Immune dysregulation

Immune dysregulationIntroduction:

Chronic uraemia has long been known to be associated with an immune deficiency since, as early as 1957, Damin et al had observed the abnormally prolonged tolerance of skin grafts in patients with end-stage renal failure. Over the past two decades, advances in knowledge of immune cells and mediators have shown that renal failure actually leads to complex immune dysregulation, with immunodeficiency and immunoactivation coexisting.

This duality that affects all cells of immunity, both specific (T and B lymphocytes) and nonspecific (monocytes and polynuclear neutrophils), also has its clinical expression.

In fact, immunodeficiency largely explains the increased susceptibility of hemodialysis patients to infections – which are the second most common cause of hemodialysis deaths – their anergy in delayed hypersensitivity reactions, their poor responses to influenza viruses and especially hepatitis B virus (HBV), and finally the abnormal frequency of autoimmune diseases and tumors.

Immunoactivation is, for its part, largely implicated in complications of predominantly inflammatory hemodialysis such as amyloid arthropathy b 2-microglobulin ( b 2m) and accelerated atheroma which, because of cardiovascular events that it involves, strike heavily the mortality of these patients.

However, studies comparing cohorts of non-dialysis uremic patients with various stages of renal failure and dialysis patients have revealed that this immune dysregulation is present from the onset of renal failure, increases steadily with progression, and hemodialysis, which adds its own pro-inflammatory component resulting from the passage of blood into extracorporeal dialysis circuits. Indeed, the bioincompatibility of the membrane and the impurity of the dialysate trigger cell activation including neutrophils – source of powerful oxidants and proteases – and monocytes producing proinflammatory cytokines.

The deleterious effects of oxidants (grouped under the term oxidative stress) are favored by the antioxidant deficiency inherent in uremia and aggravated by hemodialysis. This oxidative stress further enhances immune dysregulation via the formation of products derived from protein oxidation or advanced oxidation protein products (AOPPs) that accumulate during the progression of renal failure and behave as powerful mediators of inflammation and in particular monocytic activation. Similarly, the imbalance between monocytic cytokines and their inhibitors inherent in uremia and increased by hemodialysis promotes the pro-inflammatory effects of these cytokines that are the link between malnutrition, inflammation and atherosclerosis.

Malnutrition and iron overload are all factors that, together with uremic toxins, contribute to worsening the immune dysregulation of hemodialysis patients.

This chapter presents the cellular actors and mediators of the immune dysregulation associated with chronic renal insufficiency, then the related complications, focusing for each of these parties on this duality between immunodeficiency and immunoactivation which characterizes it and measures that could reduce the morbidity and mortality associated with it.

Actors and Cellular Mediators of Immune Dysregulation:

LYMPHOCYTES T:

The origin of the immunodeficiency associated with chronic renal insufficiency has long been attributed to the T lymphocyte although, like other types of immunodeficiency, including Acquired Immunodeficiency Syndrome (AIDS), there is no imbalance in the ratio between enhancer or helper T cells (CD4 + ) and cytotoxic / suppressor T lymphocytes (CD8 + ) is not observed in uremic patients.

Deficit of T lymphocytes:

It is objectified by the decrease in their proliferation capacity in response to most mitogens, alloantigens and anti-CD3.More recently, a decrease in the regulation capacity (down regulation) of the T cell receptor in the presence of uremic plasma has been observed.

Of the other cells that may contribute to this T cell deficiency, monocytes are good candidates and abnormalities in their antigen presentation and costimulatory capacity via B7 / CD28 have been described.

Finally, most studies have shown that the deficit of T cells is increased in the presence of autologous plasma and the demonstration that certain uremic toxins have T lymphocytes as the preferred target has been provided.

Activation of T lymphocytes:

It has been demonstrated in uremic patients by increasing the number of cells expressing the interleukin (IL) receptor (IL2R or CD25), increased membrane expression, and increased plasma levels of the soluble form. of this receptor in relation to the biocompatibility of the membrane. Our study of a large cohort of uremic (non-dialysis and dialysis) patients showed that both membrane expression and plasma CD25-soluble levels were elevated early in renal failure and increased steadily with progression, suggesting that Uremia alone is sufficient to induce T lymphocyte activation, which is still greater in hemodialysis patients. Very recently, Meier et al reported an increase in the expression of early markers of uremia-associated T cell activation (CD69) and increased by hemodialysis, in close relationship with markers of apoptosis (annexin V , CD95 [fas] and fragmentation of deoxyribonucleic acid [DNA]), thus suggesting the role of this essential cellular function in the dysregulation of the immune system of these patients.

Lymphocyte cytokines:

Whatever its mechanism, this dysregulation of T lymphocytes is associated with a sharp decrease in their ability to produce IL2 and interferon (INF) c in their protein form, along with the absence of induction. of the IL2 gene and the clear decrease in the expression of the messenger ribonucleic acid (RNA) of INF c . The hypothesis of an increased consumption of IL2 by its receptor has been proposed since 1986 by Chatenoud et al.

The existence of a dichotomy in the population of Th-lymphocytes (T helper) described in the 1980s on the basis of their production of cytokines encourages us to review their role in the immune dysregulation of patients with chronic renal failure. Let us recall here briefly that according to this concept, IL2 and INF c- producing Th1 lymphocytes are involved in cell-mediated immunity (autoimmunity, transplant rejection and delayed hypersensitivity) whereas Th2 lymphocytes, which produce IL4, IL5 and IL10 participate in humoral immunity (non-specific organ auto-immunity, allergy, parasite defense and antiviral resistance).

The Th1 / Th2 equilibrium is dependent on the Th1-produced cIN, which inhibits the proliferation of Th2 cells and Th2-produced Th1, which inhibits Th1 function. Finally, IL12 produced by activated monocytes promotes the expansion of Th1.

However, Th1 / Th2 equilibrium studies conducted to date in uremic patients have resulted in seemingly discordant results. Indeed, some authors have concluded a polarization of T cells towards the Th2 type, observation to be compared to the increased basal production of IL10 reported by Brunet et al. Conversely, other authors have concluded that Th1 lymphocytes, linked to an excess of IL-12 from activated monocytes, predominate in comparison with the relationship between non-response to HBV vaccine and the decrease in ability to produce IL10 defined by genotyping.

LYMPHOCYTES B:

Deficit of B cells:

It could explain the decrease in antibody responses and especially vaccine responses in patients with chronic renal failure. In fact, responses to vaccines against non-T cell-dependent antigens, such as tetanus toxoid vaccine, are lower and antibody levels decline more rapidly in these patients than in normal subjects. However, the response deficit is more pronounced with respect to T-dependent antigens, notably pneumococcus, influenza virus and especially HBV suggesting a T / B cooperation anomaly rather than intrinsic B cell deficiency. most in vitro studies showing a defect of B-cell responses to mitogens have used T-dependent mitogens. Finally, the interindividual variability of hemodialysis anti-HBV antibody responses does not appear to be a B-lymphocyte deficiency as it appeared to be subject to genetic determinism involving the expression of major histocompatibility complex genes. (human leukocyte antigen [HLA] A1-B8, DR3 and DR2) which themselves play a key role in the presentation of peptide antigens to T cells.

Activation of B lymphocytes:

It is not reflected by the circulating levels of immunoglobulins (Ig) (IgG or IgM) that are usually in the range of normal in patients with chronic renal failure. On the other hand, it could be objectified by the presence of high plasma levels of the soluble form of the low affinity receptor for IgE (Fc e IIR or CD23) in these patients. Like soluble CD25, soluble CD23 is present at a high rate in the early stage of renal failure, increases with progression and reaches an even higher level in hemodialysis patients, culminating at the end of the session. This observation, together with results showing that CD23 enhances T-cell activation, suggests the participation of this multifunctional molecule in the unexplained process of T-cell activation in uremic patients.

MONOCYTES:

Monocytic deficit:

A monocytic deficit may play a role in T lymphocyte deficiency. Indirect arguments in favor of this hypothesis have been reported in the literature. Thus, Ruiz et al have shown that the internalisation of opsonized particles by monocytes, via their receptor for the Fc fragment of IgG, is greatly diminished in hemodialysis patients, suggesting that their capacity to present the antigen is also impaired. The more recent demonstration of a deficiency of B7-2 expression (CD89) involved in T cell costimulation during antigen presentation, together with observations of the correction of T cell response deficiency observed in in vitro by the addition of monocytes from normal subjects, brings more direct arguments in favor of this essential function of monocytes in the immune response.

Monocytic activation:

Monocytic activation in uremic patients is much better founded. It is based on the high plasma level of neopterin (monocyte activation marker), the high proportion of monocytes expressing CD14 and CD16 (Fc c RIII), the high plasma concentrations of the soluble form of CD14 and, above all, on the functional criterion. increased constitutive production of monocytic cytokines (IL1, IL6 and TNF a .

Monocytic cytokines:

As early as 1983, Henderson et al proposed the hypothesis incriminating IL1, which is responsible for most of the acute and chronic inflammatory manifestations associated with hemodialysis, which reflect the systemic effects and privileged target organs of IL1. According to this hypothesis, the contact between the blood and the dialysis membrane, resulting in the activation of the complement which leads to the generation of biologically active factors (C5a and C3a) and the diffusion of dialysate elements (acetate buffer and endotoxin) induce activation of monocytes and their synthesis of IL1.

Since then, many groups have reported that hemodialysis patients have elevated plasma levels not only of IL1b, but also of TNFα and IL6, whose cell sources and target organs are common with those of IL1. . High intramonocyte IL1 levels have also been reported in these patients, and subsequent studies have demonstrated that passage of blood through dialysis circuits induces the expression of genes encoding these cytokines in circulating monocytes.

Non-dialyzed uremic patients also have elevated plasma levels of TNFα and IL6 but not IL1b. However, intramonocyte IL1 concentration, in the absence of any exogenous stimulation, is increased, suggesting a constitutive synthesis of IL1 in these patients. Finally, the role of iterative hemodialysis in amplifying the passage of IL1 from its intracellular form to its secreted form strongly suggests that this cytokine may be responsible for the manifestations that are observed exclusively in long-term hemodialysis patients. .

However, if certain symptoms that occur during or immediately following dialysis sessions such as fever, hypotension, exacerbation of arthralgia, drowsiness and anorexia, can be attributed to the presence of high plasma levels of pro-inflammatory cytokines, it is clear that, overall, these clinical manifestations remain moderate compared with those observed during acute systemic reactions, such as septic shock. This could be explained by the fact that the plasma concentrations of these cytokines during acute systemic infections are generally much higher than those found in hemodialysis patients. It is also likely that, in the latter, the continued presence of these cytokines leads to a decrease in the reactivity of their target cells.

The potentially deleterious effects of pro-inflammatory cytokines are partly counterbalanced by their specific natural inhibitors, synthesized concomitantly in response to exogenous stimuli. This is the case of the soluble forms of TNF receptors (TNFsR55 and TNFsR75) which, binding to TNF, prevent its interaction with its target cells, as well as the IL1 receptor antagonist (IL1 Ra) which binds competitively to the IL1 receptor without inducing transduction of the activation signal. The study of these inhibitors in the plasma of uremic patients revealed high concentrations of TNF-sR55 and TNF-sR75 at the stage of early renal failure, which increase with the deterioration of renal function, are even higher in hemodialysis patients and increase significantly during dialysis sessions. The level of IL1Ra, already high in the early stage of renal failure, also increases with the progression of uremia but is not higher in hemodialysis patients and decreases even at the end of the session because IL1 Ra diffuses through the membranes.

NEUTROPHIL POLYNUCLEAR:

Deficiency of neutrophils:

The deficit of neutrophils has been suggested since the advent of hemodialysis by observing their quasi-disappearance of circulation in the first few minutes following the branching of the artificial kidney. This neutropenia was very early attributed to the formation of activated complement products (C3a and C5a) in contact with cellulosic membranes (in particular cuprophane), which favor the sequestration of these cells in the lung. It has become much more rare and moderate since the advent of biocompatible synthetic membranes.

The functional deficit of neutrophils is objectified by a decrease in their phagocytosis and bactericidal capacities, both in dialysis patients and, to a lesser degree, in non-dialysis patients. It can be explained in part by the depletion of response capacity via opsonin receptors. However, malnutrition, anemia, hyperparathyroidism are all factors that, together with uremic toxins can contribute to the functional deficit of neutrophils.

Activation of neutrophils:

The activation of neutrophils during the passage of blood in dialysis circuits is well established. It is mainly objectified by the massive generation of oxidants, including the superoxide anion (O 2- ) and its derivatives (H 2 O 2 , OH and 12 , grouped under the generic term of reactive forms of oxygen ), which results from the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the chlorinated oxidants generated by myeloperoxidase. Like neutropenia, the production of oxidants is closely related to complement activation and as such is used as a cellular functional criterion for the biocompatibility of dialysis membranes. The activation of neutrophils also leads to their degranulation with massive release of proteases and the increased expression of their adhesion molecules, thus promoting their pulmonary sequestration.

Oxidative stress:

The conditions of onset of oxidative stress are fully met in uremic hemodialysis patient, especially since the constantly renewed production of oxidants can not be countered, because of a major deficit in antioxidant systems (including that of glutathione) present in the early stage of uremia, increasing with its progression and culminating in hemodialysis.

Assessment of oxidative stress in the hemodialysis patient   has long relied on the measurement of lipid peroxidation derivatives such as malondialdehyde (MDA) and, more recently, 4-hydroxynonenal (4-HNE) and F2-isoprostanes.Another approach focused on the measurement of oxidized low-density lipoprotein (LDL), the presence of which at high concentrations in the hemodialysis patient is associated with accelerated atheroma, and oxidized anti-LDL antibodies have also been implemented. evidence in these patients.

In contrast, and although plasma proteins are elective targets for oxidants, selective markers of oxidative protein attack have so far been little used for diagnostic or clinical research purposes. Our work aiming at a better characterization of the oxidative stress in the dialysis patients made it possible to individualize the presence, in the plasma of these patients, of the oxidation derivatives of the proteins which we named AOPP because of their close relation with the advanced glycation endproducts (AGE). The study of the role of AOPP in the immune dysregulation associated with renal insufficiency showed their presence from the early stage of uremia, and their accumulation during its progression in close relationship with markers of monocyte activation (neopterin and proinflammatory cytokines). These results have been corroborated by the observation that AOPPs formed in vitro (by treatment of albumin with chlorinated oxidants) activate the oxidative metabolism and the production of TNF by monocytes and have led us to propose that AOPPs could constitute a new family of uremic toxins and / or mediators of inflammation. The finding of a relationship between AOPP and the oxidative activity of neutrophils-dependent myeloperoxidase suggests that AOPP could, like cytokines, be mediators of communication between polynuclear and monocytes. In this hypothesis, the neutrophils, which remain the main source of myeloperoxidase, would be the main source of chlorinated oxidants responsible for the formation of AOPP and monocytes would be the preferred target of AOPP via a receptor that remains to be defined.

From a more fundamental point of view, chlorinated oxidants, previously considered microbicide species whose production is restricted to phagocytic cells, appear to be modulators of the inflammatory reaction, through their action on proteins. This new concept, according to which the molecular basis of the deleterious activity of the oxidants could involve the products of oxidation of the proteins, is remarkably illustrated in the inflammation associated with the uremia.

Clinical manifestations of immunodeficiency: infection

Infection remains a significant cause of morbidity and mortality in chronic uremic patients treated with hemodialysis or peritoneal replacement dialysis. It remains the second leading cause of death among dialysis patients after cardiovascular causes. However, the proportion of deaths from infection has decreased significantly since the beginning of dialysis, from 40% to 45%, to about 15% in the last decade in both the United States and Canada. Europe

Immunodeficiency is responsible for numerous infectious complications in dialysis uremic patients.

BACTERIAL INFECTIONS WITH COMMON GERMS:

Gram-positive organisms are the most common pathogens found in uremic patients during both general and local infections. They are highlighted in 40 to 70% of sepsis episodes. The most common causative organism is staphylococcus aureus (Staphylococcus aureus), but staphylococci (Staphylococcus epidermidis), coagulase negative, are also often responsible for bacteraemia. Other gram-positive organisms, such as streptococcus or pneumococcus, have been isolated by blood culture, but with a much lower frequency.

The most common route of entry for staphylococcal bacteremia is infection of vascular access in hemodialysis patients, or peritoneal catheters in patients treated with peritoneal dialysis. Staphylococcal sepsis can lead to multiple secondary locations including septic pulmonary infarction, endocarditis and septic arthritis.

Gram-negative germs are less frequently involved in bacteremic episodes. They were identified in about 25% of septicemia cases in the Hoen et al. Of these, colibacillus (Escherichia coli) is most commonly found, but Pseudomonas and Serratia have been isolated in blood cultures. The home of Escherichia coli septicemia is most often intestinal or genitourinary. However, urinary tract infection is common in dialysis patients, particularly in oliguric or anuric patients, and in those with polycystic kidney disease or chronic pyelonephritis.

BACTERIEMIC AND NON-BACTERIEMIC INFECTIONS:

Septicemia is responsible for more than half of infectious cause deaths in hemodialysis patients, although it is less common than localized infections. Their incidence decreased significantly between the initial dialysis period and the early 1980s, and then stabilized at a rate of 10-15 episodes / 100 patient-years on hemodialysis. In the multicenter prospective study EPIBACDIAL conducted in France in 1996 by Hoen et al, the incidence of bacteremic episodes was 11.1 / 100 patient-years.

Infection of the vascular approach is the most common local infection in hemodialysis patients. It is often used as a gateway to bacteremia. Almost inevitable in the beginning of the method where external arteriovenous shorts were used (Sribner shunt), the generalization of the use of internal arteriovenous fistulas considerably reduced the frequency, but did not cancel it. In contrast, polytetrafluoroethylene (PTFE) vascular prostheses, widely used in the United States, carry a higher risk of infection than native arteriovenous fistulas. Central venous catheters, used for a long time, are burdened with a particularly high incidence of infection at the point of skin emergence as well as bacteremia. In the EPIBACDIAL study, the frequency of bacteraemia was seven times higher in hemodialysis patients via a central catheter than in those with a radiographic arteriovenous fistula.

The major factor promoting vascular access infection is the chronic cutaneous and nasal carriage of golden staphylococci, present in more than half of patients. This finding led to the proposal of a preventive treatment with mupirocine in nasal applications once a week.

Bronchopulmonary infections are also common, accounting for 35% of non-bacteremic infections in the study by Kessler et al.

Urinary tract infections are favored by the decrease or discontinuation of diuresis resulting from the progressive loss of residual renal function. They accounted for 23% of non-bacteremic infectious episodes in the Kessler et al study, where Escherichia coli was involved in two-thirds of the cases. The treatment of these urinary infections is made difficult by the low concentration of antibacterial agents in the urine and renal parenchyma, forcing prolonged treatments by agents with high tissue diffusion, even the nephrectomy of a deeply infected kidney.

A general factor favoring bacterial infections is the iron overload that was common in patients requiring multiple blood transfusions in the pre-erythropoietin era.

Thus, a high level of plasma ferritin ( > 500 μg / L) has been identified as a risk factor, since iron overload alters the chemotactic and phagocytic activity of neutrophils and promotes growth and virulence of germs.

This factor has declined significantly since the widespread use of recombinant erythropoietin (epoetin), which has significantly reduced the use of blood transfusions and reduced iron overload through the recycling of spare iron.

RARE GERM INFECTIONS:

Opportunistic infections are rare in uremic dialysis patients because the degree of immunodeficiency secondary to the uremic state is much shallower than that observed in patients with human immunodeficiency virus (HIV) infection or in patients with subjected to prolonged immunosuppressive treatment such as transplanted.

However, infections with intracellular germs can develop in chronic renal failure, dialysis or not, with immunosuppressive treatment motivated by the underlying condition (system diseases, vasculitis, etc.).

Pneumopathies to Legionella pneumophila (Legionnaires’ disease agent) or Listeria monocytogenes endocarditis have been observed in these circumstances.

Rhizopus septicemia (mucormycosis) was observed in dialysed treated with deferoxamine for aluminum overload.

Indeed, the complex formed between this chelator and iron acts as a siderophore for Rhizopus, whose growth and pathogenicity are stimulated by iron.

Severe Clostridium difficile colitis has been reported in dialysis patients treated with broad-spectrum antibiotic therapy, a condition of malnutrition being a contributing factor.

MYCOBACTERIAL INFECTIONS:

Tuberculosis is a frequent and important problem in dialysis uremics, especially in developing countries. The incidence of tuberculosis in dialysis patients is 5 to 15 times higher than in the general population.

In a study conducted in the United States, in New Jersey, in 1994 and 1995, seven cases were diagnosed in 2 years among 4,600 dialysis patients, an annual incidence of 75/100 000 years. -patients, while the incidence of tuberculosis in the general population of this state was of the order of 11/100 000 patient-years. In a national study in Taiwan in 1997, the incidence of tuberculosis was 493/100 000 patient-years among dialysis patients, seven times higher than the incidence observed in the general population, with a mortality rate of 3, 3 times higher, due to a late diagnosis.

Hassine et al diagnosed six cases of tuberculosis in three years in 60 hemodialysis patients in a center in Tunis, an annual incidence of 3.3%, 140 times higher than the national incidence of 23/100 000 patient-years. In a recent study in Morocco, Bourquia et al observed a 7% incidence of tuberculosis in 1,800 hemodialysis patients.

Tuberculosis in chronic renal failure patients with dialysis is most often extrapulmonary, which delays diagnosis and treatment. Tuberculous involvement is peritoneal in more than one third of cases. The diagnosis is all the more difficult as cutaneous reactions to tuberculin are generally negative. The development of molecular polymerase chain reaction (PCR) detection techniques is expected to help accelerate the identification of Mycobacterium tuberculosis in biological fluids (sputum, pleural fluid or ascitic fluid).

The hypothesis of tuberculosis must always be borne in mind in case of prolonged fever or unexplained cough in a dialysis patient.

The prognosis depends on the precocity of the implementation of the treatment because the response of patients to specific antibacterial agents appears normal.

VIRAL INFECTIONS:

Hepatitis B resulted in very high morbidity and mortality in patients and staff in hemodialysis centers until the early 1980s, ie until active vaccines became available. against HBV. While routine immunization has virtually eradicated hepatitis B from hospital and dialysis staff, it has not completely eliminated the risk in patients. Indeed, because of their immunodeficiency, chronic renal failure infected with HBV are most often chronic carriers of the virus and their response to the vaccine, at least with conventional vaccination protocols, is often delayed or weak. The production of protective antibodies is all the more defective as the patients are older and the urine is more advanced.

As a result, in order to obtain effective immunization, it is necessary to use reinforced protocols comprising at least four injections followed by a one-year booster.

Various immunostimulatory strategies have been proposed to overcome the deficiency of HBV antibody production due to vaccination in dialysis patients, such as zinc supplementation, subcutaneous injection of thymopentin or INF. c , but none of these strategies have proven effective. As mentioned above, concomitant injection of IL2 appeared more promising but a randomized placebo-controlled trial using recombinant IL2 did not confirm these hopes. More recently, a stimulating effect of the coadministration of granulocyte-macrophage colony stimulating factor (GM-CSF) has been reported which needs to be confirmed.

In fact, the best strategy is to start vaccination against hepatitis B as early as possible during the pre-dialysis period, as soon as the serum creatinine level reaches 200 μmol / L, especially in the elderly, so that the patient approaches dialysis with a protective antibody level. The level of antibodies should be monitored and restarted by booster shots during dialysis treatment, especially in transplant patients.

Hepatitis C virus (HCV) hepatitis, on the other hand, remains a persistent problem in dialysis units. The frequency of transmission of HCV through blood products has, of course, been considerably reduced since the early 1990s, that is, since sensitive detection techniques could be applied to ensure the absence of HCV in the blood. blood transfusions, and that widespread use of recombinant erythropoietin (epoetin) has limited the indications for blood transfusion to emergency situations. However, HCV contamination may pre-exist at the onset of dialysis, a frequent occurrence in endemic countries, and nosocomial transmission in dialysis centers is possible. Currently, HCV infection is the most common cause of liver morbidity and mortality in dialysis and transplant patients. Since there is no HCV vaccine yet, prevention is based on strict adherence to hygiene precautions to prevent nosocomial transmission of bacteria and viruses, as well as periodic monitoring of HCV markers. in dialysis patients.

SUMMARY AND COMMENTS:

In conclusion, it is important to point out that infectious complications mainly affect patients treated with dialysis replacement, while they are much rarer in chronic renal failure patients who have not yet been dialysed, although the state of immunodeficiency related to Uremia is already present at this stage. This fact is explained by several considerations:

– dialysis does not restore normal renal function (unlike transplantation) but keeps the patient in a state of compensated chronic uremia corresponding to a glomerular filtration rate (GFR) of 15-20 mL / min, that is, major chronic renal failure;

The dialytic process, in particular of hemodialysis, further increases the dysfunction of lymphocytes, monocytes and polynuclear cells as a result of the activation of the complement system by the bio-incompatible membranes and the bacterial endotoxins passing from the dialysis bath to the blood the patient;

– dialysis technology and its environment include a large number of situations predisposing to local or bacterial infection: nasal or cutaneous carriage of staphylococci, repeated transcutaneous punctures of the vascular approach, cutaneous cracks at the entrance of the jugular or peritoneal catheters , nosocomial transmission of bacteria or virus from patient to patient or through caregivers, reduction of diuresis favoring intrarenal infections. None of these factors are present at the pre-dialysis stage.

Clinical consequences of immunoactivation: inflammation

The second aspect of immunological dysregulation associated with the uremic state, namely immunoactivation, is of more recent knowledge but has clinical consequences just as important as immunosuppression. The activation of lymphocytes, monocytes and polynuclear cells is at the origin of a chronic inflammatory state, which itself is involved in several clinical complications of chronic renal insufficiency, at the forefront of which are accelerated atheroma. , dialytic amyloidosis at 2m and malnutrition.

B -MICROGLOBULIN AMYLOSE:

Amyloid arthropathy at 2m is a frequent and painful complication that electively affects elderly patients and dialysis patients for many years. It is exceptional in patients with chronic renal failure who are not undergoing dialysis. It is characterized by amyloid deposits of b 2m around the sheath of the median nerve at the wrist (translated by carpal tunnel syndrome), in the knees, elbows, femoral necks, femoral and humeral heads, carpal bones and the cervical vertebrae, forming pseudocysts filled with b 2m. The pathogenesis of this complication is not fully elucidated, but it involves an oxidative modification of b 2m which, as modified, attracts circulating monocytes and induces the production of proinflammatory cytokines such as IL1b and TNF a . The use of high permeability hemodialysis membranes adsorbing pyrogens and an ultrapure dialysis bath, by reducing complement activation and the generation of pro-inflammatory cytokines, should help reduce the incidence of amyloidosis. at 2m.

ACCELERATED ATHERE:

Atheroma or atherosclerosis plays a key role in the morbidity and mortality of uremic patients. Indeed, cardiovascular complications are the leading cause of death in dialysis patients and, among them, the complications resulting from atheroma of large arteries are in the foreground. In addition to the classical risk factors observed in the general population, factors specific to the uremic state play a determining role at the origin of this accelerated atheroma and, in particular, the chronic inflammatory state resulting from the immunoactivation and the increase. not compensated for oxidative stress. The role of AOPP generated from the oxidation of the protein portion of LDL in the amplification of the inflammatory process and the formation of atheroma plaque is highly probable.

The reflection of the inflammatory state is the elevation of the C reactive protein (CRP), which is also correlated with the decrease of albuminemia, a reflection of malnutrition. This interrelationship led Stenvinkel et al to propose the concept of malnutrition-inflammation atherosclerosis (MIA), highlighting the relationships between accelerated atheroma and increased circulating levels of proinflammatory cytokines and the expression of adhesion molecules.

Given the lack of antioxidant defenses in chronic renal failure, vitamin E supplementation has been proposed to reduce peroxidation of membrane lipids and thus reduce the incidence of atheroma. However, the effectiveness of this measure on the clinical course has not yet been confirmed. Supplementation with N-acetylcysteine, an inducer of glutathione synthesis that has been shown to be remarkably effective in the prevention of renal injury following injection of iodinated contrast products, has been proposed and a multi-center therapeutic trial has just been initiated. in dialysis patients.

Recently, the role of chronic Chlamydia pneumoniae infection as a factor of inflammation contributing to the risk of coronary atheroma has been demonstrated in dialysis patients as well as in the general population. The search for anti-Chlamydia antibodies could be justified in uremic patients, especially those with a high CRP level, especially since prolonged treatment with macrolides can lead to the eradication of this infection.

MALNUTRITION AND HYPOALBUMINEMIA:

Caloricoproteic malnutrition is common in dialysis patients and reflects a decrease in the level of albuminemia, an independent and major prognostic factor in dialysis mortality. Hypoalbuminemia has long been attributed to nutrient deficiency alone, due to anorexia and the loss of essential amino acids in hemodialysis and peritoneal dialysis albumin. However, an important part is the protein catabolism secondary to the release of proinflammatory cytokines, in parallel with the elevation of the CRP, falling within the framework of the MIA syndrome mentioned above.

BIOCOMPATIBILITY OF MEMBRANES OF HEMODIALYSIS:

The biocompatibility of hemodialysis membranes can be evaluated by measuring the activation of complement and the generation of pro-inflammatory cytokines they induce. Other activation markers may also be evaluated, such as activation of the coagulation system, activation of the kinin / kallikrein system (responsible for anaphylactic reactions), thromboxane release by platelets and release of proteases and of reactive forms of oxygen by phagocytic cells.

With respect to cytokines, their production during hemodialysis sessions is stimulated by several mechanisms, including activated C3a and C5a complement fragments and endotoxins or endotoxin fragments passing through dialysis membranes.

High performance membranes such as polysulfone, polymethylmethacrylate (PMMA) and polyacrylonitrile are those that activate the least complement, and adsorb the most endotoxins on their surface. Their use should therefore be privileged, associated with the use of bicarbonate buffer and a bath of high purity bacteriological purity, in elderly atheromatous patients or already suffering from amyloidosis to b 2m.

Cellulose membranes coated with vitamin E have been developed to reduce the oxidative stress induced by hemodialysis. A new dialysis system called hemolipodialysis, which consists of the addition of a circuit allowing the circulation of liposomes loaded with vitamin E at the interface between the bloodstream and the membrane, via a mini-circuit, has recently been proposed in the same purpose, but the effect of these devices on the chronic evolution of patients remains to be demonstrated.

RESISTANCE TO RECOMBINANT ERYTHROPOIETIN:

Inflammation may decrease the response to erythropoietin, thus constituting a cause of resistance to the effect of both endogenous and exogenous erythropoietin (epoetin). Indeed, proinflammatory cytokines, especially IL1, TNF and INF c inhibit the growth of erythroid colonies. In particular, INF c stimulates apoptosis of erythroid progenitor cells, thus nullifying the antiapoptotic effect of erythropoietin.

Clinically, patients with elevated CRP have been found to exhibit resistance to epoetin. In a multicenter study conducted in Europe, hemodialysis patients with CRP levels greater than or equal to 10 mg / L had lower hemo-lobin levels, despite higher epoetin dosing, than patients receiving hemodialysis. whose CRP level was below this value.Experimentally, Allen et al showed that the incubation of medullary cells in culture, in the presence of autologous serum of uremic with an inflammatory state, resulted in an inhibition of the growth of erythroid precursors, this effect being suppressed by the addition of polyclonal antibodies inhibiting the effect of TNFα and INF c . A reduction in the circulating level of CRP and IL6, parallel to an improvement in the response to epoetin, was noted by Sitter et al under the effect of the use of an ultrapure dialysis bath.

The inhibition of the erythropoietic response is explained by a local action of IL1, TNF and INF c in the erythropoietic marrow, because their plasma levels were not different in 18 hemodialysis positive responders and in 15 other poor responders to epoetin, in a study by Macdougall et al. In addition, these authors found that 2-year survival of poor responders was significantly lower than that of good responders (54% vs. 88%, p < 0.05), confirming the deleterious effect of chronic inflammation. .

It therefore seems important to try to reduce the chronic inflammatory state induced by hemodialysis by the use of high biocompatibility membranes adsorbing endotoxins, and a bath of dialysis as pure as possible.

Conclusion:

In conclusion, it appears that our conceptions of immune dysregulation of uremic have changed dramatically in recent years. Initially limited to the concept of immunodeficiency responsible for increased susceptibility to infections, dysregulation has recently been enriched by the concept of immunoactivation resulting in a chronic inflammatory state, responsible for the most serious complication of chronic uremia, atheroma accelerated. Taking into account these two inseparable aspects of immune dysregulation of the uremic should reduce the morbidity and mortality of uremic patients. However, since immune dysfunction develops from the early stage of renal failure, the preventive action, to be fully effective, must be undertaken early, well before the onset of dialysis.

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Editor-in-chief of the Medical Actu website; general practitioner graduated from the Faculty of Medicine of Algiers in 2005 currently practicing as a liberal.

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