The Japanese Society for Dialysis Therapy (JSDT) guideline committee, chaired by Dr Y. Tsubakihara, presents the Japanese guidelines entitled “Guidelines for Renal Anemia in Chronic Kidney Disease.” ...These guidelines replace the “2004 JSDT Guidelines for Renal Anemia in Chronic Hemodialysis Patients,” and contain new, additional guidelines for peritoneal dialysis (PD), non‐dialysis (ND), and pediatric chronic kidney disease (CKD) patients.
Chapter 1 presents reference values for diagnosing anemia that are based on the most recent epidemiological data from the general Japanese population. In both men and women, hemoglobin (Hb) levels decrease along with an increase in age and the level for diagnosing anemia has been set at <13.5 g/dL in males and <11.5 g/dL in females. However, the guidelines explicitly state that the target Hb level in erythropoiesis stimulating agent (ESA) therapy is different to the anemia reference level. In addition, in defining renal anemia, the guidelines emphasize that the reduced production of erythropoietin (EPO) that is associated with renal disorders is the primary cause of renal anemia, and that renal anemia refers to a condition in which there is no increased production of EPO and serum EPO levels remain within the reference range for healthy individuals without anemia, irrespective of the glomerular filtration rate (GFR). In other words, renal anemia is clearly identified as an “endocrine disease.” It is believed that defining renal anemia in this way will be extremely beneficial for ND patients exhibiting renal anemia despite having a high GFR. We have also emphasized that renal anemia may be treated not only with ESA therapy but also with appropriate iron supplementation and the improvement of anemia associated with chronic disease, which is associated with inflammation, and inadequate dialysis, another major cause of renal anemia.
In Chapter 2, which discusses the target Hb levels in ESA therapy, the guidelines establish different target levels for hemodialysis (HD) patients than for PD and ND patients, for two reasons: (i) In Japanese HD patients, Hb levels following hemodialysis rise considerably above their previous levels because of ultrafiltration‐induced hemoconcentration; and (ii) as noted in the 2004 guidelines, although 10 to 11 g/dL was optimal for long‐term prognosis if the Hb level prior to the hemodialysis session in an HD patient had been established at the target level, it has been reported that, based on data accumulated on Japanese PD and ND patients, in patients without serious cardiovascular disease, higher levels have a cardiac or renal function protective effect, without any safety issues. Accordingly, the guidelines establish a target Hb level in PD and ND patients of 11 g/dL or more, and recommend 13 g/dL as the criterion for dose reduction/withdrawal. However, with the results of, for example, the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) study in mind, the guidelines establish an upper limit of 12 g/dL for patients with serious cardiovascular disease or patients for whom the attending physician determines high Hb levels would not be appropriate.
Chapter 3 discusses the criteria for iron supplementation. The guidelines establish reference levels for iron supplementation in Japan that are lower than those established in the Western guidelines. This is because of concerns about long‐term toxicity if the results of short‐term studies conducted by Western manufacturers, in which an ESA cost‐savings effect has been positioned as a primary endpoint, are too readily accepted. In other words, if the serum ferritin is <100 ng/mL and the transferrin saturation rate (TSAT) is <20%, then the criteria for iron supplementation will be met; if only one of these criteria is met, then iron supplementation should be considered unnecessary.
Although there is a dearth of supporting evidence for these criteria, there are patients that have been surviving on hemodialysis in Japan for more than 40 years, and since there are approximately 20 000 patients who have been receiving hemodialysis for more than 20 years, which is a situation that is different from that in many other countries. As there are concerns about adverse reactions due to the overuse of iron preparations as well, we therefore adopted the expert opinion that evidence obtained from studies in which an ESA cost‐savings effect had been positioned as the primary endpoint should not be accepted unquestioningly.
In Chapter 4, which discusses ESA dosing regimens, and Chapter 5, which discusses poor response to ESAs, we gave priority to the usual doses that are listed in the package inserts of the ESAs that can be used in Japan. However, if the maximum dose of darbepoetin alfa that can currently be used in HD and PD patients were to be used, then the majority of poor responders would be rescued.
Blood transfusions are discussed in Chapter 6. Blood transfusions are attributed to the difficulty of managing renal anemia not only in HD patients, but also in end‐stage ND patients who respond poorly to ESAs. It is believed that the number of patients requiring transfusions could be reduced further if there were novel long‐acting ESAs that could be used for ND patients.
Chapter 7 discusses adverse reactions to ESA therapy. Of particular concern is the emergence and exacerbation of hypertension associated with rapid hematopoiesis due to ESA therapy.
The treatment of renal anemia in pediatric CKD patients is discussed in Chapter 8; it is fundamentally the same as that in adults.
Background
The significance of HBV reactivation during immunosuppressive therapy was evaluated in three nationwide cohorts including patients with previously resolved HBV (prHBV) infection.
Methods
...The clinical features of 1061 patients with acute liver failure (ALF) or late-onset hepatic failure (LOHF) were retrospectively examined, focusing on those who experienced HBV reactivation. Additionally, 420 patients with prHBV infection were prospectively enrolled: 203 received immunosuppressive therapies immediately after enrollment, while the remaining 217 were enrolled after having received immunosuppressive therapies without the occurrence of HBV reactivation. The serum HBV-DNA levels were prospectively monitored every month, and the incidences of HBV reactivation, defined as a serum HBV-DNA level of 1.3 log IU/ml or more, were evaluated.
Results
In the retrospective study, persistent HBV infection was found in 90 patients, and HBV reactivation was responsible for liver injuries in 50 patients including 23 receiving immunosuppressive therapies (26 with HBs-antigen positivity, 7 with prHBV infection). None of seven patients with prHBV infection were rescued. In the prospective studies, HBV reactivation occurred in ten patients, but preemptive entecavir administration prevented liver injury. The cumulative reactivation rate was 3.2 % at 6 months, and the increase of the rate compared to that at 6 months was +1.5 % at 48 months.
Conclusions
HBV reactivation during immunosuppression was responsible for liver injuries in a quarter of the ALF/LOHF patients with persistent HBV infection. Early serum HBV-DNA monitoring may improve patient prognosis, since HBV reactivation typically occurs within 6 months of the start of immunosuppressive therapies in patients with prHBV infection.
The percentage manifesting dysplasia in bone marrow needed to qualify as significant is ≥10 % in each lineage. However, detailed analyses of this threshold have not been reported. Here, we analyzed ...dyserythropoiesis (dysE) in 109 myelodysplastic syndromes (MDS) patients with 21 immune thrombocytopenia (ITP)/12 hemolytic anemia (HA) patients as a control. In present study, mild megaloblastic erythroblasts were specifically named ‘red cell with abnormal chromatin clumping (RCACC)’. RCACC ≥10 % in erythroblasts was observed in 29 % of ITP patients and 58 % of HA patients. The numbers of MDS patients with RCACC in erythroblasts <10, 10–19 and ≥20 % were 1, 3, and 105, respectively. We analyzed dysE criteria according to the WHO classification (original WHO dysE). Most of our MDS patients (98 %) had original WHO dysE ≥20 %. The ITP patients with original WHO dysE ≥10 % was 48 %, and there were no ITP patients had original WHO dysE ≥20 %. Sixty-seven percent of HA patients had original WHO dysE ≥10 %, and three patients (25 %) had original WHO dysE ≥20 %. Raising the threshold of the original WHO dysE from 10 to 20 or 30 % may provide more suitable criteria. If RCACC is not included in dysE criteria, we think that ‘10 %’ is a suitable threshold for the determination of dyserythropoiesis.
Although erythropoiesis‐stimulating agents (ESAs) are effective at treating anemia, the association between hemoglobin (Hb) levels and survival is still unclear, especially for the incident Japanese ...hemodialysis (HD) population. The Japan Erythropoietin Treatment (JET) Study is an open multi‐center, prospective, observational study designed to evaluate the relationship between the maintenance of Hb levels and new HD patient prognosis after the first administration of epoetin beta. Landmark analyses were performed to examine the relationship between Hb levels at 6 months and survival. Among a total of 10 310 patients, 6631 completed the initial 6 months of epoetin beta treatment (induction phase) and were followed up for a further 2.5 years (maintenance phase). Three‐year survival rate of patients with <9 g/dL Hb levels after 6 months was 74.1%, which was significantly lower than 89.3% for patients with Hb levels 10 to 11 g/dL; the adjusted hazard ratio (HR) was 2.08 (95% CI, 1.57–2.77; P < 0.0001). Moreover, the 3‐year survival rate for poor responders defined by Hb levels <10 g/dL and weekly epoetin beta doses ≥9000 IU during the induction phase was 71.6%, which was significantly lower than 89.4% for the group, which had Hb levels 10 to 11 g/dL excluding poor responders and those with excursion; the HR was 1.71 (95% CI, 1.13–2.60; P = 0.0118). Adverse events related to the treatment were reported in 71 of 10 310 patients (0.69%). These findings suggest that the achieved low Hb levels and poor response to ESA therapy are significantly associated with high mortality.
To determine the impact of peripheral blood (PB) Wilms’ tumour 1 (WT-1) mRNA levels in patients with primary myelodysplastic syndromes (MDS), we analysed the relationships between several clinical ...variables at the time of diagnosis and the haematological response of patients treated with azacytidine. We observed overall responses in 20 (63%) patients; there were no significant differences in clinical variables, including bone marrow blast counts, IPSS scores and IPSS-R risk scores, between responders and non-responders. The responders’ PB WT-1 mRNA levels were significantly lower than those of non-responders (P = 0.03). PB WT-1 mRNA expression could be a marker for predicting the response to azacytidine in patients with de novo MDS.
The effect of recombinant human erythropoietin (rHuEPO) treatment on the progression of chronic kidney disease (CKD) has not been fully evaluated in Japan. We therefore retrospectively evaluated this ...in a sub‐cohort of a prospective multicenter study to investigate optimal hemoglobin (Hb) level of CKD patients on hemodialysis (HD) treated with rHuEPO; Japan Erythropoietin Treatment Study for Target Hb and Survival (JET study). Effect of rHuEPO treatment during predialysis period to delay initiation of HD was retrospectively assessed in 2434 patients from the JET study comparing groups with and without rHuEPO treatment. The assessment was done by Cox proportional hazards regression analysis and inverse probability‐weighted (IPW) analysis to adjust for time‐dependent confounders. The weights used in the IPW analysis were calculated using a logistic model that included baseline confounders and time‐dependent variables. During the predialysis period, 71.7% (1746 patients) were treated with rHuEPO (mean Hb level of 8.7 g/dL at initiation of rHuEPO treatment). Covariates significantly associated with initiation of rHuEPO treatment were Hb level, serum creatinine level, age, diabetes, cardiac insufficiency, and hypertension. The adjusted hazard ratio for time until HD initiation under rHuEPO treatment was 0.272 (95% CI, 0.223–0.331; P < 0.001) in the Cox analysis and 0.63 (95% CI, 0.53–0.76; P < 0.0001) in the IPW analysis. This retrospective study suggests that rHuEPO treatment during the predialysis period has preventive effects on the progression of CKD although further prospective investigation on the efficacy is needed.
Cyclosporine A (CsA) has become one of the leading agents for the treatment of pure red cell aplasia (PRCA). However, further studies are necessary to determine the relapse-free survival (RFS) and ...overall survival (OS) of patients treated with this drug, the minimum duration of therapy for induction of remission, and whether or not there is need for maintenance treatment.
We conducted a nationwide survey in Japan. From a total of 185 patients (with 73 primary idiopathic PRCA and 112 with secondary PRCA), we evaluated 62 patients with primary idiopathic PRCA for this report.
The remission induction therapy for these patients included CsA (n=31), corticosteroids (CS) (n=20) or other drugs (n=11). CsA and CS produced remissions in 23 (74%) and 12 (60%) patients, respectively. The salvage treatment produced remissions in 58 patients (94%). Forty-one and 15 patients were maintained on CsA+/-CS (CsA-containing group) or CS alone (CS group), respectively. The median RFS in the CsA-containing group was 103 months, longer than that seen in the CS group (33 months) (p<0.01). Of 14 patients whose CsA was discontinued, 12 patients (86%) relapsed after a median of 3 months (range 1.5 to 40 months), while only 3 of 27 patients (11%) relapsed during CsA-containing maintenance therapy. Thus, the discontinuance of maintenance therapy was strongly correlated with relapse (p<0.001). Four patients in the CsA-containing group died; however, the OS of this group was not significantly different from that of the CS-groups (p=0.104).
CsA-containing regimens sustain prolonged RFS more effectively than CS in primary idiopathic PRCA and seem to be important to prevent relapse.
Thrombopoietin (TPO) is a critical regulator of hematopoiesis. We previously reported that a severe aplastic anemia (SAA) who received a short-term administration of pegylated recombinant human ...megakaryocyte growth and development factor (rHuMGDF). A trilineage hematologic response was induced, however the patient was diagnosed with leukemia after nine years and eight months from administration of rHuMGDF. In recent reports, somatic mutations in myeloid cancer candidate genes were present in one-third of the AA. A mutant clone may be expanded by rHuMGDF in our patient. The long-term safety of patients treated with TPO and eltrombopag remains unknown. Careful observations are warranted hereafter.
Progression of anemia in patients with chronic kidney disease (CKD) is associated with an increased risk of death and hospitalization. It is not sufficiently clear whether treating renal anemia with ...recombinant human erythropoietin (rHuEPO) has a beneficial effect on early survival after hemodialysis (HD) initiation in patients with CKD. The study was an open‐label multicenter retrospective cohort study to evaluate the relationship between rHuEPO treatment and early survival after HD initiation in patients with CKD. Predialysis patients with CKD were divided into two groups: an rHuEPO‐treated group (rHuEPO group) and a non‐treatment group. The primary endpoint was all‐cause mortality in the year after HD initiation. A total of 3261 patients were enrolled (2275 in the rHuEPO group and 986 in the non‐treatment group). One‐year survival was 95.36% in the rHuEPO group and 90.36% in the non‐treatment group. The survival rate was significantly higher in the rHuEPO group (P < 0.0001). The results of multivariate analysis confirmed that predialysis treatment with rHuEPO is a predictor for reduced mortality risk (hazard ratio = 0.61, 95% confidence interval: 0.42–0.87, P = 0.006). Risk for the composite event of death/hospitalization was also lower in the rHuEPO group (hazard ratio = 0.88, 95% confidence interval: 0.78–0.98, P = 0.026). The results of this study suggest that treatment with rHuEPO can decrease early mortality risk after initiation of HD in patients with CKD. A prospective study is needed to further investigate early survival after HD initiation.
About 5-10 % of chronic myelogenous leukemia (CML) patients show variant Philadelphia (Ph) translocations. The formation mechanisms and clinical significance of variant Ph translocations remain ...unclear. We report a CML case with a novel five-way complex translocation. Although the result of initial G-banding was 46,XY,t(7;11;9)(q22;q13;q34),t(9;22)(q34;q11.2), fluorescence in situ hybridization (FISH) demonstrated t(7;11;9;22;9)(q22;q13;q34;q11.2;q34) consisting of sequential rearrangements involving five chromosomes. The patient was successfully treated by imatinib and obtained a major molecular response. To our knowledge, this is the tenth CML case with a complicated Ph translocation involving five chromosomes and the third one treated by imatinib. Good response with imatinib therapy suggested that a single-event rearrangement was involved in the chromosomal changes.
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