Infectious Morbidity and Detects of Phagocytic Function in End-Stage Renal Disease: a Review1

Infectious Morbidity and Detects of Phagocytic Function in End-Stage Renal Disease: A Review1

Raymond Vanholder2 and Severin Ringoir

morbid events in uremia. Treatment by dialysis, a!- though life saving in Se, may add to the suppression R. Vanholder, S. Ringoir. Nephrology Department. Uni- of the immune system. versity Hospital, Ghent, Belgium The pathophysiobogy of these interferences is to be (J. Am, Soc. Nephrol. 1993; 3:1541-1554) considered in depth, to allow directed therapeutic and preventive approaches. Comprehensive reviews are, however, scant ( 1 ,2) and do not contain the new information generated during the last 5 yr. It was ABSTRACT therefore thought appropriate and timely to review Infectious diseases remain among the most morbid the present state of the art on this subject. events and are an important cause of death in ESRD. These events are related to an acquired immuno- THE ACQUIRED IMMUNODEFICIENCY OF ESRD deficiency that progresses during the development of uremic retention, as part of the broader spectrum, Several clinical facts indicate that ESRD results in displayed by the TMuremic syndrome”. A central role an acquired immunodeficlency: ( 1 ) enhanced suscep- in the hose defense against bacterial infection is tibility to infection (3), (2) enhanced risk for cancer played by the phagocytic polymorphonucIear white (4), (3) attenuation of autoimmune disorders (5), (4) development of skin anergy at delayed hypersensitiv- blood cells, which are characterized by the capacity ity testing (6), and (5) suppression of response to to ingest bacteria (phagocytosis), which is followed vaccination (7). by the destruction of those bacteria (killing capac- Among those. infection is a factor of major morbidity). This article reviews the mechanisms of develop- ity and mortality (3.8,9). In 1977, as well as in 1989, ment and the potential causes that have been held Keane et at. demonstrated that infection was respon- responsible for this aspect of the defective immune sible for about one third of the fatalities in a dialysis function. The observed changes are attributed to unit (3,10). In a 1991 article by Mailboux et at. a alterations in receptor expression, although more similar contribution of infection to overall mortality convincing evidence points in the direction of met- was confirmed ( 1 1 ), especially in the population abolic functional disturbances, especially in the younger than 60 yr. Thus, even today. with all mod- NAD(P)H-oxidase-dependent production of oxygen em acquirements of optimized adequacy of treatment, infectious disease remains the main cause of free radicals. The most important causative factors death in the hemodlabyzed population. are: uremic toxicity, iron overload, renal anemia, Regarding the causative Importance of different dialyzer bioincompatibility, and the type of renal bacterial species, the majority of isolates are gram replacement therapy. It is concluded that the phag- positives (3), among which staphylococci play a pre- ocytic defect in ESRD is multifactorial and that each dominant role. Especially metastatic, Staph ytococ- factor should be managed by specific therapeutic cus aureus (Staph A) bacteremia carries a substan- approaches. tial mortality risk (12). Key Words: Immune system, uremia, uremic toxicity, poly- Thus, uremia is related to a high infectious risk, and morphonuclear cells, phagocytosis, infection infection, especially with Staph A, causes important morbidity and mortality: this is of critical importance, in view of the high present number of patients D ysfunction of the host defense against infection treated by dialysis (more than 500,000 worldwide). in ESRD has major clinical and socioeconomic The effect is even more striking if patients with pre- implications: Infectious diseases are among the most end-stage renal failure and patients with acute renal failure are taken equally into account.

‘ReceIved May 19, 1992. Accepted December 2, 1992. 2Correspondence to Dr. R. Vanhoider, Nephrology Department. UnIversIty Hos- FACTORS CONTRIBUTING TO THE SUSCEPTIBIL- pital, Dc Plntelaan, 185, B9000, Ghent, BelgIum. ITY TO INFECTION OF UREMIC PATIENTS 1046-6673/0309-1541$03.00/0 Journal of the American socIety of Nephrology Contributing factors to the susceptibility to Infec- Copyright C 1993 by the American socIety of Nephrology tion of the uremic population are multiple (1,13,14):

Journal of the American Society of Nephrology 1541 Phagocytosis and Uremia

physical, nutritional, and metabolic condition; per- fled by the presence of marked beukocytopenia. In sona! hygiene: underlying chronic infectious disease, contrast to the data collected during cuprophane di- together with the disruption of cutaneous protective alysis, polymorphonuclear beukocyte (PMN) activity barriers; and the affinity of bacteria for foreign po- remains unaltered during dialysis with other, non- lymeric materials, once dialysis is started. complement-activating diabyzer membranes (35,47, A pivotal role in the immune defense is played by 59,66,71,72,75-80) (Table 3). In summary, the ma- phagocytosls, I.e. , the ingestion and destruction of jority of studies point to a suppression of phagocyte bacteria by phagocytic leukocytes. It Is acknowledged function in ESRD, which is present before the start that other systems may equally affect immune de- of dialysis and is enhanced by dialysis with the com- fense (e.g. , cellular immunity). In this review, we will, plement-activating cuprophane membrane. however, focus on phagocytosis, in view of Its key position In the defense against bacteria. PATHOPHYSIOLOGY Alterations at Cellular Level PHAGOCYTIC FUNCTION IN UREMIA Changes in PMN function may result from abtera- Phagocytic function in the uremic state has been tions at different bevels: ( 1 ) receptor expression and submitted to repeated study. Results are sometimes activation; (2) particle ingestion; (3) signal transfer conflicting. Many factors may contribute to this di- by secondary messengers and target proteins; (4) versity of results: ( 1 ) variability in the composition dysfunction of the metabolic pathways. of the patient groups; (2) insufficient numbers to Receptor Expression, Particle Ingestion. Changes disclose statistical significance; (3) alteratIon of in receptor expression and in particle ingestion have phagocytic function or selection of functionally effete been demonstrated in uremic and/or hemodlalyzed cells by isolation techniques (2, 1 5); (4) flaws related patients (46,77). An intradlalytic decrease in receptor to methodology, e.g. , the use of artificial stimuli in- expression is described for formyb-methlonine-leu- stead of live bacteria or the presence of free radical cine-phenylalanine (f-MLP) (69) and Fc receptors scavengers in uremic media (16,17). (67,70) (results possibly biased by a selection of less- The results of 34 studIes evaluating the response reactive cell populations [2,15]). to various stimuli (1 5, 1 6, 1 8-49) in ESRD, in contin- In contrast, Roccatelbo et at. concluded that cupro- uous ambutatory perltoneat dIalysIs (CAPD) pa- phane did not affect Fc receptor expression (77) but tlents, and in prediatysls samptes of hemodialyzed rather affected only particle interiorization because patients are summarized in Table 1 . A decrease in of exhaustion of energetic sources. functional capacity Is described in 26 (77%) of 34 Surface receptor binding of f-MLP and casein was studies, whereas only 4 studies suggest an enhance- not affected during dialysis with cellulose acetate ment (27,37,39,48). The latter studies, based on dlalyzers (15,73). Skubitz and Craddock (81) de- chemiluminescence measurements, may, however, scrlbed a marked refractoriness of granulocytes to have been subjected to flaws, which are difficult to stimulation with C5a during cuprophane hemodl- control (50-53). alysis, suggesting a down-regulation of cellular re- In Tables 2 and 3, data concerning the evolution of sponses to this chemotactic stimulus. In parallel, phagocytosis durIng dlatysts are displayed (Table 2, Lewis et at. (15,73) descrIbed a suppression of the dialysis with complement-activating dlalyzers; Table density of the surface expression of C5a receptors 3, dialysis with noncomplement-activating dia- when normal white blood cells were passed through byzers). celbubosic dialyzers. These changes were not con- There is now ample evidence that, during dialysis firmed in vivo in uremic patients (73). with the cuprophane membrane (first use), the com- Results concerning receptor expression in uremia plement cascade is activated (54-56), which is prob- and/or during dialysis are thus inconsistent. A ably a trigger for leukocyte activation (57-61), al- change, If any, seems mainly related to a down- though isolated activation, even in the absence of regulation of the response to complement. complement factors, may occur (62-65). The central Dysfunction of Metabolic Pathways. A central question is whether these primarily activated beuko- role in the destruction of ingested bacteria is played cytes still can cope with additional naturab stimuli, by NAD(P)H-oxidase, an enzyme that converts oxygen such as microorganisms. This aspect was subjected to superoxide free radicals (Figure 1). The latter are to repeated study only during the last few years. transformed into other free radicals, e.g., hydrogen The evidence that phagocyte function upon stim- peroxide and hypochborite. The energy necessary for ulation is suppressed during dialysis with comple- this process is delivered by the hexose monophos- ment-activating cuprophane Is overwhelming (Table phate shunt that breaks down glucose into CO2. The 2) (15,32,35,42,44,49,59,66-80). This functional robe of this key metabolic process in PMN defense disturbance, per phagocytic cell, is further Intensi- function has received little attention until recently.

1542 Volume 3’ Number 9’ 1993 TABLE 1. Summary of literature data (last 15 yr) on phagocytic function in ESRD, CAPD, and hemodialysis#{176}

Patient Authors, Year (Ref. No.)Method Result Population

Greene et a!., 1976 (18) ESRD Chemotaxis HD Chemotaxis

Hosking et a!., 1976 (19) HD Particle ingestion = Abrutyn et a!., 1977 (20) ESRD Particle ingestion = BJOrksten et oL, 1978 (21) HD Chemotaxis Siriwatratananonta et a!., 1978 ESRD Chemotaxis (22) HdIIgren et a!., 1979 (23) ESRD Particle ingestion HD Particle ingestion Lespier-Dexter et aL, 1979 (24) ESRD Adherence = HD Adherance

Sutowicz et a!., 1979 (25) ESRD Free radical = HD Free radical = Wardle and Williams, 1980 (16) ESRD Metabolic activity Ritchey el a!., 198 1 (26) HD Free radical Tuma et a!., 198 1 (27) HD Free radical =/ Briggs et aL, 1983 (28) HD Metabolic activity Charpentier et aL, 1983 (29) HD Free radical HD Particle ingestion Clarke et a!., 1983 (30) AE Clearance bacteria =/j

Nelson et 01., 1983 (3 1) AE Inflammatory response = Wierusz-Wysocka et a!., 1983 (32) HD Chemotaxis

Casciato et a!., 1984 (33) HD Bacterial killing = HD Free radical HD Chemotaxis Glazer et a!., 1984 (34) HD Free radical Nguyen et a!., 1985 (35) HD Free radical =fl Waterlot et a!., 1985 (36) HD Particle ingestion

HD Free radical =

HD Bacterial killing = Eckardt et a!., 1986 (37) ESRD Free radical HD Free radical I Flament et aL, 1986 (38) HD Free radical Rhee et a!., 1986 (39) ESRD Free radical I CAPD Free radical I HD Free radical I Gallimore et a!., 1987 (40) AE Clearance bacteria Lewis et a!., 1987 (15) HD Complement receptor binding HD Free radical Cantinieaux et aL, 1988 (41) HD Particle ingestion =fl Hirabayashi et aL, 1988 (42) ESRD Free radical ESRD Particle ingestion

CAPD Free radical = HD Free radical I

HD Particle ingestion = Lewis et a!., 1988 (43) HD Chemotaxis CAPD Free radical I

Jacobs et a!., 1989 (44) HD Particle ingestion = HD Free radical Lucchi et aL, 1989 (45) ESRD Free radical I HD Free radical I Ruiz eta!., 1990 (46) HD receptor function I Hoag-Weber et aL, 1991 (47) CAPD Metabolic activity HD Metabolic activity I Paul etaL, 1991 (48) HD Free radical I Vanholder eta!.. 1991 (49) ESRD Metabolic activity I HD Metabolic activity I

#{176}HD,hemodialysis; AE: animal experiments: free radical production, mainly estimated from chemiluminescence production or nitroblue tetrazollum reduction; 1. decreased function: , increased function; =, function unaltered versus normal.

Journal of the American Society of Nephrology 1543 Phagocytosis and Uremia

TABLE 2. Summary of literature data on the TABLE 3. Summary of literature data on the intradialytic evolution of phagocytosis during intradialytic evolution of phagocytosis during dialysis with complement-activating dialyzers dialysis with noncomplement-activating dialyzers (cuprophane, cellulose diacetate)#{176} Authors, Year (Ref. No.) Method Result Authors, Year (Ref. No.) Method Result

Henderson et aL, 1975 Particle ingestion = Henderson et a!., 1975 (66) Particle ingestion I (66) Chemotaxis I Chemotaxis I Mobility I Mobility =

Klempner et aL, 1980 (67) Rosette formation I Bauer et a!., 1983 (7 1) Free radical =

Wissow etaL, 1981 (68) Free radical I Nguyen et a!., 1985 (35) Free radical =

Cohen et a!., 1982 (69) Free radical I Heierli et aL, 1986 (72) Free radical =

Spagnuolo et aL, 1982 (70) Adhesiveness I Markert et aL, 1988 (74) Free radical = Fc receptor expres- I Aggregation =

sion Markert et aL, 1988 (75) Free radical =

Aggregation I Neceveral et aL, 1988 Free radical = Bauer eta!., 1983 (71) Free radical I (76)

Wierusz-Wysocka et aL, Migration I Roccatello et aL, 1989 Particle ingestion =

1983 (32) (77) Receptor expression =

Nguyen et aL, 1985 (35) Free radical I Freeradical =

Heierli et aL, 1986 (72) Free radical I Vanholder et aL, 1990 Metabolic activity = Lewis et aL, 1987 (73) Compl recept binding I (78)

Lewis et a!., 1987 (15) Compl recept binding I Kuwahara et aL, 1988 Free radical =

Hirabayashl et a!., 1988 Free radical = (59)

(42) Descamps-Latscha et aL , Free radical = Markert et aL, 1988 (74) Free radical I 1991 (79) Aggregation I Haag-Weber et a!., 1991 Metabolic activity =11 Marked et aL, 1988 (75) Free radical I (47)

Neceveral et aL. 1988 (76) Free radical I Vanholder et a!., 1991 Metabolic activity = Jacobs et aL, 1989 (44) Ingestion I (49) Free radical I Roccatello et a!., 1989 (77) Particle ingestion I 0 Same abbreviations and symbols as described in the footnote to Receptor expression = Table 1. Free radical I Vanholder et aL, 1990 (78) Metabolic activity I Kuwahara et a!., 1988 (59) Free radical I uremia. The enzymatic activity of myeboperoxidase, Descamps-Latscha et a!. , Free radical I in the transformation of superoxide to other free 1991 (79) radicals, may be affected as webb. Himmelfarb etaL, 1991 (80) Free radical I Vanholder et aL, 1991 (49) Metabolic activity I Causative Mechanisms

0 Same abbreviations and symbols as described In the footnote to Opsonization Defect. The uremic status may af- Table 1. fect both the quality and the quantity of opsonins,

e.g. , fibronectins (85). Abrutyn et at. , however, considered changes in the quality of opsonization as This process can be studied by the measurement of pathophysiobogicabby unimportant (20). Also, in the the degree of CO2 production In response to various hands of the authors, phagocytic gbycolytic activity stimuli in different stages of the uremlc condition was the same for both unopsonized and opsonized (49,78,82-84). The data demonstrate a profound dis- particles. turbance of PMN glycolysis in response to challenge, A defect in opsonization may be more important in both in nondialyzed and in maintenance hemodi- the perltoneab cavity of CAPD patients, where a de- alysis patients (49). This inhibition is parallel for pletion of opsonins has been evidenced (86,87). various stimuli (latex, zymosan, Staph A, f-MLP, Uremic Toxicity. Phagocytic dysfunction by toxic phorbol myristic acid [PMA]) (78). The fact that all of suppression is conceivable (88,89). Uremic serum these stimuli (including PMA, a direct activator of and/or ubtrafiltrate suppress pobymorphonuclear protein kinase C) show a similar depression, in spite function (26,45,90,9 1). of different activation mechanisms, suggests that a The knowledge concerning the responsibbe factors common distal metabolic pathway is disturbed. remains speculative (Table 4). Hallgren et at. found Thus, energy delivery for the phagocytic destruc- a negative correlation between serum phosphate and tlon of bacteria by NADPH-oxidase is disturbed in phagocytic activity (23). However, this correlation

1544 Volume 3 ‘ Number 9 - 1993 Vanholder and Ringoir

TABLE 4. Toxic factors possibly affecting [iAPH AII.II.P..1 phagocytic function

“V Phosphate? / [ZYMOSAN Ii:: LII1 Potassium? Urea? Polyamines Spermine [PHAGocYTosisi [1EMBRANE RECEPTOR Spermidine 44 1 INTERACTION Endorphins Polypeptides Parathormone Antioxidants#{176} [Pro::inkinsssC.1444444444 444444 Phenols V OXYGEN Phenolic acids Indoles E1’”””” 1i(P)H.OXi ‘i’,’’,. FREE V RADICALS p-Cresol Uric acid

Figure 1 . Flow chart of the metabolic pathways involved in 0 May also act as direct inhibitors of metabolic activity. oxygen free radical production. Currently used challengers of metabolic activity are illustrated by the shaded, double- lined boxes: particles (above) and humoral stimuli (right- hand side). 1g. immunoglobulin; C, complement; HMS, hex- with a high PTH (97). Other factors were, however, ose monophosphate shunt. Protein kinase C activates not considered. Massry et at. observed an enhanced NAD(P)H-oxidase, resulting in the production of oxygen free ebastase release by PMN cells after their contact in radicals (superoxide, singlet oxygen, hypochlorite, hydro- vitro with PTH, however, at concentrations exceeding gen peroxide, chloramines). The necessary energy is deliv- those currently encountered in the uremic condition ered by the hexose monophosphate shunt after the break- (98). AccordIng to Alexlewicz et at. , elevated resting down of glucose to CO2. Intraphagocytic levels of Ca2”, decreased ATP con- tent, and a smaller rise in Ca2’ in response to stim- does not necessarily point to a causative relationship. ubation are all consistent with the notion that excess Lespier-Dexter et at. found weakly significant corre- PTH may play an Important robe in the impaired lations with potassium and the potassium/sodium phagocytosis of hemodialyzed patients (99). Other ratio (24). Glazer et at. added urea to a suspension of enhancers of cellular calcium should, however, not normal monocytes to a final concentration of 200 be disregarded. mg% and found a marked suppression of superoxide It is thus conceivable that uremic toxicity plays a anion production (34). Others found no such suppres- role in the functional disturbances of the phagocytic sion (16), and in general, it is accepted that urea in beukocytes. The responsible compounds are, how- concentrations currently encountered In uremia is ever, not exactly known, and we are probably con- not toxic (89). According to Wardle and Williams, fronted with several factors in combination. It is phenols and phenolic acids depress leukocyte lodi- interesting to note that most of the compounds nation and the activity of myeloperoxldase (16). claimed to interfere with PMN function show a reten- Phenols, indoles, and even uric acid may exert their tion pattern and kinetic behavior during dialysis that action In part as antioxidants (1 7). PrelimInary re- differs from those of urea and creatinine, the uremic sults from our group point to a negative effect of the solutes “en vogue” for the estimation of uremic reten- phenolic compound p-cresol on PMN glycolytic activ- tion and dialytic elimination. The question arises ity and on chemlluminescence production. Current whether optimizing dialysis adequacy according to well-known markers of uremic retention, such as the rules of urea kinetic modeling will at the same creatinine, had no such effect. According to Ferrante, time optimize the elimination of solutes affecting human neutrophil locomotion is suppressed by the phagocytic function (100). polyamlnes spermine and spermidine (92). Endor- Iron Overload. Iron overload is frequently encoun- phins, which are retained in renal failure (93), may tered in hemodialyzed patients because of over- suppress the response of leukocytes to stimuli (94). administration of iron, blood hemolysis, and over- Most Interestingly, H#{244}rbet at. recently described a transfusion. High serum ferritin as an index of iron 28,000-D polypeptlde with granubocyte inhibitory overload has been related to disturbed phagocytosis characteristics (95). (38,41) and increased incidence of bacteremia (101). Parathyroid hormone (PTH) affects several bio- One way to suppress body iron stores is by the chemical functions (96). According to Esposito et at., administration of erythropoletln (EPO). In eight pa- phagocytosis was more affected in renal patients tients with an average serum ferritin of 1,860 JL,

Journal of the American Society of Nephrology 1545 Phagocyfosis and Uremia

an improvement of phagocytosis, together with a de- alpha (TNF-cr), and inter!eukin-2 receptor levels in crease of serum ferritin, was found after EPO admin- uremic and/or dialyzed patients (1 23- 1 33). These istration ( 1 02). The authors’ group also found an effects may be partially dialysis membrane rebated improvement of phagocytic gbycolytic activity in EPO- (125,126,133). treated patients (1 03) but could not confirm a corre- The questions arise to what extent will changes in bation with serum ferritin. Patients with extreme iron cytokine production affect the response mechanisms overload are becoming exceptional today because of the host defense system and in what direction, blood transfusions are applied more carefully since positive or negative. The paradox is that suppression the advent of EPO. Is the main problem with the immune system in Renal Anemia. PMN CO2 production improves dur- uremia, whereas cytokines are generally considered ing treatment with EPO (103), which parallels the as enhancers of immune activity. reports of better exercise tolerance as an illustration It cannot be excluded that the enhanced avaibablb- of metabolic improvement under EPO (104). Acute in ity of cytokines may result in the exhaustion of the vItro abteratlon in whole-blood samples of ei-ythrocyte immune system. In possible agreement with this hy- counts did not, however, change metabolic response pothesis, monocyte activation in response to the cu- (R. Vanhobder et at. unpublished results), suggesting prophane membrane results in a transient refracto- that the improvement in PMN metabolic response is riness of these monocytes to further stimulation (80). rather due to a gradual and overall metabolic im- In a recent in vitro study, under nonuremic condi- provement. Note that a beneficial effect of EPO has tions, Schbeiffenbaum and Fehr demonstrated that also been demonstrated for other aspects of the im- the preincubation of PMN cells with TNF caused mune system (105-109). functional deactivation of respiratory burst, corre- Deficiencies. Leukocyte functions in uremia may sponding with a down-regulation of TNF receptors be affected not only by retention of toxins, but also (134). by deficiencies, e.g., of fibronectin (85), zinc (1 10), Endotoxin Transfer to the Bloodstream. A host of and 1 ,25-dihydroxy-vltamin D (1 1 1). The batter effect mostly gram-negative species have been identified in is mainly restricted to monocytes and macrophages. dialysate circuits (1 35). Although bacteria and endo- Bio(in)compatibility of Artificial Organ Treat- toxins are by definition not supposed to cross intact ment. The necessity to treat uremic retention by diabyzer membranes, they may enter the circulation dialysis has created a new series of pathologies, cur- through microscopic defects. Moreover, endotoxin rentby referred to as bio(in)compatibility-rebated prob- might be broken down into smaller fragments, with lems. These problems will obviously also affect the macrophage- and complement-activating properties, immune system. that may be abbe to cross smaller pores (136). Recurrent Comptement Activation. Complement- Back-filtration/back-diffusion of endotoxin frag- activating diabyzer membranes, such as cuprophane ments is especially suspected with large-pore dialy- ( 1 1 2), may have a negative effect on the response of zers, if a low or even negative transmembrane pres- phagocytes (Table 2), in addition to their acute and sure is opposed to a positive counterpressure in the chronic effect on circulating leukocyte counts. These dialysate; both minimize compulsory transmem- findings parallel the poor response to various stimuli brane ultrafiltration (1 37, 1 38). More recent in vitro of PMN function with acute infection (1 1 3), burns studies demonstrated the passage of monocyte-acti- (1 1 4), or trauma (1 1 5), which are also attributed to vatlng material through low-flux cellubosic mem- excess complement activation ( 1 1 6). Neutrophibs branes (1 22). Note that the transfer of bacteria from preexposed to high concentrations of activated com- contaminated water may exceptionably be another plement are inhibited In their subsequent migratory cause of pyrogenicity (139,140). responses (117). However, this deactivation Is mainly Again, the influence of this potential endotoxin related to locomotion and not to indices of respiratory load on overall defense is not clear. Whereas bipo- burst activity (118). Alternatively, neutrophibs acti- pobysaccharide may activate the response to second- vated during passage through the dialyzer may be ary stimuli, the latter response is suppressed, rather sequestered in the vasculature (56,81,119), beading than activated, in uremia. to an increase in the proportion of functionally effete The SpecIfic Probtem of CAPD. During treatment cells in circulation (67). with CAPD, sterile fluids are introduced into the per- The Interleukln/Cytokine Hypothesis. A group of itoneal cavity at frequent, regular intervals; this is compounds playing a role in bloincompatibility re- rebated to the frequent occurrence of peritonitis (141), actions are the cytokines (120-122). Their produc- especially by gram-positives. Although the Ingestion tion is related to beukocyte, especially monocyte, ac- of bacteria by peritoneab macrophages harvested tivation. from CAPD effluent may be normal, the suppression Several authors found arguments that conform to of bactericidal activity has been reported (142). Pe- elevated serum interleukin- 1, tumor necrosis factor- terson et at. reported a suppressed chemilumines-

1546 Volume 3’ Number 9’ 1993 Vanholder and Pingoir

cence response and killing capacity towards Candlda tributed to the development of compensatory mech- albtcans in peritoneal macrophages from CAPD pa- anisms or to the gradual removal of toxic com- tients (143). Goldstein et at. concluded that perito- pound(s). The selection of patients Is bess probable, neal macrophages from CAPD patients were reba- because a prospective study by the authors of a pa- tively immature (144). tient group remaining intact for more than 1 .5 years It Is clear from studies evaluating the responsible also yielded results showing improvement of PMN mechanisms that peritoneal dialysis fluid has a neg- functional capacity over time (R. Vanholder et at., ative effect on multiple functions of the phagocytic unpublished results). Note that patients after long- cell. A major defect is the opsonic defIciency, espe- term dialysis show higher values of interleukin- 1 daily recognized in the effluent of CAPD fluid of secretion than not-yet-dialyzed uremic patients patients with a high incidence of infection (145-147). (1 3 1). Also, the levels of circulating soluble interleu- Additional factors may be the presence of uremic kin-2 receptors are positively correlated to the dura- toxins, high glucose concentrations, and fluid hyper- tion of hemodialysis (156). toniclty. These data indicate that one should be careful in DIsruptIon ofProtectlve Barriers. Changes in pro- the interpretation of study results on PMN and im- tective barriers may influence infection rate. Al- mune function in dialysis patients, because the com- though of no direct Influence on the immune system, position of the groups with respect to the time since these changes may increase the challenge of the the start of dialysis may affect the results. immune system by enhancing the load of bacteria Type of Renal Replacement Therapy. It has rarely entering the body. been considered whether host defense capacities of Dialysis necessitates the perforation of the protec- circulating blood are different, depending on the type tlve skin barrier by tubings, catheters, or needles; all of renal replacement therapy applied. The authors vascular access applications enhance the risk for found a similar degree of dysfunction of phagocyte infection (1 0, 1 48). The nadir in intradiabytic immune gbycolytic activity in the blood of patients on hemo- activity, if any, at Minute 15, comes almost immedi- dialysis and CAPD (R. Vanhobder et al. , unpublished ately after the insertion of dialysis needles or cathe- results). Transplanted patients had a better func- ters and the disruption of the skin barrier. tionab capacity than did dialyzed patients, although Bacterial contamination is a potential risk of dia- still below that of healthy controls. lyzer reprocessing when sterilization is inadequate (1 39, 1 40). Bacteremia may also result from the in- fusion of contaminated fluids, e.g. , heparin solutions (1 49). Another source may be infected dialysate THE RELATION OF DEFECTIVE FUNCTION TO transferred through dialyzers with a damaged mem- INFECTION brane surface (150). The final question that arises is whether these AffInIty of Bacterlafor Foreign Matertat. Polymer functional disturbances and the known susceptibll- surfaces may have increased affinity for bacteria ity to infection in uremia are interrelated. In isolated (1 5 1 , 1 52). In dialyzed patients, the risk of infection reports, it is demonstrated that uremic patients dis- is substantial for exogenous vascular access systems playing a more defective phagocyte function have a composed of foreign material that are applied over higher infection incidence than do those with a better longer time periods, e.g. , indwelling central vein functional status (46,49). catheters (1 48, 1 53) or graft material for the substi- It should be kept in mind that several studies refer tutlon of arterlovenous fistulas (154). to a deficient response towards Staph A (36,49,68). Time Since Start of Dialysis. It is possible that Staph A is one of the most frequent Invading micro- shifts in PMN function occur during the long-term organisms that causes infection in dialyzed uremic follow-up of dialyzed patients. The authors observed patients (1 57- 1 60). Many of those infections are the a severe suppression of phagocyte response during consequence of bacteremia occurring early during the first weeks after the start of dialysis (49). In both the dialysis procedure, whereas much data point to a a cross-sectional and a prospective study, this func- nadir in responsive capacity early after the start of tional capacity improved when dialysis treatment dialysis (Table 2). was prolonged (83). A better defense capacity after Uremia is characterized by a number of defects prolonged dialysis was also reported earlier by the (suppression of chemiluminescence production, hex- group of authors using the skin window test as an ose monophosphate shunt deficiency) that are simi- index of macrophage functional capacity (155). Hall- lar to those found in carriers of the homozygous form gren et at. reported a similar nadir In PMN uptake of of chronic granubomatous disease (CGD) (161 ,162), a immunoglobulin 0-coated particles during the first disease with a defect in the NADPH-oxidase system 4 months after the start of dialysis (23). (163) characterized, bike the uremic status, by a high The functional improvement over time may be at- incidence of staphylococcal Infections (164).

Journal of the American Society of Nephrology 1547 Phagocytosis and Uremia

PHARMACOLOGIC INTERVENTIONS WITH TABLE 5. Main causes of PMN cell dysfunction in POTENTIAL BENEFICIAL EFFECTS ON uremia-preventive and therapeutic measures PHAGOCYTOSIS Preventive and Cause , Several pharmacologic strategies are available to Therapeutic Measures Improve phagocytic function. EPO may be one of those. Whereas most antibiotics are suppressive or neutral in respect to immune function (165), the Dialyzer Bioincompati- Use of noncomplement-acti- bility vating dialyzer membranes third-generation cephabosporin cefodizime has a Uremic Toxicity Optimal solute elimination; clearly stimubatory effect in immune-depressed pursue elimination of both uremic patients (84, 1 66) and may be preferred to its hydrophylic and hydropho- alternatives. The use of stimulants of Immune func- bic compounds; better defi- tion, such as cytokines or interferon, might improve nition of responsible toxins immunologic function ( 1 67), but we are not aware of Improvement in PMN EPO; avoid immunosuppres- any data that disclose their effect on infection risk Function sive medication (e.g., some in uremia. The response towards hepatitis B vacci- antibiotics); Cefodizime; In- nation was improved in long-term hemodiabysis pa- terferon?; Cytokines? tients by the administration of recombinant human Iron Overload EPO; avoid unnecessary iron and blood transfusions: des- “y-interferon ( 1 68). Similar measures were favorable ferrioxamine in the correction of the phagocyte defect In CGD Infection Through Vas- Rigid asepsis; use of materials ( 1 69). The question is whether these measures would cular Access Sites with low affinity for bacteria not enhance bloincompatibibity reactions and trans- Chronic Infection Car- Preventive chronic antibiotics? plant rejection. The point is that circulating and in- riership tracellular bevels of cytokines already appear to be Increased in exactly those treatment modalities (e.g., cuprophane dialysis) in which decreased immune response has been suspected. Once the responsible toxin(s) for suppressing phag- In contrast, thymopentin, a biologically active pen- ocytic function is recognized, it might be suitable to tapeptide related to thymopoietin, had no influence develop specific adsorption systems to replace or to on the antibody response versus hepatitis B vacci- complete aspecific dialysis, e.g. , in infected patients. nation in hemodialysis patients (170). Until then, the only means by which to optimize phagocytic function in chronic dialysis patients in CONCLUSIONS relation to dialysis adequacy are to pursue a treat- The defect of PMN phagocytosis in uremia is mub- ment that is as efficient as possible, with the ebimi- tifactorial and is mainly related to uremic toxicity, nation of small water-soluble compounds as well as dialyzer membrane bloincompatibility, anemia, and larger and/or hydrophobic compounds. iron overload. The changes of PMN function are an Pharmacologic intervention with potentially posi- illustration of the interference between a biologic tive effects on phagocyte function (EPO, cefodizime, system, uremic toxicity, and the strategies that cytokines, interferon) has been discussed extensively should reduce this toxicity. Dialysis removes toxins above. but may exhibit its own toxicity because of bloincom- Iron and blood transfusions should be used with patibility. The main causes of dysfunction, together care. This can be realized more easily since the ad- with the possible preventive and therapeutic meas- vent of proper methods to estimate body iron stores ures, are summarized in Table 5. and since the availability of EPO. We strongly feel Our present knowledge necessitates extreme care that iron overload will become more and more excep- with certain dialyzer membrane types. The cupro- tiona! as EPO treatment becomes routine. Treatment phane membrane apparently affects PMN response of iron overload with desferrioxamine may induce both acutely and chronically. People starting on cu- immune dysfunction by itself, because desferriox- prophane dialysis show a progressive decline in PMN amine may act as an antioxidant. response in the following 2 to 4 wk (49). Recent Care should be taken to avoid the introduction of preliminary data confirm the enhanced infectious bacteria at the insertion sites of dialysis catheters. risk in patients treated by cuprophane dialysis (171). Indwelling catheters for bong-term use (either CAPD This has important implications for the treatment of or hemodialysis) should be developed in materials both acute and chronic renal failure and suggests with a low affinity for bacteria. that cuprophane should be discarded, even if dialysis Chronic risk patients for Infection might be treated

Is foreseen for only short periods, e.g. , in acute events with prophylactic long-term, bow-dose antibiotics, as or for transplant candidates. This is especially the has been proposed for COD (164). Antibiotic prophy- case in septicemic intensive care patients with ATN. laxis has successfully been administered to nasal

1548 Volume 3 Number 9 1993 Vanholder and Pingoir

carriers of Staph A (1 57), resulting in a decrease of 1 3. Tolkoff-Rubin NE, Rubin RH: Uremia and host Infection of access sites, skin, and soft tissue. defenses. N Engi J Med 1990:322:770-772. The main problem at the moment is that the fun- 14. Kaplowitz LG, Comstock JA, Landwehr DM, Dalton HP, Mayhall GO: A prospective study damental pathophyslobogic events are not exactly de- of infections in hemodialysis patients: patient fined. This is especially the case for the complement hygiene and other risk factors for infection. activation- and/or dialyzer incompatibility-rebated Infect Control Hosp Epidemiob 1988:9:534- events and for toxic retention factors. Further study 541. 15. Lewis SL, Van Epps DE, Chenoweth DE: Is necessary to allow a more specific preventive and Analysis of density changes and chemotactic therapeutic approach. receptors of leukocytes from chronic hemodi- Nevertheless, all of the factors summarized in abysis and peritoneab dialysis patients. Blood Table 5 contribute to the propensity of infection in Purif 1987:5:138-154. 1 6. Wardle EN, Williams R: Pobymorph leukocyte the continuously growing population with renal fail- function in uremia and jaundice. Acta Haema- ure. Taking into account and counteracting these tob 1980;64:157-164. factors should necessarily decrease the number, se- 17. Wardle EN: Chemibuminescence and superox- verity, and mortality of these infections, improving ide anions generated by phagocytes in uraemia life quality and survival of end-stage renal patients. [letter]. Nephron 1985;40:379. 1 8. Greene WH, Ray C, Mauer SM, Quie PG. The effect of hemodiabysis on neutrophil chemotac- REFERENCES tic responsiveness. J Lab Clin Med l976;88: 971-974.

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Journal of the American Society of Nephrology 1549 Phagocyfosis and Uremia

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66:195-204. 1 2 1 . Floege J, Granolleras C, Bingel M, et at. : /32- 1 06. Schaefer RM, Paczek L, Heidiland A: Improved Microgbobulin kinetics during haemodialysis immunoglobulin production by B-lymphocytes and haemofiltration. Nephrob Dial Transplant from uremic patients treated with rEPO [Ab- 1 987; 1:223-228. stract]. Nephrol Dial Transplant 1990;5:742. 122. Lonnemann G, Bingel M, Floege J, Koch KM, 107. Sennesael JJ, Van der Niepen P, Verbeelen Shaldon S, Dinarello CA: Detection of endo- DL: Treatment with recombinant erythropoie- toxin-like interleukin- 1 inducIng activity dur- tin Increases antibody titers after hepatitis B Ing in vitro dialysis. Kidney Int 1988:33:29- vaccination In dialysis patients. Kidney Int 3. 1991:40:121-128. 1 23. Luger A, Kovarik J, Stummvoll H, Urbanska 108. Collart FE, Dratwa M, Wittek M, Wens R: Ef- A, Luger TA: Blood-membrane interaction In fects of recombinant human erythropoietin on hemodlabysis beads to increased cytokine pro- T lymphocyte subsets in hemodiabysis patients. duction. Kidney Int 1987:32:84-88. Trans Am Soc ArtIf Intern Organs 1990:36: 1 24. Haeffner-Cavaillon N, Cavaillon JM, Cian- M2 1 9-M223. cioni C, Bade F, Delons S, Kazatchkine MD: 109. Kalechman Y, Gafter U, Sredni B, Levi J: In vivo induction of interleukln- 1 durIng he- Enhanced cytokine production by erythropoie- modialysis. Kidney Int 1989:35:1212-1218. tin [Abstract]. J Am Soc Nephrol 1990; 1:400. 125. Schindler R, Lonnemann G, Shaldon 5, Koch 110. Briggs WA, Pedersen MM, Mahajan SK, Sillix KM, Dinarello CA. Transcription, not synthe- DH, Prasad AS, McDonald FD: Lymphocyte sis of interleukin- 1 and tumor necrosis factor and granulocyte function in zinc-treated and by complement. Kidney Int 1990:37:85-93. zinc-deficient hemodiabysis patients. Kidney 126. Bingel M, Lonnemann G, Koch KM, Dinarello

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CA, Shaldon 5: Plasma interleukin- 1 activity Staphylococcus aureus peritonitis in continu- during hemodialysis: The influence of dialysis ous ambulatory peritoneal dialysis. Am J Med membranes. Nephron 1 988;50:273-276. 1 984;76: 1035-1040. 1 27. Lonnemann G, Koch KM, Shaldon 5, Dinar- 143. Peterson PK, Lee D, Suh HJ, Devalon M, Nd- do CA: Studies on the ability of hemodialysis son RD, Keane WF: Intracellular survival of membranes to induce, bind, and clear human candida albicans in peritoneab macrophages

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1 3 1 . Herbelin A, Urena P, Nguyen AT, Zingraff J, MIcnobiol 1984:20:199-203. Descamps-Latscha B: Influence of first and 147. Keane WF, Comty CM, Verbrugh HA, Peter- long-term dialysis on uraemla-associated in- son PK: Opsonic deficiency of penitoneal di- creased basal production of interleukin- 1 and alysis effluent in continuous ambulatory pert- tumor necrosis factor alpha by circulating toneab dialysis. Kidney Int !984;25:539-543. monocytes. Nephrol Dial Transplant 1991:6: 148. Vanholder R, Hoenich N, Ringoir 5: MorbIdity 349-357. and mortality of central venous catheter he- 132. Beaurain G, Naret C, Marcon L, et aL: In vivo modialysis: A review of 1 0 years’ experience. T cell preactivation in chronic hemodiabyzed Nephnon 1987:7:274-279. and non-hemodlabyzed patients. Kidney Int 1 49. Kantor RJ, Carson LA, Graham DR, Petersen 1989:36:636-644. NJ, Favero MS: Outbreak of pyrogenic reac- 133. Ghysen J, Dc Plaen JF, van Ypersele de tions at a dialysis center. Association with in- Strihou C: The effect of membrane character- fusion of heparinlzed saline solution. Am J Med istics on tumour necrosis factor kinetics during 1983:74:449-456. hemodlalysls. Nephrol Dial Transplant 1990; 1 50. Bommer J, Ritz E: Water quality-a neglected 5:270-274. problem in hemodlabysis. Nephron 1 98746: 1- 1 34. Schleiffenbaum B, Fehr J: The tumor necrosis 6.

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Journal of the American Society of Nephrology 1553 Phagocyfosis and Uremia

1 58. Nsouli KA, Lazarus JM, Schoenbaum SC, 1982:72:711-716. Gottlieb MN, Lowrie EG, Schocair M: Bacter- 166. Vanholder R, Darosa E, Van Landschoot N, emic infection in hemodiabysis. Arch Intern Waterloos MA, Ringoir S: Effect of antibiotics Med 1979:139:1255-1258. on phagocytosis-associated respiratory burst 159. Quarles LD, Rutski EA, Rostand SG: Staphy- activity in uraemic patients on chronic hae- bococcus aureus bacteremia in patients on modiabysis: A comparison of cefodizime and chronic hemodlalysis. Am J Kidney Dis 1985; cotnimoxazobe. Nephron 1993:63:65-72. 6:412-419. 167. Cheesman SH, Rubin RH, Stewart JA, et at.: 1 60. Dobkin JF, Miller MH, Steigbigel NH: Septi- Controlled clinical trial of prophylatic human- cemia in patients on chronic hemodialysis. Ann leukocyte interferon in transplantation. N Engb Intern Med 1978;88:28-33. J Med 1979:300:1346-1349.

1 6 1 . Baehner RI, Nathan DC, Karnovsky ML: Con- 1 68. Quiroga JA, Castillo I, Porres JC, et at. : Re- rection of metabolic deficiencies in the beuko- combinant gamma-interferon as adjuvant to cytes of patients with chronic granubomatous hepatitis B vaccine in hemodiabysis patients. disease. J Clin Invest 1970:49:865-870. Hepatobogy 1 990; 12:661-663. 162. Repine JE, White JG, Clawson C, Holmes BM: 169. Ezekowitz RAB, Dinauer MC, Jaffe HS, Orkin Effects of phorbol myristate acetate on the me- SH, Newburger PE: Partial correction of the tabolism and ubtrastructure of neutrophils In phagocyte defect in patients with X-binked chronic granubomatous disease. J Clin Invest chronic granubomatous disease by subcuta- 1974:54:83-90. neous interferon gamma. N Engb J Med 1988; 163. Clark RA, Malech HL, Gallin JI, et at.: Genetic 319: 146-151. variants of chronic granubomatous disease: 170. Dumann H, Meuer SC, Renschin G, KOhler H: Prevalence of deficiencies of two cytosolic com- Influence of thymopentin on antibody re- ponents of the NADPH oxidase system. N Engb sponse, and monocyte and T cell function in J Med 1989:321:647-652. hemodiabysis patients who fail to respond to 164. Gallin JI, Buescher ES, Seigman BE, Nath J, hepatitis B vaccination. Nephron 1 990;55: Gaither T, Katz P: Recent advances in chronic 136-140. granubomatous disease. Ann Intern Med 171. Levin NW, Zasuwa G, Dumler F: Effect of ‘1983:99:657-674. membrane type on causes of death in hemodi- 165. Hauser WE, Remington JS: Effects of antibi- alysis patients [Abstract]. J Am Soc Nephrob otics on the immune response. Am J Med 1991:2:335.

1554 Volume 3’ Number 9’ 1993