High Target Hemoglobin With Erythropoiesis‐Stimulating Agents Has Advantages in the Renal Function of Non‐Dialysis Chronic Kidney Disease Patients

We investigated the long‐term effects of maintaining high hemoglobin (Hb) on renal function in patients with chronic kidney disease not on dialysis. Subjects (Hb < 10 g/dL and serum creatinine (Cr) 2–6 mg/dL) were randomized to either a high Hb group (N = 161, 11.0 ≤ Hb < 13.0 g/dL) receiving darbepoetin alfa or to a low Hb group (N = 160, 9.0 ≤ Hb < 11.0 g/dL) with epoetin alfa, stratified according to baseline Hb and serum Cr levels, comorbidity of diabetes, and study centers. Primary endpoints were composites of the following events: doubling of serum Cr, initiation of dialysis, renal transplantation, or death. Three‐year cumulative renal survival rates (95% CI) were 39.9% (30.7–49.1%) and 32.4% (24.0–40.8%) in the high and low Hb groups, respectively (log‐rank test; P = 0.111). A Cox proportional‐hazards model adjusted by age, sex and the randomization factors showed a significantly lower event rate in the high Hb group (P = 0.035). The estimated hazard ratio (95% CI) for the high versus the low Hb group was 0.71 (0.52–0.98), the risk reduction was 29% in the high Hb group. Incidences of serious adverse cardiovascular events did not differ significantly between the high and low Hb groups (3.1% and 4.4%, respectively). No safety issues were noted in either group. Maintaining higher Hb levels with darbepoetin alfa better preserved renal function in patients with chronic kidney disease not on dialysis.     

Effect of Predialysis Recombinant Human Erythropoietin on Early Survival After Hemodialysis Initiation in Patients With Chronic Kidney Disease: Co‐JET Study

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.     

Hepcidin/Ferritin Ratios Differ Among Non‐Dialyzed Chronic Kidney Disease Patients,and Patients on Hemodialysis and Peritoneal Dialysis

The serum levels of hepcidin generally increase in patients with chronic kidney disease (CKD) due to inflammation or a decline in the glomerular filtration rate. However, the differences in the ferrokinetics among dialysis modalities are unclear. We investigated the relationship between serum levels of hepcidin and ferritin among non‐dialyzed CKD (ND), hemodialysis (HD), and peritoneal dialysis (PD) patients. We recruited 285 CKD patients (117 ND, 80 HD, and 88 PD patients) and measured the serum levels of hepcidin‐25, ferritin, hemoglobin, iron, transferrin saturation (TSAT), albumin, and high sensitivity C‐reactive protein (hs‐CRP). Hepcidin‐25 levels were elevated in all CKD patients and were significantly higher in PD than in ND and HD patients. The hepcidin/ferritin ratio was significantly higher in PD patients independent of TSAT, hemoglobin, hs‐CRP, and serum albumin. Hepcidin/ferritin ratio, associated with both dialysis modality and inflammation, is expected to be a useful indicator of anemia in CKD.     

2008 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

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.     

Hepcidin modulation in human diseases： From research to clinic

By modulating hepcidin production, an organism controls intestinal iron absorption, iron uptake and mobilization from stores to meet body iron need. In recent years there has been important advancement in our knowledge of hepcidin regulation that also has implications for understanding the physiopathology of some human disorders. Since the discovery of hepcidin and the demonstration of its pivotal role in iron homeostasis, there has been a substantial interest in developing a reliable assay of the hormone in biological fluids. Measurement of hepcidin in biological fluids can improve our understanding of iron diseases and be a useful tool for diagnosis and clinical management of these disorders. We reviewed the literature and our own research on hepcidin to give an updated status of the situation in this rapidly evolving field.     

Anaphylactic Shock Secondary to Intravenous Iron Sucrose in Chronic Kidney Disease

Intravenous (IV) iron is an essential component of therapy of anemia of chronic kidney disease (CKD). We present a rare case in which iron sucrose was infused to a patient of CKD and resulted in severe anaphylaxis and cardiac arrest minutes after starting the infusion. He was aggressively resuscitated with adrenaline and other measures following which he recovered. The use of parenteral iron is associated with several adverse drug reactions (ADR) which were seen with preparations like iron dextran but became rare with the use of newer safe preparations like iron sucrose or gluconate. The ADR can be mild or can have severe life threatening features like syncope, cardiac arrhythmias, seizures, bronchospasm and rarely cardio respiratory arrest like in our case. Iron sucrose is generally given as a IV infusion of 100–200 mg over 15–30 min and has a very low rate of ADR even with higher doses or bolus injections. But still necessary precautions and appropriate monitoring must be done in all patients. The patients who are allergic to iron sucrose may be treated with other safer preparations or by desensitisation techniques.     

Changes in Hepcidin and Reticulocyte Hemoglobin Equivalent Levels in Response to Continuous Erythropoietin Receptor Activator Administration in Hemodialysis Patients: A Randomized Study

Inadequate iron availability limits the response to erythropoiesis‐stimulating agents (ESA) and hepcidin is a key regulator of iron metabolism. However, there is little information concerning time‐dependent changes in hepcidin in response to the change of accelerated iron demand due to ESA‐induced erythropoiesis. In this study, iron‐related parameters, including hepcidin levels, were explored in comparison to patients receiving continuous erythropoietin receptor activator (CERA) and epoetin beta (EPO) treatment. Ninety‐four patients were randomized to receive monthly CERA (N = 47) or EPO three times/week (N = 47). After the titration period, hemoglobin levels and iron‐related parameters were examined. Data for 71 patients were evaluated (CERA, N = 34; EPO, N = 37). Compared with EPO treatment, CERA treatment caused significant decreases within 1 week in hepcidin (?93.5 ± 46.9 vs. ?1.3 ± 38.3 ng/mL, P < 0.01), reticulocyte hemoglobin equivalent (Ret‐He) (?4.03 ± 2.64 vs. ?1.13 ± 1.41 pg, P < 0.01), ferritin (?58.9 ± 30.5 vs. ?12.2 ± 23.8 ng/mL, P < 0.01) and transferrin saturation (?13.2 ± 9.1 vs. 1.0 ± 11.9%, P < 0.01) and significant increases within 2 weeks in the levels of hemoglobin (0.42 ± 0.38 vs. ?0.02 ± 0.48 g/dL, P < 0.01). In conclusion, hepcidin, Ret‐He, ferritin and transferrin saturation levels decreased within 1 week and hemoglobin increased within 2 weeks after CERA administration. Time course of iron‐related parameters including hepcidin demonstrated accelerated iron utilization appropriately according to ESA‐induced erythropoiesis.     

High Hemoglobin Levels Maintained by an Erythropoiesis‐Stimulating Agent Improve Renal Survival in Patients with Severe Renal Impairment

Our goal was to investigate the effect modification of maintaining a high Hb target range through erythropoiesis‐stimulating agent therapy on the renal outcome with respect to chronic kidney disease (CKD) stage and concurrent diabetes condition in patients with CKD. We used data from a previously reported randomized controlled trial involving 321 CKD patients not on dialysis, with Hb levels of <10 g/dL, and serum creatinine (Cr) of 2.0 to 6.0 mg/dL, and in which maintaining Hb levels at 11.0–13.0 g/dL with darbepoetin‐α (High Hb group) resulted in a greater renal protective effect than maintaining Hb levels at 9.0–11.0 g/dL with epoetin‐α (Low Hb group). We conducted a post‐hoc analysis of the effects of baseline CKD stage and concurrent diabetic condition on the renal composite endpoint, consisting of death, initiation of renal replacement therapy, and doubling of the serum Cr level. Both groups with stage 4 CKD had a 3‐year cumulative renal survival rate of 53.8%, whereas in patients with stage 5 CKD, the rate in the High Hb group (31.0%) was significantly (P = 0.012) higher than that in the Low Hb group (19.1%). The observations made in patients with stage 5 CKD were maintained on further analysis of non‐diabetic patients, but were not seen in those with diabetes or stage 4 CKD. These results suggest that in patients with stage 5 CKD, especially those without diabetes, achieving a higher target Hb level with erythropoiesis‐stimulating agents is associated with a greater renoprotective effect.     

The Role of Labile Iron in Kidney Disease and Treatment with Chelation

There are two major forms of kidney disease: acute renal failure [also referred to as acute kidney injury (AKI)] and chronic kidney disease (CKD). Acute renal failure is an abrupt loss of kidney function within 48 h, whereas CKD is a loss of kidney function greater than 3 months. There is a large amount of experimental evidence for an increase of labile iron in a wide variety of models of kidney disease. Additionally, iron chelators provide protection, indicating an important role of labile iron in these diseases. These observations suggest that iron chelators may provide a new modality of prevention and treatment of kidney disease.     

Role of Testosterone in the Pathogenesis,Progression, Prognosis and Comorbidity of Men With Chronic Kidney Disease

Testosterone deficiency and hypogonadism are common conditions in men with chronic kidney disease (CKD). A disturbed hypothalamic‐pituitary‐gonadal axis due to CKD is thought to contribute to androgen deficiency. Data from experimental studies support the hypothesis that exogenous administration of testosterone may induce the activation of the renin–angiotensin system (RAS), the production of endothelin and the regulation of anti‐ or/and proinflammatory cytokines involved in the pathogenesis of hypertension and kidney damage. On the other hand, low testosterone levels in male patients with CKD are paradoxically associated with a higher risk of morbidity and mortality, possibly explained by anemia, osteoporosis and cardiovascular disease. In this article, we present an overview of clinical and experimental studies of the impact of testosterone on the progression and prognosis of male patients with CKD; even today, this remains a controversial issue.     

Addressing the challenges of renal anaemia: how nurses can make a difference

Nephrology nurses play a central and wide-ranging role in renal care. However, they have inadequate time to manage their responsibilities as patient volume increases due to earlier diagnosis and improved survival, and patient care becomes more complex. The challenge to achieve and maintain target haemoglobin levels with current agents compounds nursing workload. Early recognition and treatment of anaemia, a multidisciplinary approach and patient management algorithms can improve outcomes and nursing time utilisation. Innovative erythropoietic agents produce stable haemoglobin levels at extended administration intervals, offering time-savings. Such initiatives may allow nurses more time to focus on other aspects of patient care.     

Therapeutic Potential of Low‐Density Lipoprotein Apheresis in the Management of Peripheral Artery Disease in Patients With Chronic Kidney Disease

Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD). Patients with CKD are reported to have a significant greater risk of CVD‐associated mortality than that of the general population after stratification for age, gender, race, and the presence or absence of diabetes. CKD itself is also an independent risk factor for the development of atherosclerosis, and in particular, patients undergoing dialysis typically bear many of the risk factors for atherosclerosis, such as hypertension, dyslipidemia and disturbed calcium‐phosphate metabolism, and commonly suffer from severe atherosclerosis, including peripheral arterial disease (PAD). Low‐density lipoprotein (LDL) apheresis is a potentially valuable treatment applied to conventional therapy‐resistant hypercholesterolemic patients with coronary artery disease and PAD. Although previous and recent studies have suggested that LDL apheresis exerts beneficial effects on the peripheral circulation in dialysis patients suffering from PAD, probably through a reduction of not only serum lipids but also of inflammatory or coagulatory factors and oxidative stress, the precise molecular mechanisms underlying the long‐term effects of LDL apheresis on the improvement of the peripheral circulation remains unclear and warrants further investigation.