OPTA—Influence of inflammation/infection on anaemia therapy in haemodialysis patients
1Universitätsklinik Würzburg, Medizinische Klinik und Poliklinik I, Abteilung Nephrologie, Josef-Schneider-Straße 2, 97080 Würzburg, Germany, 2Department of Renal Medicine, York District Hospital, Wiggington Road, York YO31 8HE, UK, 3Départment Néphrologie, Hopital E. Herriot, Place d'Arsonval, 69437 Lyon CEDEX 03, France and 4Department of Renal Medicine K56, Karolinska University Hospital Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden
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Introduction |
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 Top Introduction Diagnosis of inflammation and...Potential sources of...Treatment of...Concomitant anaemia treatmentReferences |
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The optimal treatment of renal anaemia—OPTA—is an initiative aiming to improve anaemia care management and to achieve recommended target haemoglobin levels of >11 g/dl with highest efficiency (European Best Practice Guidelines—EBPG; [1]). Anaemia and epoetin therapy is influenced by a variety of factors such as dialysis dose, iron status, blood loss and nutritional status. Underlying inflammation and infection are very common in dialysis patients and one of the major treatment influencing factors in the management of anaemia [2–4].
The acute phase response, inflammation and infections interact with haematopoiesis on several levels. Erythropoiesis is influenced directly via reduced erythrocyte stem cell proliferation, suppressed erythropoiesis and endogenous erythropoetin production, accelerated destruction of erythrocytes, and blunting of the reactive increase in erythropoetin in response to reduced haemoglobin levels [5]. Indirectly, acute or chronic inflammation and infection also inhibit intestinal iron absorption and release of iron from macrophages and hepatocytes by hepcidin [6,7]. Hyporesponsiveness to epoetin therapy (target haemoglobin level > 11 g/dl) or escalating epoetin doses to overcome low response to epoetin treatment are the consequences. Epoetin dose requirement is an independent predictor of total mortality in haemodialysis patients after adjustment for haematocrit [8].
Among several inflammatory biomarkers used to assess inflammation and infection (interleukin-6, fibrinogen, ferritin, S-albumin, fetuin and procalcitonin), high sensitive C-reactive protein (hsCRP) has been shown to be the most accurate predictor of morbidity and mortality [9,10]. Elevated hsCRP-levels (>5 mg/l) also increase the risk of hospitalization [11]. A study showed that hsCRP levels above 10 mg/l lead to an increase of epoetin dosage by 34% in comparison with patients with a CRP level below 10 mg/l [3].
The following information and recommendations of the OPTA inflammation/infection working group cover the action steps to be taken for an optimal treatment of inflammation and infection. Consequently, those recommendations trigger the improvement of epoetin response in haemodialysis patients by both reaching the recommended target haemoglobin level and influencing the cost effectiveness.
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Diagnosis of inflammation and infection |
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TopIntroductionDiagnosis of inflammation and...Potential sources of...Treatment of...Concomitant anaemia treatmentReferences |
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Current status of inflammation in dialysis patients
Although the ranges of CRP may be a continuum from micro-inflammation to inflammation progressing to infection, the working group recommends CRP staging into different categories of levels for diagnostic purposes (Table 1). A number of publications from different countries throughout Europe have shown that at least 40–50% of patients demonstrate a CRP level > 5 mg/l, 35–45% are between 5 and 50 mg/l and roughly 10% of patients are above 50 mg/l, with a median of 7.4 mg/l [10]. A pragmatic level for a normal range in an end-stage renal failure patient would be a CRP serum concentration of up to 5 mg/l (normal median in a middle-aged American from the general population is 1.5 mg/l). In the haemodialysis population a single episode of sepsis is known to be associated with an increased risk of all-cause mortality and also of acute myocardial infarction for up to 5 years [12].
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Patients with type 2 diabetes mellitus usually have slightly but significantly higher CRP levels, as they also require higher epoetin dosages to achieve the same benefit in respect to haemoglobin target levels [13]. Both genetic factors and ethnicity impact CRP levels.
Considering that even a CRP value of 2–3 mg/l is associated with an increased vascular risk in the non-renal population [14], a CRP up to 5 mg/l may not be considered as normal in dialysis patients. On the other hand, published data on cohorts of dialysis patients showed that CRP of 10 mg/l based on the Receiver Operated Curve (ROC) has the best predictive value for cardiovascular mortality [10]. Forthcoming guidelines agree upon 10 mg/l as a limit and the definition of normal CRP can still be discussed.
Clinical and diagnostic procedures in a unit and on an individual level
When chronically raised (CRP 5–50 mg/l), the impact of inflammation on efficacy and effectiveness of the anaemia therapy is underestimated. Patients often do not discriminate minor symptoms following an inflammatory stimulus and require an active work-up. This work-up should be carried out monthly. The average (median) CRP of a centre is elevated when specific conditions (contaminated dialysate, higher percentage of diabetics or grafts) are prominent. A unit population distribution curve may reveal a higher power of discrimination and is appropriate to detect a more general problem in the unit. To allow benchmarking, comparison with regional or national data is necessary. Analyses from Sweden, Germany and southern Italy demonstrate that the distribution curves of CRP in centres enrolled in clinical studies are rather similar [10]. In agreement with other studies, CRP levels > 16 mg/l were in the upper quartile of the unit population with the highest cardiovascular and all-cause mortality over a 5-year period. It should be mentioned that severely infected patients where excluded from this study. A work-up on an individual level should first investigate those patients being in the upper quartile of the distribution curve of CRP levels (Table 2). Certainly the most difficult patients, where most intense efforts have to be undertaken, are those with a smouldering or chronically raised CRP in the range of 5–50 mg/l. Often, recurrent underlying renal disease (vasculitis induced renal failure), comorbidities and de-novo or recurrent malignancy are among the causes. The latter diagnoses clearly show a dynamic in the individual CRP distribution curve over time.
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| Recommendations
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Dialysis patients with stable hsCRP between 5 and 50 mg/l should undergo a thoroughly clinical work-up, whether they exert clinical symptoms or not. |
Potential sources of inflammation/infection |
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TopIntroductionDiagnosis of inflammation and...Potential sources of...Treatment of...Concomitant anaemia treatmentReferences |
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Whereas prominent infection can result from a single cause, inflammation usually occurs from a variety of factors. Table 3 lists a number of most common causes of inflammation and infections. Several of the causes, categorized in the CRP range of 5–50 mg/l, may well contribute to an elevated CRP in the higher range (>50 mg/l). For example, when immunosuppression is tapered or withdrawn, a failing kidney transplant may evolve to an active rejection with pain and macrohaematuria. A persistent elevation of CRP in CAPD patients has been found when ischaemic heart disease is present [15]. Patients with a history of systemic disease causing renal failure are at risk of recurrence or exacerbation of the disease. Occasionally, a flare-up of the underlying primary renal disease, such as systemic lupus erythematosus or Wegener's disease may occur. A dental examination should also be performed.
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Peritoneal dialysis (PD) patients may have a number of specific causes for high CRP that are different from those in haemodialysis patients (Table 4). The causes are connected to the dialysis procedure itself, including the biocompatibility and, under very rare circumstances, the impurity of the dialysis solution. Exit site infections require an ultrasound work-up to detect the involvement of the tunnel in the infective process. PD patients usually exhibit a higher volume status than their haemodialysis counterparts. In heart failure patients with volume overload the leaky gut hypothesis has been proposed to explain increased CRP levels in this patient group. Studies have not been performed to investigate whether this is a contributing factor to raised CRP levels in PD patients. So far, it has been hypothesized that endotoxin transfer from the gut to the systemic circulation takes place in cases of venous pooling during volume overload [19]. At least the peritoneal transport is enhanced during high fluid status in CAPD patients [20]. Sclerosing peritonitis can occur with ultra-filtration failure, inflammatory response and bowel obstruction.
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Treatment of inflammation/infection |
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TopIntroductionDiagnosis of inflammation and...Potential sources of...Treatment of...Concomitant anaemia treatmentReferences |
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Diagnosis of the underlying cause is key in order to eliminate the cause of infection. Specific antibiotic therapy or surgical intervention can improve epoetin resistance. Similarly, detection and treatment of recurrent vasculitis or malignancy may also have a high impact. If no cause of high CRP is detected (Table 5–appendix) a clotted arterial graft should be removed, when appropriate. In order to achieve this goal, a regular audit with benchmarking should be performed, together with a regular review of individual patients with particular emphasis on Table 3.
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On rare occasions, if the screen for sepsis is negative and the patient is believed to have a non-infective inflammatory condition, administration of steroids might be considered (e.g. extensive deposit of calcium phosphate on soft tissues).
The multiple causes that may be the reason of inflammation are more complex to approach and the various proposals to treat inflammatory conditions require confirmation in larger trials. However, clinical decisions for treatment may be justified by a deteriorating clinical course. According to published literature the most frequent causes are displayed according to their impact in Table 6.
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| Recommendations
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An observational clinical recommendation would be the review of dental hygiene and the use of an electric tooth brush to help improve dental health and reduce CRP in a high-risk group. This is equally important in transplant patients on calcineurin inhibitors.
Concomitant drug therapy, prescribed in dialysis patients, may decrease oxidative stress and inflammation and thereby epoetin dose. For example, Statins or Renin-Angiotensin-Aldosterone blockers seem to be promising therapies. However, studies are not yet conclusive due to the fact that some data suggest a decrease in the haemoglobin levels.
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Concomitant anaemia treatment |
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TopIntroductionDiagnosis of inflammation and...Potential sources of...Treatment of...Concomitant anaemia treatmentReferences |
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It has been estimated that the epoetin dose, required to maintain a target haemoglobin level, may on average be increased by 30 to 70% in dialysis patients with a CRP > 10 mg/l [23,24]. Despite high doses of epoetin, the European Survey on Anaemia Management (ESAM) study showed that patients who had a CRP level > 50 mg/l exert lower haemoglobin levels than those with CRP < 50 mg/l [23]. It suggests that every patient should have the opportunity to receive a dose of epoetin. The epoetin effect being dose dependant, the administration of higher doses can overcome the inhibitory effect of circulating cytokines on erythropoiesis. Practically, doses can be increased up to 300 IU/Kg (definition of epoetin resistance) whilst investigating the factors that cause epoetin resistance. The most impacting actions to overcome epoetin resistance secondary to inflammation/infection are displayed in Table 6 (working-group opinion).
Infections and high CRP levels can inhibit iron mobilization. As a result, functional, but not absolute, iron deficiency often occurs and influences anaemia.
In summary, the OPTA working group on inflammation and infection felt focusing on both individual and population factors in anaemia management provides the best opportunity to improve dialysis patient care.
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References |
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