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Fever during neutropenia may be a symptom of severe life threatening infection, which must be treated immediately with antibiotics. If signs of infection persist, therapy must be modified. Diagnostic measures should not delay treatment. If the risk of febrile neutropenia after chemotherapy is ≥20%, then prophylactic therapy with G-CSF is standard of care. After protocols with a risk of febrile neutropenia of 10–20%, G-CSF is necessary, in patients older than 65 years or with severe comorbidity, open wounds, reduced general condition. Anemia in cancer patients must be diagnosed carefully, even preoperatively. Transfusions of red blood cells are indicated in Hb levels below 7–8 g/dl. Erythropoiesis stimulating agents (ESA) are recommended after chemotherapy only when hemoglobin levels are below 11 g/dl. The Hb-level must not be increased above 12 g/dl. Anemia with functional iron deficiency (transferrin saturation <20%) should be treated with intravenous iron, as oral iron is ineffective being not absorbed. Nausea or emesis following chemotherapy can be classified as minimal, low, moderate and high. The antiemetic prophylaxis should be escalated accordingly. In chemotherapy with low emetogenic potential steroids are sufficient, in the moderate level 5-HT3 receptor antagonists (setrons) are added, and in the highest level Aprepitant as third drug.
Neutropenia is a common complication in patients undergoing cytostatic chemotherapy and one of the most important risk factors for infections. Additional factors that contribute markedly to the increased susceptibility to infections include damage to the skin and to the mucous membranes of the oral pharynx and gastrointestinal tract, which can be due to toxic effects of chemotherapy or radiotherapy, or to the neutropenia itself. Fever is often the only indication of infection in neutropenic patients.
While 50% of febrile neutropenic patients have a documented infection initially, infection cannot be localized in the other patients. Even if the infection site cannot be identified, antibiotic therapy must be started immediately to prevent progression to a life-threatening infection. This means that therapy will usually be empirical, based on the results of therapeutic trials and local experience.
Prognostic parameters for infection progression are mainly neutropenia as a surrogate marker and such factors as mucosal damage, severe comorbidity, or antibody deficiency.
Neutropenia is defined as a neutrophil count <500/μl, i.e. (segments and bands) or <1000/μl with predicted decline to 500/μl within the next 2 days.
Fever is defined as a temperature taken orally or at the tympanon without any signs of non-infectious causes temperature of ≥38.3°C once or a temperature of ≥38.0°C twice, lasting for at least 1 h or measured twice within 12 h.
Note: Simultaneous infections can be expected in up to 5% of all patients receiving blood transfusions.
Numerous study groups have tried to incorporate further risk-adapted concepts into the decision-making process of empirical therapy. In the case of the so-called low risk group, there are two different concepts: outpatient management and therapy with oral antibiotics. So far, the definitions are not satisfactory, but they can be used for orientation. Apart from general criteria, the low risk definitions that have been used so far include criteria for oral therapy and outpatient management (Table 1 (Tab. 1)). In non-selected patients approximately 30–40% of all febrile neutropenic episodes can be classified as low risk. The initial classification can be changed during the course of the infection. The state of a patient who initially fails to meet low risk criteria might have stabilized after 12–24 h of therapy, hence outpatient management and oral therapy might be feasible after re-classification. Some investigators never include patients with hematological neoplasia in the low risk group.
The MASCC (Multinational Association for Supportive Care in Cancer) has established a risk index by evaluation of non-selected consecutive patients with febrile neutropenia, according to which low risk patients were defined as defervescing during antibiotic therapy without developing any of the complications listed in Table 2 (Tab. 2) .
In approximately one-third of all patients, the causative pathogen can be identified during the initial infection phase. In approximately 20–30% of cases, pathogenic evidence can be found at a later stage. The species listed in Table 3 (Tab. 3) represent 90% of all proven microorganisms, though fungal infections may initially play a more significant role in pulmonary infiltrates. If pathogens are identified after more than 5 days, fungi can be identified in approximately 30–40% of all microbiologically documented infections.
Infections in febrile neutropenia can be classified in accordance with the recommendations of the consensus conference of the International Immunocompromised Host Society and the Infectious Diseases Society of America as follows.
Unexplained fever or fever of unknown origin (FUO) is defined as a new fever not accompanied by clinical or microbiological evidence of infection: single incident of fever (oral) without any evident cause, temperature ≥38.3°C or ≥38.0°C lasting for at least one hour, or measured twice within 12 hours.
Clinically documented infection (CDI) is defined as fever accompanied by unambiguous, clinically localized evidence, e.g. in the case of pneumonia or skin/tissue infection when pathogens cannot be identified or examined microbiologically.
A microbiologically documented infection (MDI) is present if the infection has been localized and microbiologically plausible evidence, which is also plausible with regard to timing, has been found, or if an infectious agent can be demonstrated in a blood culture even if a localized infection site has not been identified. koagulase-negative staphylococci and corynebacteria must be demonstrated at least twice in separate blood cultures. A single isolation of these potential pathogens is viewed as contamination. In the case of pulmonary infiltrates, pathogen isolation from blood or a bronchoalveolar lavage specimen is regarded as a reliable source. Throat swabs, sputum, saliva, or a mouth rinse can only be viewed as reliable if a true pathogen is found in a timely correlation with the development of the pulmonary infiltrates. If there are symptoms of abdominal infection, evidence of Clostridium difficile toxin from stool culture is acceptable, whereas other potentially pathogenic agents must be found in at least two consecutive stool cultures. In catheter-associated infections, positive blood culture in conjunction with evidence of the same pathogen from the sampled catheter material or a swab taken from the infected entry site is required. For urinary tract infections a significant pathogen count is necessary; for wound infections, swab or puncture material is acceptable.
Before initiation of antimicrobial therapy thorough clinical examination covering:
(The examination procedures mentioned above should repeated every day if fever persists.)
Further imaging and other diagnostics according to clinical symptoms or risk situation:
Check diagnostics with specialist.
If microorganisms are detected in any culture, a further sample should in any case be taken, even if the treatment is successful, so that a surveillance culture can be established to ensure microbiological effectiveness. Susceptibility testing for medication in use is required for all cultures of potentially pathogenic agents.
Minimial diagnostic requirements twice a week before and during therapy:
Leukocytes and differential blood count, hemoglobin, platelets, SGOT, SGPT, LDH, alkaline phosphatase, gamma GT, bilirubin, uric acid, creatinine, sodium, potassium, Quick's test, partial thromboplastin time, D-Dimers, C-reactive protein (CRP); repeated lactate examination if there are signs of sepsis; procalcitonin.
For patients receiving aminoglycosides it is recommended that plasma trough levels be determined at least twice a week or more often if indicated. For patients with renal failure, particularly those simultaneously receiving other potentially nephrotoxic substances, the intervals for plasma level determination should be shortened if aminoglycosides cannot be avoided. It is recommended that creatinine clearance be determined at the outset to guide dosage decisions and evaluate potential nephrotoxicity.
The diagnostic procedures described above should be repeated if radiography of the lungs is still negative and persistent neutropenia: high resolution computed tomography of the lungs abdominal ultrasound.
1. Fever and neutropenia <500/μl or <1000/μl if decline to <500/μl is expected
Type of fever: single (oral) temperature of ≥38.3°C or ≥38.0°C lasting for at least one hour or measured twice within 12 hours without any evident cause. Exception: fever which is known to be due to non-infectious causes.
or in addition (see separate protocols)
or in addition
2. Signs of infection in afebrile neutropenia
Therapy is empiric or calculated, the proof of an infection by a microbial organism cannot be awaited.
Treatment must begin within 2 hours, diagnostic should not delay its initiation.
Essentially, either combination therapies or monotherapy are possible. Antibiotics chosen should have been adequately investigated and must be effective against enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus and streptococci. Monotherapies should only be administered by an experienced team. Patients must be examined regularly and monitored closely for early detection of treatment failure, additional infections, side effects and resistant pathogens.
The hospital- and ward-specific susceptibility patterns of pathogens have to be considered when an antibiotic regimen is chosen. For several years, 60–70% of all documented infections have been caused by gram-positive pathogens, primarily coagulase-negative staphyloccoci and Corynebacterium jeikeum. The prognosis of these infections is favourable even if initial therapy was not directed against them, compared to the life-threatening infections by the gram-negative microorganisms Staphylococcus aureaus, viridans streptococci and pneumococci.
The classification follows the criteria described in Table 1 (Tab. 1).
Schedule see Figure 1 (Fig. 1).
For standard risk patients (see Table 1 (Tab. 1) and Table 2 (Tab. 2)) eligible for oral antibiotic therapy, we recommend the combination of ciprofloxacin plus amoxicillin/clavulanic acid. This combination is also suitable for sequential therapy (possibly only after initial intravenous pre-treatment and stabilization). A high rate of attributable gastrointestinal adverse effects should be taken into account.
Monotherapy with ciprofloxacin or ofloxacin has not been investigated sufficiently. In the case of penicillin allergy, amoxicillin/clavulanic acid can possibly be replaced by clindamycin or cefalexin (little experience) or cefuroxim-axetil. For patients with questionable compliance or contraindications for oral therapy, the parenteral medication recommended for intermediate and high risk patients should be used. See Table 4 (Tab. 4) and Table 5 (Tab. 5) for dosages.
Antibiotic therapy: piperacillin-tazobactam or ceftazidime or cefepime or imipenem/cilastatin or meropenem combined with antimycotic therapy: liposomal amphotericin B or caspofungin or voriconazole (see also Table 6 (Tab. 6)).
Assessment criteria should be based on the recommendations of the consensus conference of the International Immunocompromised Host Society and the Infectious Diseases Society of America .
If success criteria are met within 72 hours of antimicrobial treatment and the neutrophil granulocyte count is stable at <1000/μl, the regimen should be continued until the patient is afebrile for seven consecutive days. If, however, the neutrophil granulocyte count has risen to >1000/μl, two consecutive afebrile days are sufficient. Treatment should not be shorter than 7 days. After completion of antimicrobial therapy a follow-up period of 7 days is necessary to detect a relapse or a secondary infection. Some infections only become apparent after an increase in the neutrophil count. Patients with an adequate neutrophil count whose clinical state is improving thus also require follow-up, e.g. on an outpatient basis.
G-CSF for stimulation of granulopoesis in persistent neutropenia is indicated in case of severe or progressive infection, pneumonia or fungal infection.
In severe hypogammaglobulinemia 7S-polyvalent intravenous immunoglobulins should be substituted.
Many cytotoxic substances impair the function of leukocytes and their production from pluripotent and comitted hematopoietic stem cells in the bone marrow. Frequent sequelae of cytostatic chemotherapy therefore are anemia, thrombocytopenia, leukocytopenia and especially neutropenia, which is a significant risk factor for morbidity and mortality associated with infections. Neutropenia is one of the most severe toxicities of chemotherapy, with its extent and duration being correlated with and increasing risk of serious infections , , . As most important dose limiting toxicity, neutropenia can compromise the success of antineoplastic therapy.
Hematopoietic growth factors such as G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte-macrophage colony stimulating factor) stimulate the generation of neutrophils. G-CSF and GM-CSF are increasingly produced by T-cells, macrophages and monocytes if the neutrophil counts are decreasing, in order to stimulate proliferation and differentiation of comitted progenitor cells. They are termed “myeloid” growth factors.
In the 1980s G-CSF was described, biochemically characterized, its gene cloned and developed as recombinant molecule for clinical application , . The prophylactic use of recombinant G-CSF (filgrastim, peg-filgrastim, lenograstim) or GM-CSF preparations (molgramostim, sagramostim) after myelosuppressive chemotherapy accelerates the regeneration of granulocytes to protective levels , , . After autologous bone marrow or stem cell transplantation, G-CSF and GM-CSF both accelerate the recovery of granulopoiesis , , , . The prophylactic use of G-CSF is associated with faster neutrophil engraftment and shorter length of post-transplant hospital stay without affecting time to platelet engraftment in patients undergoing autologous transplantation. Following allogeneic stem cell transplantation, G-CSF reduces the time to neutrophil recovery, but has no influence on day 30 or day 100 transplant-related mortality. G-CSF neither affects graft-versus-host disease nor leukemia-free survival .
Duration and severity of neutropenia as well as infection-associated risks can significantly be reduced by prophylaxis with myeloid hematopoietic growth factors. that In many cases, hazardous neutropenia can be prevented completely , , . Meta analyses showed, that infection related mortality and all cause mortality can by reduced by the use of CSFs , .
Febrile neutropenia (FN) is the most important sign of infection in patients after myelosuppressive chemotherapy. FN is defined as an oral temperature ≥38°C along with granulocyte counts <500/µl, or <1000/µl, if a decrease <500/µl within 48 hours is anticipated , . Fever during neutropenia is caused by an infection in more than 95% of cases, however in 50–70% of patients no infectious pathogen can be detected , , , .
In cancer patients infections are the most frequent therapy-associated causes of death. The risk of febrile neutropenia and of life-threatening infections correlates with the severity and duration of neutropenia . The mortality due to neutropenia-associated infections post-chemotherapy may be up to 5.7%, and is relatively higher when infection occurs early after onset of neutropenia , , , .
A multivariate analysis of 41,779 patients with different types of cancer and FN showed the following risk factors for a lethal outcome: Gram-negative sepsis (relative risk: 4.92), invasive aspergillosis 3.48, invasive candidiasis 2.55, pulmonary disease 3.94, cerebrovascular disease 3.26, renal disease 3.16, liver disease 2.89, pneumonia 2.23, gram-positive sepsis 2.29, hypotension 2.12, pulmonary embolism 1.94, heart disease 1.58, leukemia 1.48, lung cancer 1.18, and age ≥65 years 1.12 . An increasing number of concomitant diseases further increases mortality rates , .
Relative dose intensity (RDI) is the proportion of planned dose intensity per planned time interval. With the exception of hematopoietic stem cell transplantation, many treatment protocols achieve the planned relative dose intensity only if neutropenia and febrile neutropenia are avoided or limited to a clinically acceptable extent . This is especially true for dose-dense protocols with short intervals between cycles and increased dose intensities, for example in Hodgkin’s lymphoma , aggressive Non-Hodgkin’s lymphoma , , , and breast cancer .
It is a common strategy to reduce the dose of chemotherapy in subsequent cycles or prolonging intervals between treatment cycles, when severe or febrile neutropenia have occurred after a preceding course. Randomized clinical trials in adult solid tumor and malignant lymphoma patients showed a relative dose intensity (RDI) of 71.0% to 95.0%, with a mean RDI of 86.7% (median RDI, 88.5%). Among G-CSF–treated patients, the average RDI ranged from 91.0% to 99.0%, with a mean RDI of 95.1% (median RDI, 95.5%). RDI differences between study arms ranged from 2.8% to 20.0%, with average differences of 8.4% (P=.001) .
In some tumors it has been shown that reducing the RDI can have a negative impact on the success of chemotherapy, e.g., in adjuvant chemotherapy for breast cancer , , , , in diffuse large cell Non-Hodgkin’s lymphoma .
In Non-small-cell lung cancer it has been clearly shown, that patients >56 years have a siginificant longer survival, if they receive a combination chemotherapy as compared with a single agent therapy .
The most important factors for febrile neutropenia (FN) following chemotherapy are the type of chemotherapy and its dose intensity. Without G-CSF or GM-CSF, the risk of FN is constant for all chemotherapy cycles , . However, it is greater following the first cycle only, if hematopoietic growth factors are given for subsequent cycles . If neutropenic complications occur, then the risk of febrile neutropenia remains high for further chemotherapy cycles.
Combination chemotherapy protocols increase the risk of FN compared to monotherapies, as well as drugs toxic to bone marrow or mucous membranes. Significant predictors for severe or febrile neutropenia are the use of high-dose cyclophosphamide or etoposide for treatment of malignant lymphomas as well as high-dose antracyclines for early breast cancer .
According to various guidelines, the intensity of chemotherapy protocol correlates directly with the risk of FN. An overview on frequently used protocols is given in Table 7 (Tab. 7), with the risk of FN categorized as high (≥20%), intermediate (10–20%) or low (<10%) .
Besides the type of chemotherapy, patient- and tumor-specific factors have an impact on the risk of febrile neutropenia (Table 8 (Tab. 8)).
A review of the literature showed that higher age, especially ≥65 years, consistently correlates with a higher risk of febrile neutropenia among independent patient-specific risk factors . In elderly patients, chemotherapy may be underdosed in fear of neutropenic complications, although they would benefit from conventional-dose treatment regimen as younger patients do .
Apart from higher age, independent risk factors for febrile complications during neutropenia are advanced disease, previous episodes of FN and lacking prophylaxis with G-CSF or antibiotics . Other patient- or tumor-related risk factors for FN, such as reduced general condition, impaired nutritional status or comorbidity, have been identified with a lower level of evidence by retrospective analyses. Patients with malignant diseases of hematopoiesis or lymphopoiesis have an increased risk by the disease itself and the intensity of the treatment than patients with solid tumors.
In the group of patients older than 70 years, increasing age does not increase the risk of severe or febrile neutropenia further, but the type of the malignancy, a planned dose intensity ≥85%, therapy with cisplatinum or anthracyclines, previous chemotherapy, increased urea and increased alkaline phosphatase .
Most data on clinical efficacy of recombinant myeloid growth factors is derived from studies using G-CSF. The principle of reducing neutropenia with myeloid growth factors is shown in Figure 4 (Fig. 4). Neutropenia can be shortened mainly by an accelerated recovery of neutrophils.
Primary G-CSF prophylaxis in patients receiving cancer chemotherapy is recommended for all patients with an expected ≥20% risk of FN , , , . If using a chemotherapy regimen associated with 10%–20% FN risk, G-CSF prophylaxis should be considered based on treatment intention and individual patient risk factors. The patient’s FN risk should be reassessed prior to each cycle of chemotherapy. This is particularly important for chemotherapy regimens with 10%–20% FN risk, as patient-related risk factors may vary throughout chemotherapy cycles, and thus their FN risk could increase throughout the treatment course. For patients at <10% FN risk, G-CSF prophylaxis generally is not recommended.
Prophylactic antibiotics are not advised in standard risk patients with an anticipated risk of neutropenia for <7 days , , . Fluoroquinolone prophylaxis should be considered for high-risk patients with expected durations of prolonged and profound neutropenia (ANC <100 cells/µl for >7 days) .
Figure 5 (Fig. 5) shows the algorithm for deciding to use G-CSF after chemotherapy.
The aim of therapeutic use of myeloid growth factors is the reduction of morbidity and mortality due to infections emerging during neutropenia. In patients with solid tumors and high risk FN, therapeutic G-CSF in addition to antibiotic therapy was beneficial by reducing the duration of neutropenia and hospitalisation with significantly less serious medical complications . However, there is less evidence supporting the therapeutic use of G- or GM-CSF in addition to antibiotics. A meta-analysis showed a shorter hospital stay and shorter time to neutrophil recovery, but no influence on mortality . Interventional application of recombinant myeloid growth factors can be considered for patients with risk factors for poor clinical outcome or infection-related complications such as age ≥65 years, sepsis syndrome, severe neutropenia with an absolute neutrophil count <100µl, anticipated duration of >10 days of severe neutropenia, pneumonia, or invasive fungal infections .
Patients under prophylaxis with G-CSF, who develop febrile neutropenia, should continue this prophylaxis.
Available growth factors are the G-CSFs filgrastim, pegfilgrastim, lenograstim and the GM-CSFs sargramostim, molgramostim. Primary prophylaxis should be given beginning with the first cycle of chemotherapy in solid tumors and non-myeloid malignancies until post nadir recovery of neutrophils . Administration of CSFs on same of chemotherapy is not recommended . Alternative dosing schedules are not recommended .
G-CSF should be given 24–72 hrs following the last dose of chemotherapy and continued until the recovery of neutrophils for three days above 500 cells/µl or until reaching an ANC of at least 2,000 to 3,000/µl.
Filgrastim is given subcutaneously (s.c.) at a dose of 5 µg/kg per day, lenograstim at 150µg/m2 per day.
The long acting pegylated G-CSF (pegfilgrastim) is given s.c. once at a dose of 6 mg 24 hours after completion of each cycle of chemotherapy. The 6 mg formulation should not be used in infants, children, or small adolescents weighing <45 kg.
The GM-CSF sargramostim (glycosylated), which is not available on the market in many countries, is licensed for prophylactic use following chemotherapy in patients with acute myeloid leukemia, or after autologous or allogeneic bone marrow transplantation. The manufacturer’s instructions for administration are limited to those clinical settings. GM-CSF should be initiated on the day of bone marrow transfusion, not less than 24 hours from the last chemotherapy and not earlier than 12 hours from the most recent radiotherapy. GM-CSF should be continued until an ANC greater than 1,500 cells/µl for 3 consecutive days is obtained. The drug should be discontinued early or the dose be reduced by 50% if the ANC increases to greater than 20,000 µl. The recommended doses are 250 micrograms/m2/day for GM-CSF for all clinical settings, given subcutaneously.
The GM-CSF molgramostim (non-glycosylated) is licensed for use in patients receiving myelosuppressive therapy (cancer chemotherapy) to reduce the severity of neutropenia, thereby reducing the risk of infection and allowing better adherence to the chemotherapeutic regimen, in patients undergoing autologous or syngeneic bone marrow transplantation to accelerate myeloid recovery. Recommended dosage regimens are for cancer chemotherapy 5 to 10 µg/kg per day administered subcutaneously, initiated 24 hours after the last dose of chemotherapy and continued for 7 to 10 days, And after bone marrow transplantation 10 µg/kg per day administered by i.v. infusion over 4 to 6 hours, beginning the day after BMT, and continued until the absolute neutrophil count (ANC) reaches ≥1000/µl. The maximum duration of treatment is 30 days.
Several studies suggest, that the application of the long lasting Pegfilgrastim provides an optimal dosing of G-CSF and might thus be more effective than the daily injected G-CSF, which some patients might receive in suboptimal daily schedules . One metaanalysis comparing pegfilgrastim with filgrastim found a significant lower rate of febrile neutropenia with Pegfilgrastim .
Anemia causing clinical symptom is characterized as a decline of hemoglobin below 12 g/dl. Initially, the incidence is about 50% or more, depending on the type and stage of cancer .
Following anemia due to iron deficiency, the anemia of chronic disease is the second most form, which is caused by the activated immune system .
An anemia should be evaluated and treated accordingly, see Table 9 (Tab. 9).
ACD is chracterized by normochromic or hypochromic, microcytic erythrocytes (MCV, MCH normal or slightly decreased), anisocytosis, poikilocytosis. The reticulocyte count can be normal or decreased.
Reticulocyte hemoglobin (CHr) <26 pg, or al level of >10% hypochomic erythrocytes is typical.
Ferritin levels are elevated due to inflammation, the transferrin saturation is low.
The Erythropoietin serum levels are higher than at normal hemopglobin levels, but not sufficiently increased .
The indication for blood transfusions has to be assessed if the hemoglobin level is below 8g/dl and the patients has symptoms of anemia. The German Board of Physicians recommends transfusions in chronic anemia only, if the hemoglobin level is below 7–8 g/dl . Only if patients do not tolerate that level, then transfusions can be given at higher hb-levels.
However, the risks of blood transfusions should be considered, such as infections, intolerance, sensitizing, higher mortality, secondary malignant lymphomas, and higher risk of tumor relapse , , , , .
a) Iron deficiency due to bleeding or nutritional deficiency, no inflammation, no active tumor.
a1) Oral iron substituion: 100 mg/d Fe(II) sulfate or other Fe(II) compound.
a2) Intravenous iron substitution, in intolerance or ineffectiveness of oral preparations.
b) Iron deficiency in anemia of chronic diesease (ACD) in inflammation or tumor, functional iron deficiency; combination of i.v. iron with erythropoietic agents (ESA).
c) In ACD without chemotherapy only i.v. iron or blood transfusions (if hb<8 g/dl) are recommended.
ESAs are not approved in anemic patients with radiotherapy.
Chemotherapy can induce nausea and vomiting, which are among the most important side effects. However actual standard therapy can prevent vomiting in almost all patients. Nausea still being a major subjective problem. Preventing nausea and vomiting is an essential supportive measure in oncology.
In order to avoid anticipatory vomiting, it is necessary to apply the antiemetic medication as prophylaxis during tumor therapy. The American Society of Clinical Oncology (ASCO) and the Multinational Association of Supportive Care in Cancer (MASCC) have published guidelines for prevention and control of nausea and vomiting, which are summarized in the following , .
Table 12 (Tab. 12) summarizes the recommendations for antiemetic prophylaxis.
The author has received lectureship honoraria from Amgen, Janssen, Hexal/Sandoz, Teva, Vifor-Pharma; research funding from Amgen and consultancy honoraria from Amgen, Teva, Vifor-Pharma.