Growing concerns about using hypoxia-inducible factor prolyl hydroxylase inhibitors for the treatment of renal anemia.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as a novel therapeutic class for treating anemia in patients with chronic kidney disease. Small molecule analogs of α-ketoglutarate (AKG), an essential substrate for 2-oxoglutarate-dependent dioxygenases (2-OGDDs), including prolyl hydroxylase domain proteins (PHDs), inhibit PHDs pharmacologically and thereby prevent HIF degradation. HIF stabilization alleviates anemia through several stimulatory effects on erythropoiesis, but it also affects the expression of many anemia-unrelated genes whose protein products exert important functions in vivo. Therefore, the pleiotropic effects of HIF stabilization under normoxic conditions deserve to be examined in more detail. Specifically, we believe that particular attention should be given to epigenetic modifications among the various AKG-based metabolic systems that may be altered by HIF-PHIs. It is noteworthy that AKG has been reported to exert health-protective actions. AKG-based metabolic systems include enzymes associated with the tricarboxylic acid cycle and amino acid metabolism, as well as 2-OGDD-mediated processes, which play important roles in many biological reactions. In this review, we examine the multifaceted effects of HIF-PHIs, encompassing not only their on-target effect of HIF stabilization but also their off-target inhibitory effects on various AKG-based metabolic systems. Furthermore, we examine its potential relevance to cardiovascular complications, based on clinical and animal studies suggesting its involvement in vascular calcification, thrombogenesis and heart failure. In conclusion, although HIF-PHIs offer a promising avenue for anemia treatment in CKD patients, their broader impact on multiple biological systems raises substantial concerns. The intricate interplay between HIF stabilization, AKG competition and cardiovascular complications warrants extensive, long-term investigations to ensure the safety and usefulness of HIF-PHIs in clinical practice.

Effect of iron administration on the aortic iron content and vascular calcification in phosphorus-loaded chronic kidney disease rats.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD) and could be related to oxidative stress. Vascular calcification (VC) has been established as a critical risk factor for accelerated CVD. In CKD, phosphorus (Pi), iron (Fe) and Nrf2 are modulators of VC and important agonists and antagonists of oxidative stress. The aim of this study was to determine whether Fe administration, which is commonly used to treat renal anemia, affects aortic Fe overload and VC, and whether Nrf2 and its related genes, ferritin H and HIF-1α, are involved in the development of VC. METHODS: A CKD model was created in rats by administering adenine and simultaneously feeding a high-Pi diet. In addition to control and CKD rats without Fe administration (No-Fe group), Fe was administered orally (PO-Fe group) or intraperitoneally (IP-Fe group) to CKD animals to clarify the effects of Fe administration on the aortic Fe and calcium (Ca) contents and the involvement of Nrf2 and its induced antioxidative proteins, ferritin H and HIF-1α, in VC. RESULTS: The aortic Fe content increased significantly in the IP-Fe group, which was closely correlated with liver HAMP (hepcidin) expression in all animals. Fe administration had no significant effect on the aortic Ca and Pi contents regardless of the route of Fe administration. The aortic mRNA level of Nrf2 was significantly increased in the IP-Fe group and correlated with serum Pi levels and aortic Fe contents, which could respond to oxidative stress. Notably, the mRNA level of Nrf2 was also significantly correlated with the mRNA levels of ferritin H and HIF-1α. Since we could not measure Nrf2 protein levels in this study, we confirmed the upregulation of HMOX1 and NQO1 mRNA expression in parallel with Nrf2 mRNA. CONCLUSION: Parenteral Fe administration increased aortic Fe in parallel with the liver HAMP mRNA level but did not affect VC. Aortic Nrf2 mRNA levels correlated significantly with aortic Fe and serum Pi levels and with aortic mRNA levels of ferritin H and HIF-1α as well as HMOX1 and NQO1.

Not baseline but time-dependent erythropoiesis-stimulating agent responsiveness predicts cardiovascular disease in hemodialysis patients receiving epoetin beta pegol: A multicenter prospective PARAMOUNT-HD Study.

BACKGROUND: Responsiveness to erythropoiesis-stimulating agents (ESAs) has been reported to be associated with increased cardiovascular disease (CVD) and mortality in patients undergoing hemodialysis (HD). However, the association between hyporesponsiveness to the long-acting ESA, epoetin beta pegol (CERA), and CVD remains unknown. METHODS: This multicenter prospective study included 4034 patients undergoing maintenance HD. After shifting from prior ESA to CERA, we studied the association between erythropoietin resistance index (ERI) at six months and outcomes, including cardiac events, major adverse cardiovascular events (MACE), and all-cause mortality, using Cox proportional hazards models (Landmark analyses) and marginal structural models to adjust for time-dependent confounding factors, including iron-containing medications and hemodiafiltration (HDF). RESULTS: The median dialysis vintage and the observational period were 5.0 years and 22.1 months, respectively. The landmark analyses revealed that the highest tertile of baseline ERI (T3) was associated with a significantly higher all-cause mortality than the lowest tertile (T1) (hazard ratio [HR]: 1.48, 95% CI: 1.03-2.13). Furthermore, marginal structural models revealed that time-dependent ERI T3 was significantly associated with increased cardiac events (HR: 1.59, 95% CI: 1.14-2.23), MACE (HR: 1.60, 95% CI: 1.19-2.15), all-cause mortality (HR: 1.97, 95% CI: 1.40-2.77), and heart failure (HF) (HR: 2.05, 95% CI: 1.23-3.40) compared to T1. A linear mixed effects model showed that iron-containing medications and HDF are negatively associated with time-dependent ERI. CONCLUSIONS: Baseline ERI at six months predicted only all-cause mortality; however, time-dependent ERI was a predictor of cardiac events, all-cause mortality, MACE, and HF. The widespread use of iron-containing medications and HDF would ameliorate ESA hyporesponsiveness.

TAFRO syndrome with renal biopsy successfully treated with steroids and cyclosporine: a case report.

BACKGROUND: TAFRO syndrome is an acute or subacute systemic inflammatory disease with no apparent cause, presenting with fever, generalized edema, thrombocytopenia, renal damage, anemia, and organ enlargement. Interleukin-6, vascular endothelial growth factor, and other cytokines are thought to be the etiologic agents that increase vascular permeability and cause the resulting organ damage. Only few reports of renal biopsy performed in patients with TAFRO syndrome exist. CASE PRESENTATION: A 61-year-old woman, with a history of Sjogren's syndrome, was admitted to our hospital with anasarca and abdominal distension. Based on the clinical course and various laboratory findings, we diagnosed TAFRO syndrome. Renal biopsy revealed thrombotic microangiopathy, including endothelial cell swelling, subendothelial space expansion, and mesangiolysis. She was treated with oral prednisolone and cyclosporine, with consequent resolution of anasarca, pleural effusion, and ascites, and improvement in renal function and urinary findings. The patient's platelet count also normalized after 2 months of treatment. CONCLUSIONS: Given that only few reports of improvement in the systemic symptoms of TAFRO syndrome using steroids and cyclosporine exist, our study investigating the relationship between the pathogenesis of TAFRO syndrome and renal disorders, as well as treatment methods, provides valuable insights.

Hemodiafiltration Improves Low Levels of Health-Related Quality Of Life (Qol) and Nutritional Conditions of Hemodialysis Patients.

We compared the effects on the nutritional condition and health-related quality of life (HR-QoL) of the treatment of patients with on-line hemodiafiltration (OL-HDF) and conventional hemodialysis (CHD) using a superflux dialyzer. In total, 47 maintenance (M) HD patients were treated by CHD with a high-flux dialyzer for the first 4 months (1st CHD) and were then switched to predilution OL-HDF for the next 4 months (OL-HDF), after which CHD was resumed for the last 4 months (2nd CHD). We assessed the clinical parameters, fat mass value, muscle mass value, and HR-QoL. In patients with low serum albumin levels, these levels significantly (p < 0.05) increased in the OL-HDF period. Moreover, the fat mass values significantly (p < 0.05) increased in patients with decreased fat mass values in the OL-HDF period. Although there was no significant difference in the patients with higher scores of physical functioning, role physical, vitality, and social functioning, patients with lower scores in the 1st CHD period had significantly increased (p < 0.05) in the OL-HDF period. In this crossover study, we revealed that OL-HDF treatment significantly improved the nutritional conditions and HR-QoL scores compared with the improvement observed after CHD with a superflux dialyzer, especially for maintenance hemodialysis patients with malnutrition and a low QoL.

Long-acting erythropoiesis-stimulating agent (ESA) induces physiological erythropoiesis via improvement of iron availability.

PURPOSE: Previous studies reported that the long-acting erythropoiesis-stimulating agent (ESA) significantly suppresses the expression of hepcidin, which regulates iron availability. In this study, we compared the iron availability for erythropoiesis between short and long-acting ESA over a long period. METHODS: We enrolled 69 hemodialysis patients in this study. All patients were treated with short-acting ESA (epoetin-α or epoetin-ß) for the first 30 months. Then, all patients switched to long-acting ESA (continuous erythropoietin receptor activator-methoxy polyethylene glycol-epoetin beta) for the next 30 months. We measured their blood levels of Hb, ferritin, iron, total iron-binding capacity, intact-parathyroid hormone, calcium, phosphate, albumin, and highly sensitive CRP level. RESULTS: There was no significant change in the dose of short or long-acting ESA during the study period. Compared with the short-acting ESA period, the mean hemoglobin (Hb) and transferrin saturation levels were significantly increased in the long-acting ESA period (from 10.3 ± 0.2 to 10.6 ± 0.3 g/dL). On the other hand, the mean serum ferritin level (from 72 ± 22.2 to 56.3 ± 14 ng/mL) and the dose of IV iron (from 108 ± 63 to 53 ± 27 mg/month) were significantly decreased in the long-acting ESA period. CONCLUSION: In this study, we found that anemia treatment with long-acting ESA attenuated the iron utilization for erythropoiesis and maintained target Hb levels without requiring a higher dose of IV iron or ESA.

Association Between Bone Mineral Density of the Distal Third of the Radius and Mortality in Patients on Hemodialysis, a Retrospective Cohort Study.

INTRODUCTION: Although several investigators have reported the relationship between bone mineral density (BMD) and mortality in patients on hemodialysis, it is unclear BMD of which site is most strongly associated with mortality. METHODS: We examined the factors related to fractures in patients on hemodialysis in 2009. Based on these data, we investigated the influence of BMD of different sites on mortality in this cohort of 81 patients on hemodialysis. BMD was measured at the distal third of the radius (1/3 Rad), lumbar spine, and total hip. Fifteen patients had prevalent vertebral fractures and seven had prevalent hip fractures. The influences of age, body mass index (BMI), serum creatinine (Cr), serum albumin (Alb), dialysis vintage, and parathyroid hormone (PTH, measured as whole PTH) on mortality were also studied. RESULTS: Fifty-two patients died by August 31, 2018. BMD was significantly higher in the survival group than in the deceased group only for the 1/3 Rad group (P < .001). Although patients with prevalent hip or vertebral fractures showed a higher mortality rate than those without fractures, no significant difference was observed. In the deceased group, age was significantly higher, and BMI and Cr levels were significantly lower than those in the survival group (P < .001, P < .05, and P < .01; respectively). After adjustment for these parameters, BMD of the 1/3 Rad remained a significant prognostic factor. CONCLUSION: Although this was a study with a limited number of patients, BMD of the 1/3 Rad appears to be associated with mortality in patients on hemodialysis.

Saccharated ferric oxide attenuates haematopoietic response induced by epoetin beta pegol in patients undergoing haemodialysis.

BACKGROUND: Decreased erythropoietin levels and impaired iron metabolism due to excessive hepcidin levels are responsible for renal anaemia in patients undergoing haemodialysis. Recently, erythroferrone (ERFE) has been identified as a factor that regulates hepcidin. In addition, fibroblast growth factor 23 (FGF23), which has been recognized as a phosphorus-regulating hormone, appears to be involved in haematopoietic regulation. Clarification of the detailed mechanism of haematopoiesis could lead to the improvement of renal anaemia treatment. METHODS: Epoetin beta pegol (CERA) was administered to patients undergoing haemodialysis at week 0, and the same amount of CERA with saccharated ferric oxide (SFO) was administered at week 4. The changes in haematopoiesis-related biomarkers, including ERFE, intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23), and inflammatory markers, were examined. RESULTS: Administration of CERA increased ERFE levels, decreased hepcidin levels, and stimulated iron usage for haematopoiesis, leading to an increase in reticulocytes (Ret) and haemoglobin (Hb). Simultaneous administration of SFO with CERA (CERA + SFO) significantly attenuated the responses of ERFE, Ret, and Hb compared with CERA alone. Although iFGF23 levels were not affected by either CERA or CERA + SFO, cFGF23 was significantly elevated from baseline after CERA. Since cFGF23 levels were not affected by CERA + SFO, cFGF23 levels after CERA + SFO were significantly lower than those after CERA alone. The ratio of iFGF23 to cFGF23 (i/cFGF23 ratio) was significantly higher after CERA + SFO than that after CERA alone. In addition, high-sensitivity C-reactive protein (hsCRP) levels were significantly higher after CERA + SFO than after CERA alone. CONCLUSION: Administration of SFO suppressed haematopoietic responses induced by CERA. Elevation of i/cFGF23 ratio and hsCRP could account for the inhibitory effects of SFO on haematopoiesis. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network (ID UMIN000016552 ).

Potential hazards of recent trends in liberal iron use for renal anemia.

A randomized controlled trial,the Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL), has recently shown that a high-dose ('proactive') intravenous iron regimen was superior to a low-dose ('reactive') regimen for hemodialysis patient outcomes and overall safety. However, even in the low-dose group, a substantial amount of iron was administered to maintain serum ferritin >200 ng/mL. This type of comparison may have strongly affected the safety results. Iron has two opposite effects on erythropoiesis: it activates erythroid differentiation directly by supplying iron but inhibits it indirectly by stimulating hepcidin and enhancing oxidative stress. Hepcidin plays an essential role not only in iron homeostasis and the anemia of chronic kidney disease, but also in its complications such as atherosclerosis and infection. Its main stimulation by iron-and to a lesser degree by inflammation-should urge clinicians to avoid prescribing excessive amounts of iron. Furthermore, as serum ferritin is closely correlated with serum hepcidin and iron storage, it would seem preferable to rely mainly on serum ferritin to adjust iron administration, defining an upper limit for risk reduction. Based on our estimations, the optimal range of serum ferritin is ∼50-150 ng/mL, which is precisely within the boundaries of iron management in Japan. Considering the contrasting ranges of target ferritin levels between end-stage renal disease patients in Japan and the rest of the world, the optimal range proposed by us will probably be considered as unacceptable by nephrologists abroad. Only well-balanced, randomized controlled trials with both erythropoiesis-stimulating agents and iron will allow us to settle this controversy.

Low transferrin saturation (TSAT) and high ferritin levels are significant predictors for cerebrovascular and cardiovascular disease and death in maintenance hemodialysis patients.

Patients with high serum ferritin and low transferrin saturation (TSAT) levels could be considered as presenting with dysutilization of iron for erythropoiesis. However, the long-term safety of iron administration in these patients has not been well established. An observational multicenter study was performed over 3 years. In 805 patients undergoing maintenance hemodialysis (MHD), we defined dysutilization of iron for erythropoiesis in patients with lower TSAT (<20%) and higher ferritin (≥100 ng/mL) levels. A time-dependent Cox hazard model was used for the evaluation of the association between dysutilization of iron for erythropoiesis and adverse events and survival. Patients with low TSAT levels showed an increased risk of cerebrovascular and cardiovascular disease (CCVD) and death compared to patients with normal or higher TSAT levels. Patients with low ferritin and high TSAT levels had a significantly lower risk of CCVD and death compared with patients with high ferritin and low TSAT levels. Higher TSAT levels were associated with male gender, age, the absence of diabetes, low levels of high-sensitivity CRP, and low ß2 microglobulin levels, but not with intravenous iron administration or ferritin levels. Although patients with low TSAT levels had a significantly higher risk of CCVD or death, high TSAT levels were not linked with iron administration. Patients, who were suspected of dysutilization of iron for erythropoiesis, had a higher risk of CCVD and death. The administration of iron should be performed cautiously for improving TSAT levels, as iron administration could sustain TSAT levels for a short term.

[Iron dysregulation in chronic kidney disease].

Anemia remains an important complication of patients with chronic kidney disease (CKD). Relative erythropoietin deficiency was assumed to be the main cause of anemia in CKD. In contrast, it is possible that iron dysregulation for erythropoiesis in CKD patients also affects not only anemia but also cardiovascular event or survival of these patients. A prospective observational study was conducted for 3 years on 1,000 maintenance hemodialysis patients. In time-dependent cox hazard analysis, we found the higher risks of cardiovascular disease (HR: 4.45, p<0.001) and all-cause mortality (HR: 5.8, p< 0.001) in patients with low transferrin saturation (TSAT) (<20%) and high ferritin levels (≥100 ng/ml) who are suspected to have iron dysregulation for erythropoiesis compared with patients with high TSAT and low ferritin level. From these results, we hypothesized that iron dysregulation in CKD patients is closely associated with various complications and survival. Moreover, iron administration should be approached with caution in patients who present with iron dysregulation for erythropoiesis.

The pathogenesis of CKD complications; Attack of dysregulated iron and phosphate metabolism.

Chronic kidney disease (CKD) patients have a tremendously higher risk of developing cardiovascular disease (CVD) and infection than the non-CKD population, which could be caused by intertwining actions of hyperphosphatemia and CKD associated misdistribution of iron. CVD is often associated with vascular calcification, which has been attributed to hyperphosphatemia, and could be initiated in mitochondria, inducing apoptosis, and accelerated by reactive oxygen species (ROS). The production of ROS is principally linked to intracellular ferrous iron. For infection, the virulence and pathogenicity of a pathogen is directly related to its capacity to acquire iron for proliferation and to escape or subvert the host's immune response. Iron administration for renal anemia can sometimes be overdosed, which could decrease host immune mechanisms through its direct effect on neutrophils, macrophages and T cell function. Hyperphosphatemia has been demonstrated to be associated with an increased incidence of infection. We hypothesized two possible mechanisms: 1) fibroblast growth factor-23 levels are increased in parallel with serum phosphate levels and directly impair leukocyte recruitment and host defense mechanisms, and 2) circulating non-transferrin-bound iron (NTBI) is increased due to decreased iron binding capacity of the carrier protein transferrin in high-phosphate conditions. From these observations, maintaining an adequate serum range of phosphate levels and minimizing intracellular iron accumulation could attenuate the development of CKD complications.

The pharmacokinetics of oral metronidazole in patients with metronidazole-induced encephalopathy undergoing maintenance hemodialysis.

BACKGROUND: Metronidazole-induced encephalopathy (MIE) is a rare disease caused by an adverse reaction to metronidazole (MNZ). Furthermore, the pharmacokinetics of MNZ during hemodialysis (HD) treatment have not been revealed. CASE PRESENTATION: In a 70-year-old woman undergoing maintenance HD, MNZ was administered intermittently for the treatment of recurrent hepatic cyst infections. She complained of vomiting, dizziness, and dysarthria after 65 consecutive days of MNZ administration. In brain fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), we found a high signal intensity in the cerebellar dentate nuclei and splenium of the corpus callosum. We diagnosed the patient with MIE. MNZ administration was withdrawn immediately, and HD treatment was performed for 3 consecutive days. Accompanying the remarkable decrease in serum MNZ levels, MIE symptoms were attenuated after three consecutive days of HD. In a brain MRI at 9 days, the high-intensity areas in the cerebellar dentate nuclei and splenium of the corpus callosum had disappeared. CONCLUSION: In this patient, we diagnosed MIE in the early stage using MRI, and 3 consecutive days of HD rapidly attenuated the symptoms associated with MIE, accompanied by a significant decrease in serum MNZ levels.

Health economic evaluation of peritoneal dialysis based on cost-effectiveness in Japan: a preliminary study.

BACKGROUND: In Japan, the medical expenditures associated with dialysis have garnered considerable interest; however, a cost-effectiveness evaluation of peritoneal dialysis (PD) is yet to be evaluated. In particular, the health economics of the "PD first" concept, which can be advantageous for clinical practice and healthcare systems, must be evaluated. METHODS: This multicenter study investigated the cost-effectiveness of PD. The major effectiveness indicator was quality-adjusted life year (QALY), with a preference-based utility value based on renal function, and the cost indicator was the amount billed for a medical service at each medical institution for qualifying illnesses. In comparison with hemodialysis (HD), a baseline analysis of PD therapy was conducted using a cost-utility analysis (CUA). Continuous ambulatory PD (CAPD) and automated PD (APD) were compared based on the incremental cost-utility ratio (ICUR) and propensity score (PS) with a limited number of cases. RESULTS: The mean duration since the start of PD was 35.0±14.4 months. The overall CUA for PD (179 patients) was USD 55,019/QALY, which was more cost effective (USD/monthly utility) compared with that for HD for 12-24 months (4,367 vs. 4,852; p<0.05). The CUA reported significantly better results in the glomerulonephritis group than in the other diseases, and the baseline CUA was significantly age sensitive. The utility score was higher in the APD group (mean age, 70.1±3.5 years) than in the CAPD group (mean age, 70.6±4.2 years; 0.987 vs. 0.860; p<0.05, 9 patients). Compared with CAPD, APD had an overall ICUR of USD 126,034/QALY. CONCLUSION: The cost-effectiveness of PD was potentially good in the elderly and in patients on dialysis for <24 months. Therefore, the prevalence of PD may influence the public health insurance system, particularly when applying the "PD first" concept.

Inhibition of the Mammalian Target of Rapamycin May Augment the Increase in Soluble Klotho Levels in Renal Transplantation Recipients.

BACKGROUND/AIMS: α-Klotho is mainly expressed in the kidneys, and its soluble form can prevent vascular calcifications. Inhibition of the mammalian target of rapamycin (mTOR) upregulates Klotho. We assessed serial changes in the levels of soluble Klotho (sKlotho) in recipients before and after renal transplantation and investigated the effects of an mTOR inhibitor. METHODS: Serum sKlotho levels were measured in 36 recipients before and 1 year after transplantation and compared between those taking everolimus and those not taking everolimus. RESULTS: sKlotho levels were higher after transplantation than before transplantation (369.3 vs. 211.8 pg/mL). After transplantation, sKlotho levels were significantly higher in recipients taking everolimus than in those not taking everolimus (536.7 vs. 332.4 pg/mL). CONCLUSION: Our results suggest that mTOR inhibition may augment the increase in sKlotho levels in transplant recipients. Further studies are needed to examine whether mTOR inhibitors suppress the development of vascular complications via upregulation of Klotho expression in renal transplant recipients.

Effect of Progression in Malnutrition and Inflammatory Conditions on Adverse Events and Mortality in Patients on Maintenance Hemodialysis.

BACKGROUND/AIM: In maintenance hemodialysis (MHD), protein-energy malnutrition and chronic inflammation can be critical and are two of the main causes of mortality. METHOD: We compared the change in nutrition and inflammatory conditions between younger and older MHD patients during a 2-year period. Furthermore, using Kaplan-Meier analysis, we evaluated the correlations between changes in each parameter and any adverse events. RESULT: During the observational period, body mass index (BMI) and serum albumin levels decreased significantly in older patients. In Kaplan-Meier analysis, patients who showed a decline in BMI had an associated elevated risk for cerebro-cardiovascular disease and hospitalization. Moreover, patients who showed a decline in albumin also had an associated higher risk for infectious disease and hospitalization. CONCLUSION: This study revealed that the downward trend in nutritional status was prominent in elderly patients. Furthermore, changes in nutritional and inflammatory conditions during MHD were associated with adverse events in MHD patients.