routinely produce dialysate free of these substances?

It is relatively simple to produce solutions free of both viable organisms and intact endotoxin by filtra- tion. Filtration through polysulfone ultrafilters was used to provide sterile, pyrogen-free replacement solution in the early days of hernofiltration (9), and more recently, polyamide hernofilters have been used as point-of-use filters to provide sterile, pyro- gen-free dialysate for high-flux hemodialysis ( 10). However, point-of-use ultrafiltration will not remove small molecules that pass across much less permeable dialysis membranes.

Currently, the only filtration process that will re- move essentially all species down to a molecular size of about 100 daltons is reverse osmosis. Since it is extremely costly to use reverse osmosis as a point- of-use process in preparing water for dialysate, re- verse osmosis must be combined with a water distri-

10).