Rosa Jofré,
Patrocinio Rodriguez-Benitez,
Juan M. López-Gómez and
Rafael Pérez-Garcia
Servicio de Nefrología, Hospital Gregorio Marañón, Madrid, Spain
Address correspondence to: Dr. Juan M. López Gómez, Dialysis Unit, Hospital Gregorio Marañón, Dr. Esquerdo 46, 28007 Madrid, Spain. Phone: +34-91-426-5140; Fax: +34-91-586-8315; E-mail: juanmlopez{at}senefro.org
Mortality is markedly elevated in hemodialysis (HD) patients.Between 30 and 50% of prevalent patients have elevated serumlevels of inflammatory markers such as C-reactive protein andIL-6. The presence of inflammation, chronic or episodic, hasbeen found to be associated with increased mortality risk. Thecauses of inflammation are multifactorial and include patient-relatedfactors, such as underlying disease, comorbidity, oxidativestress, infections, obesity, and genetic or immunologic factors,or on the other side, HD-related factors, mainly depending onthe membrane biocompatibility and dialysate quality. The adequateknowledge of these causes and their prevention or treatmentif possible may contribute to improving the inflammatory stateof patients who are on HD and possibly their mortality.
Between 30 and 50% of prevalent patients who are on hemodialysis(HD) have elevated serum levels of inflammatory markers. Insome patients, this elevation is chronic, and in some, it isintermittent and generally is associated with breakthrough processes.Furthermore, on many occasions, HD sessions trigger inflammationin a way that is not always identifiable with the conventionalmarkers. Inflammatory markers are powerful predictors of mortalityafter adjustment for other risk factors (1–7). Inflammationalso is responsible for other mortality risk factors, such asanemia, malnutrition, vascular disease, and left ventricularhypertrophy. For lowering the high morbidity/mortality ratein patients who are on HD, inflammation must be tackled. How?First, by identifying the causes, then preventing or treatingthem. This review examines the causes of inflammation in HD(Table 1) and how to approach them.
The gold standard among the microinflammatory markers in HDis C-reactive protein (CRP) (1–5). It is easy to measureand a good predictor of short-term (1 to 2 yr) mortality andhas become a routine test in HD units to warn of inflammation.IL-6 probably is more related to mortality and is associatedwith more causes of inflammation than CRP (6,7); however, itis more difficult to measure, and it is of little use in clinicalpractice. All acute- phase reactants are inflammation markers.At the present, new markers that are more sensitive to specificsituations are being sought, such as procalcitonin (8).
Underlying disease per se can result in a chronic inflammatorystate, as in the cases of autoimmune diseases and amyloidosis.Moreover, comorbidity, mainly as a result of ischemic cardiopathy,peripheral vascular disease, or diabetes, can be a risk factorfor inflammation and oxidative stress (9,10).
Among the nonconventional cardiovascular risk factors, oxidativestress and vascular calcification gradually are gaining importance.Glycoxidation products and advanced oxidation protein productsshow a close relationship with inflammatory markers such asCRP and IL-6 (11–13). Therefore, the end products of theseprocesses could act as inflammatory markers.
The generalized use of intravenous iron to treat anemia in HDunits is noteworthy. Intravenous iron administration may releasefree iron that could react with hydrogen peroxide and generatefree radicals. This results in an increase in advanced oxidationprotein product levels, which are related to CRP levels (14),and in common carotid artery intima-media thickness (15). Therefore,treatment with intravenous iron could be considered as an additionalinflammatory factor, as well as a risk factor for atherosclerosisin HD patients.
Vascular calcification is more frequent and more severe in HDpatients than in the general population. Both artery intimaland artery medial calcifications occur and constitute a significantmorbidity/mortality marker that is associated with coronaryatherosclerosis and arterial stiffness. Its cause is multifactorial.On the one hand, mineral metabolism alterations plays an importantrole, especially when there is an increase in serum phosphateor calcium-phosphorus product (16,17). On the other hand, thereare certain vascular calcification inhibitors, such as fetuin-Aand matrix Gla protein, that are inversely correlated with inflammationmarkers (18–20) and with coronary calcifications (21).
Several studies have demonstrated that infection by some microorganismsmay participate in the development of inflammation and vasculardamage in the general population (22–24). Infection withChlamydia pneumoniae or Helicobacter pylori and periodontaldisease are the most frequent. In HD patients, the presenceof IgG or IgA antibodies to C. pneumoniae is associated witha greater risk for cardiovascular events, and mortality is significantlyhigher (25,26). Furthermore, the carotid artery intima-mediathickness has been reported to be greater in patients with IgAantibodies compared with patients without antibodies (27), andthe number of atherosclerotic plaques is related to the titerof IgG antibodies in smokers but there is no such relationshipin nonsmokers (28). In contrast, other authors found no differencesin atherosclerosis scores between patients with and withoutantibodies (29), and the association with atherosclerotic diseasewas found to be very weak (30). Therefore, the relationshipbetween infection with C. pneumoniae and atherosclerosis hasnot been established clearly. There is no clear connection betweeninflammation and H. pylori infection in HD patients either,as recently demonstrated (30). Consequently, further studiesto establish the possible relationship between these infectionsand atherosclerosis are needed.
Periodontal disease is frequent in HD patients and is relatedto age, diabetes, smoking, HD duration, malnutrition, and inflammation(31). IgG antibodies to some periodontal bacilli are relatedto higher CRP levels (32). Moreover, CRP levels and erythrocytesedimentation rate significantly decrease after periodontaltreatment (33). Periodontitis, therefore, is a frequent occultsource of chronic inflammation that could contribute to theatherosclerosis process and resistance to erythropoietic agents.
The prevalence of tuberculosis, mainly extrapulmonary, is increasedamong dialysis patients as a consequence of the depression ofcellular immunity (34). Although the relationship with the inflammatorystate has not been evaluated yet, it probably can be a contributoryfactor.
The type of HD vascular access is of prime importance for theevolution of HD patients. Patients with an indwelling catheterhave higher comorbidity and a poorer survival on HD (35). However,its relationship with the inflammatory state has not been assessedsufficiently. It was demonstrated recently that patients withan indwelling tunnelled catheter have higher CRP levels andgreater resistance to erythropoietin than those with arteriovenousgrafts (AVG) or an arteriovenous fistula, who have the lowestvalues (36). Furthermore, patients with clotted AVG have elevatedCRP, advanced glycation end products, and endothelial adhesionmolecule levels (37–39). This demonstrates that clottedvascular access may play an important role in the inflammatoryprocess. The elimination of these clotted grafts may resultin a significant improvement in inflammation parameters (37).These findings suggest the need to monitor inflammation markersin patients with old clotted AVG, so they must be removed whenin doubt.
Genetic factors such as single-nucleotide polymorphisms mayinfluence significantly the immune response, the levels of inflammatorymarkers, and body composition, as well as the prevalence ofvascular calcification in patients with chronic renal failure.Although genetic variations in the TNF-–308 and IL-10–1082single-nucleotide polymorphisms seem to be associated consistentlywith adverse clinical outcome in patients with ESRD, the resultsregarding genetic variations in the IL-6 gene have been conflicting(40).
Returning to HD after kidney transplant failure is becomingmore frequent, especially in countries with high transplantationrates. It is standard practice to leave the nonfunctioning kidneytransplant in place, even with low dosages of immunosuppressors,to maintain a minimum residual function. However, recent studieshave demonstrated that, at least in some cases, the nonfunctioningkidney graft could act as a potent mediator of inflammationand erythropoietin resistance. In some cases, this situationmay be completely asymptomatic but with the only evidence ofelevated inflammatory markers. Only surgical removal of thegraft can reverse the inflammatory state in these patients (41).
This is a rare complication in peritoneal dialysis patients,and it means that they have to be placed on HD. These patientshave elevated levels of biochemical inflammatory markers anda very poor prognosis (42). The best treatment is prophylaxis,with early detection of the disease in the peritoneal effluentin high-solute transporters. This disease currently is treatedwith pentoxifylline or tamoxifen with encouraging results (43,44).
Although relative erythropoietin deficiency is a major factorin the anemia that is associated with chronic kidney disease,the chronic inflammatory state of uremic patients is an importantassociated factor. Stimulated mononuclear cells release numerousinflammatory cytokines such as IL-1, IL-6, TNF-, and IFN- thatmay contribute to erythropoiesis suppression. Although the exactmechanism for this effect is not yet clear, the induction ofapoptosis in erythroid progenitor cells is an important factor(45). Then, anemia mainly is a consequence of the inflammatorystate instead of a cause. However, in recent years, hepcidinhas been implicated as a complementary mechanism. This antimicrobialpeptide, synthesized in the liver, inhibits intestinal ironabsorption and is released into the circulation from the macrophages.It is stimulated by iron overload, hypoxia, and inflammation.The transcription of hepcidin is induced by IL-6 (46,47). Inview of all this, hepcidin may be the link between inflammationand anemia (48,49), acting as an indicator of functional irondeficiency (50).
Patients who are on HD and have a history of heart failure mayhave higher CRP levels (51). Furthermore, left ventricular hypertrophyhas been associated with chronic inflammation states and oxidativestress (50,52–54). Recent studies have demonstrated thathigh-sensitivity CRP levels correlate positively with left ventriclemass and negatively with ejection fraction, and the multivariantanalysis revealed that the chronic inflammatory state may beconsidered an independent risk factor for the development ofcardiac hypertrophy and ventricular dysfunction in HD patients(52). However, whether control of the inflammatory state isaccompanied by an improvement in cardiac size and function isnot so clear.
Obesity is part of the inverse epidemiology described for HDpatients. In contrast to what occurs in the general population,HD patients with lower body mass index have a greater risk formortality (55,56), and patients with excess weight have improvedsurvival (57,58). Loss of adipose tissue may be the result ofan inflammatory state, in which the release of proinflammatorycytokines may give rise to anorexia, predisposition to malnutrition,and weight loss (59–61). However, adipocytes are an importantsource of proinflammatory cytokines such as IL-6 and TNF-, usuallyproduced by monocytes, but they also are capable of producingother, more specific proteins, such as leptin and adiponectin.The latter is produced in a larger quantity than leptin andis inversely related with body mass index and resistance toinsulin. Therefore, low adiponectin levels are associated withinflammatory markers and act as a predictor of cardiovascularevents and mortality (61,62).
HD technique may contribute to maintaining the inflammatorystate in many HD patients. Several theoretical mechanisms maybe implicated: (1) The retention or nonelimination of proinflammatorymolecules usually eliminated by the kidney; (2) potentiationof oxidative stress; and (3) stimulation of antigen-presentingcells, mainly monocytes, either directly or through contaminants.These cells in HD patients usually are preactivated, expressingCD-14 and CD-16 phenotypes in a greater proportion than in thegeneral population (63).
Among the molecules that may be eliminated by convective transportusing hemodiafiltration techniques are complement components(64), asymmetric dimethylarginine (65), and cytokines (66).It would be through this mechanism, by elimination of proinflammatorysubstances, that the preservation of renal function correlatesinversely with inflammatory markers (67). HD regimens with greaterdepuration of all kinds of substances, such as nocturnal HD,also would have this effect (68). Techniques with a high middlemolecule clearance, such as on-line hemodiafiltration, may contributeto decreasing inflammation in HD patients. Some protein-leakingdialyzers can improve chronic inflammation in HD patients (69).
Oxidative stress forms part of the inflammation mechanism. HDoften is associated with an oxidative imbalance, in which oxidationof different lipids and proteins are predominant (68). Lossof some antioxidants, such as carnitine, during HD may contributeto this disorder (70). There is a clear interconnection betweeninflammation and oxidative stress in HD (71,72).
Several current HD components may provoke inflammation in patients.There is an intermittent, multiple stimulation during each HDsession. Among these components are acetate, pyrogenic substances,and activation of the complement mainly as a result of dialysismembranes.
Exposure to 2 to 4 mmol/L acetate, which is contained in thebicarbonate dialysate, produces in many patients pathologicincreases in acetatemia that could initiate inflammation orintolerance to the dialysis technique (73–75). Techniquessuch as acetate-free biofiltration or acetate-free dialysatecould prevent this increase (74,75).
It has been demonstrated that pyrogenic substances are transferredto the blood through the dialysis membrane (Table 2). This dependsnot only on the amount of pyrogenic substances but also on itsquality, and although this transfer occurs mainly by backfiltration(76), low molecular weight substances also may enter by backdiffusion.Endotoxins can cross any type of HD membrane; however, it hasbeen reported that this occurs more easily with highly permeablemembranes, in which backfiltration is more common. Reactionsto pyrogens are much more frequent with high-permeability membranesthan with low-permeability ones (77). Dialysis membranes thatare capable of absorbing/retaining endotoxins, such as polysulfone,polyamide, posidine, and polyethersulfone, may decrease endotoxintransfer (78). Once in the blood, endotoxins are capable ofactivating monocytes and inducing cytokine release (79). Thismonocyte activation is not linear, and several factors interveneto increase or decrease cytokine production. It is a multifactorialprocess that is influenced by the type and the level of toxin,the type of membrane, various plasma factors, and the concomitantaction of other monocyte activation and inactivation systems(79). It is known that the presence of proteins or whole bloodis a potentiating factor in this activation process. Currently,at least two proteins are known: LPS-binding protein, a transporter,and a bactericidal permeability-increasing protein. These twoproteins are necessary for this process to be carried out (80).The concomitant presence of other stimuli or signs, such asthe activation of the complement, is very important. Finally,to make this process even more complex, some cytokine downregulatorscome into play, such as IL-10 (81). All of the above emphasizesthe importance of the patient’s nutritional and immunesystem status in this field and explains the different patientresponses to the same HD technique.
Table 2. Bacterium-derived pyrogens and their detection
The dialysis membrane and its capacity to stimulate monocytes,either directly or through activation of the complement, increasingcytokine production, is another specific inflammatory factorin HD patients. The behavior of HD membranes varies greatly,and some of them clearly are more biocompatible than others.
Monocytes, as effector cells, respond to the various stimuliand produce a chronic release of cytokines. Knowing that monocytesexpress the endotoxin receptor antigen CD14 (82) confirms thatendotoxins are their primary stimuli. Nevertheless, for cytokinesto be secreted, other concomitant stimuli are needed, such asthe complement CD16 (82).
To prevent this inflammatory state, several actions must betaken: prevent and treat bacteria contamination of the dialysate;eliminate endotoxins from the dialysate by using suitable filtersin the HD equipment hydraulic circuit; prevent or treat chronicinfections in HD patients; use ultrapure dialysate; use biocompatiblematerials to prevent concomitant stimuli of the monocytes; andeliminate acetate, even low levels, in the dialysate. Maintaininga good nutritional status in HD patients may contribute to animproved immune response. Acting on LPS-binding protein andbactericidal permeability-increasing protein or on monocyteor cytokine receptors still is in the preliminary stages. Theelimination of some of these stimuli could decrease the inflammatoryresponse in patients who are on HD and are identified by plasmalevels of inflammatory markers (8).
HD patients with inflammation have a poorer prognosis. Biochemicalinflammatory markers help us to identify these patients. Inmost cases, the cause of inflammation can be determined throughclinical investigation, and some of them may be eliminated orcorrected. The prevention and the treatment of inflammatorysyndrome is of high priority in patients who are on HD.
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Abstract
Introduction
–308 and IL-10–1082 single-nucleotide polymorphisms seem to be associated consistently with adverse clinical outcome in patients with ESRD, the results regarding genetic variations in the IL-6 gene have been conflicting (40). 
that may contribute to erythropoiesis suppression. Although the exact mechanism for this effect is not yet clear, the induction of apoptosis in erythroid progenitor cells is an important factor (45). Then, anemia mainly is a consequence of the inflammatory state instead of a cause. However, in recent years, hepcidin has been implicated as a complementary mechanism. This antimicrobial peptide, synthesized in the liver, inhibits intestinal iron absorption and is released into the circulation from the macrophages. It is stimulated by iron overload, hypoxia, and inflammation. The transcription of hepcidin is induced by IL-6 (46,47). In view of all this, hepcidin may be the link between inflammation and anemia (48,49), acting as an indicator of functional iron deficiency (50). 
