Shoichiro Daimon

Anemia is common in patients with nondialysis-dependent (NDD) and dialysis-dependent (DD) chronic kidney disease (CKD). Insufficient erythropoietin (EPO) production is regarded as the main cause of renal anemia and, under sufficient iron supplementation, erythropoietin-stimulating agent (ESA) administration has been recommended for renal anemia treatment. Anemia is also common in patients with heart failure. Structural renal disease, which can reduce EPO production, is infrequent but is characterized by a low serum EPO level in these populations. Although intravenous iron repletion has a beneficial effect on quality of life for patients with heart failure independent of the presence of anemia, ESA use for anemia treatment in patients with heart failure is not recommended because there is no benefit and more thromboembolic adverse events occur. CKD and heart failure coexist frequently, and anemia, which is associated with these disorders, is termed cardiorenal anemia syndrome (CRAS). However, evaluation and management of anemia in CKD and patients with heart failure is not the same, especially with regards to the use of ESA, creating a dilemma for clinicians treating CRAS. For the treatment of anemia in patients with CKD, the influence of heart failure with volume overload should also be considered. The initiation and dosing of ESA therapy in patients with CKD should be determined by balancing the contributions of CKD and heart failure, rather than by targeting a specific hemoglobin level.

Anemia is common in patients with nondialysis-dependent (NDD) and dialysis-dependent (DD) chronic kidney disease (CKD). Although the capacity to produce substantial erythropoietin (EPO) remains high in these patients, insufficient EPO production is regarded as the main cause of renal anemia. Although erythropoietin-stimulating agent (ESA) administration has become the mainstay of renal anemia treatment, this treatment results in an unfavorable prognosis when the hemoglobin level becomes > 13 g/dL with the administration of these agents, and evidence for the optimal lower limit of hemoglobin level is scarce. Anemia is also common in patients with heart failure. Structural renal disease, which can reduce EPO production, is infrequent but is characterized by a low serum EPO level. ESA use for anemia treatment in heart failure patients is associated with more thromboembolic adverse events and is therefore not recommended. Given that milder forms of heart failure or cardiac stress caused by volume overload are common in oliguric or anuric patients with NDD- and DD-CKD, cardiac stress caused by volume overload can also be an important cause of anemia in these patients. The dynamics of serum endogenous EPO and reticulocyte levels differ according to the cause of anemia. During gradual anemia exacerbation due to renal dysfunction in patients with NDD-CKD, the serum endogenous EPO and reticulocyte levels do not decrease but rather increase. These levels increase after massive hemorrhage in patients on hemodialysis. In contrast, the serum EPO and reticulocyte levels decrease during anemia exacerbation due to mild cardiac stress caused by volume overload in patients on hemodialysis. After water removal, anemia is ameliorated without ESA administration, which is not due to hemoconcentration. In patients with NDD- and DD-CKD, in addition to decreased EPO production capacity, there are other causes of anemia. Thus, the strategy for anemia management should not be uniform. To improve the outcomes of these patients, in addition to the current strategy for anemia management in which target hemoglobin levels are achieved by adjusting the ESA dose, other approaches for anemia management based on the cause of anemia are needed. Possible problems and future improvements in the current strategy for anemia management in patients with NDD- and DD-CKD are discussed.

Background: Although a deficiency in erythropoietin relative to decreased hemoglobin levels is presumed to be the predominant cause of renal anemia, other factors may also exist that are not fully understood. Case presentation: A 58-year-old man with pyelonephritis who had been on hemodialysis for 18 years presented a gradually decreasing serum creatinine level, possibly due to voluntary dietary restrictions, accompanied by a gradual increase in the cardiothoracic ratio from 48% to 56%. Concomitantly, his hemoglobin level decreased gradually from 14.5 to 8.7 g/dL by 6 months. Although he had no symptoms of heart failure and his left ventricular ejection fraction was 66.3%, which was almost identical to his condition 2 years prior, a drastic reduction in posthemodialysis body weight from 71.0 to 68.6 kg in 9 days was performed without apparent intrahemodialysis hypotension. His cardiothoracic ratio and serum prehemodialysis N-terminal pro-brain natriuretic peptide level decreased steeply, from 56% to 49% by 2 weeks and from 6139 to 647 pg/mL by 8 weeks, followed by a gradual increase in his hemoglobin level from 8.7 to 15.1 g/dL by 3 months. The patient was administered 50 mg/day sodium ferrous citrate but no erythropoietin-stimulating agents or hypoxia-inducible factor prolyl hydroxylase inhibitors. Although a modest increase in the serum protein level was observed immediately after the rapid reduction in posthemodialysis body weight, the patient’s hemoglobin level increased markedly and gradually, suggesting an improvement in anemia rather than hemoconcentration. Conclusions: Cardiovascular stress induced by the volume load is one of the causes of anemia in hemodialysis patients.

Oral ferric citrate hydrate (FCH) is effective for iron deficiencies in hemodialysis patients; however, how iron balance in the body affects iron absorption in the intestinal tract remains unclear. This prospective observational study (Riona-Oral Iron Absorption Trial, R-OIAT, UMIN 000031406) was conducted at 42 hemodialysis centers in Japan, wherein 268 hemodialysis patients without inflammation were enrolled and treated with a fixed amount of FCH for 6 months. We assessed the predictive value of hepcidin-25 for iron absorption and iron shift between ferritin (FTN) and red blood cells (RBCs) following FCH therapy. Serum iron changes at 2 h (ΔFe2h) after FCH ingestion were evaluated as iron absorption. The primary outcome was the quantitative delineation of iron variables with respect to ΔFe2h, and the secondary outcome was the description of the predictors of the body’s iron balance. Generalized estimating equations (GEEs) were used to identify the determinants of iron absorption during each phase of FCH treatment. ΔFe2h increased when hepcidin-25 and TSAT decreased (−0.459, −0.643 to −0.276, p = 0.000; −0.648, −1.099 to −0.197, p = 0.005, respectively) in GEEs. FTN increased when RBCs decreased (−1.392, −1.749 to −1.035, p = 0.000) and hepcidin-25 increased (0.297, 0.239 to 0.355, p = 0.000). Limiting erythropoiesis to maintain hemoglobin levels induces RBC reduction in hemodialysis patients, resulting in increased hepcidin-25 and FTN levels. Hepcidin-25 production may prompt an iron shift from RBC iron to FTN iron, inhibiting iron absorption even with continued FCH intake.

Oral ferric citrate hydrate (FCH) is effective for iron deficiency in hemodialysis patients.; however, it remains unclear how iron balance in the body affects iron absorption from the intestinal tract. This prospective, observational study (Riona-Oral Iron Absorption Trial, R-OIAT, UMIN 000031406), conducted at 42 hemodialysis centers in Japan, wherein 268 hemodialysis patients without inflammation were enrolled and treated with a fixed amount of FCH for 6 months. We assessed the predictive value of hepcidin-25 for iron absorption and iron shift between ferritin (FTN) and red blood cells (RBCs) following FCH therapy. Serum iron changes at 2 h (ΔFe2h) after FCH ingestion were evaluated as iron absorption. The primary outcome was the quantitative delineation of iron variables on ΔFe2h and the secondary outcome was the description of the predictors of body iron balance. Generalized estimating equations (GEE) were used to identify the determinants of iron absorption during each phase of FCH treatment. ΔFe2h increased when hepcidin-25 and MCH decreased (-0.155, -0.242 to -0.068, p = 0.001; -2.574, -4.421 to -0.726, p = 0.006, respectively) in GEE. Hepcidin-25 increased when erythropoiesis-stimulating agent (ESA) decreased (-0.002, -0.002 to -0.001, p=0.000). FTN increased when RBC and ESA decreased (-0.466, -0.605 to -0.327, p=0.000; -0.002, -0.004 to -0.000, p=0.05, respectively. Limiting erythropoiesis to maintain hemoglobin levels induces RBC reduction in hemodialysis patients, resulting in increased hepcidin-25 and FTN levels. Hepcidin-25 production may prompt an iron shift from RBC-iron to FTN-iron, inhibiting iron absorption even with continued FCH intake.

Background: Although the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan has demonstrated a valuable effect on cardiac function in patients with heart failure with a reduced ejection fraction, the effect of this agent in hemodialysis patients is not well known. Case presentation: Sacubitril-valsartan was administered to two anuric hemodialysis patients, an 81-year-old woman and a 79-year-old man, after aortic valve replacement for aortic stenosis. Following sacubitril-valsartan administration, the two patients’ N-terminal pro-brain natriuretic peptide levels decreased from 110,373 to 47,742 and 22,723 to 7692 pg/mL within one month, respectively, and were sustained within the lower levels thereafter. Although the patients’ left ventricular ejection fractions were 40.0% and 28.4%, respectively, these values did not change at seven and four months after sacubitril-valsartan administration (41.0% and 30.0%, respectively) but increased gradually to 56.6% and 54.9% at 11 and 13 months, respectively, and were sustained at the same levels thereafter. Conclusions: Long-term sacubitril-valsartan administration can improve cardiac function in hemodialysis patients with a reduced ejection fraction.

Hypoxia-inducible factor prolyl hydroxylase inhibitors improve anemia in CKD and dialysis patients and were approved for anemia treatment with these populations in Japan. An 89 year-old man with anemia and on maintenance hemodialysis was successfully treated with a dose-up of darbepoetin alfa from 10 to 20 μg per week, and the dose was gradually tapered to 5 μg. Later, serum hemoglobin levels decreased with the newly occurring sustained inflammation and left pleural effusion of an unknown cause, and the darbepoetin alfa dose was increased again to 20 μg per week, which was not effective. Darbepoetin alfa was switched to 4 mg of daprodustat daily, which was fairly effective under sustained inflammation, with serum hemoglobin levels maintained at 11–12 g/dL. The increase in hemoglobin levels was ascribed to the increase in the number of red blood cells, not the mean corpuscular hemoglobin level. During the inflammatory state, despite the contrasting effect on anemia by the 20 μg of darbepoetin alfa weekly and 4 mg of daprodustat daily, the reticulocyte counts were equivalent. The serum erythropoietin levels during daprodustat administration were within the physiological range (8.5–18.8 mIU/mL). For anemia treatment in hemodialysis patients, daprodustat is less influenced by the inflammatory status than darbepoetin alfa, and one of the possible reasons for this includes the extended red blood cell lifespan.

Mechanisms of impaired fatty acid metabolism may not be the same in nondialysis and hemodialysis patients. Correlations between the serum free carnitine concentration (FC), acylcarnitine concentration (AC), acyl to free carnitine ratio (AC/FC) and estimated glomerular filtration rate (eGFR) in the nondialysis population and the duration of hemodialysis in hemodialysis patients were investigated. As the eGFR decreased, the FC and AC increased, and as the duration of hemodialysis became longer, the FC and AC decreased. The AC/FC increased consistently as the eGFR decreased and the duration of hemodialysis increased. As an exception, the AC/FC decreased in the patients with a hemodialysis duration less than 90 days, which was not explained by carnitine removal by hemodialysis. In nondialysis patients, a functional, rather than an absolute, carnitine deficiency is a main cause of impaired fatty acid metabolism. Long‐term hemodialysis exacerbates absolute carnitine deficiency, whereas hemodialysis treatment may improve impaired fatty acid metabolism.