Yukitoshi Sakao

Association of Prohepcidin and Hepcidin-25 with Erythropoietin Response and Ferritin in Hemodialysis Patients

Hepcidin is a key regulator of iron metabolism. In this study, we examined whether measurement of hepcidin is useful in assessing recombinant human erythropoietin (rHuEPO) responsiveness in regular hemodialysis (HD) patients in a cross-sectional fashion. We examined the association between serum prohepcidin, a prohormone of hepcidin, and rHuEPO dosage and the rHuEPO/hemoglobin (Hb) ratio in 75 HD patients. We also semiquantatively measured the peak intensity of serum hepcidin-25, the major form of mature hepcidin, in 24 HD patients by using surface-enhanced laser desorption ionization time of flight time mass spectrometry, and compared those between rHuEPO-hyporesponsive (rHuEPO 192 ± 10 [126–252] IU/kg/week, n = 15) and responsive patients (rHuEPO 40 ± 9 [0–81] U/kg/week, n = 9). A significant but weak relationship was found between serum prohepcidin and rHuEPO dosage (r = 0.24, p < 0.05) and rHuEPO/Hb ratio (r = 0.22, p = 0.06). However, prohepcidin did not become an indicator of hematopoietic parameters by multiple regression analysis. Serum hepcidin-25 intensity was significantly and positively correlated with ferritin (r = 0.51, p < 0.01) but not with log-transformed C-reactive protein. There was no difference in the intensities of serum hepcidin-25 between rHuEPO-hyporesponsive and responsive patients (64 ± 10 vs. 52 ± 16 AU, p = NS). It follows from these findings that the assessment of serum hepcidin using currently available assays was not valid in predicting rHuEPO responsiveness in chronic HD patients.

A Comparison of Systemic Inflammation-Based Prognostic Scores in Patients on Regular Hemodialysis

Background/Aims: Systemic inflammation-based prognostic scores have prognostic power in patients with cancer, independently of tumor stage and site. Although inflammatory status is associated with mortality in hemodialysis (HD) patients, it remains to be determined as to whether these composite scores are useful in predicting clinical outcomes. Methods: We calculated the 6 prognostic scores [Glasgow prognostic score (GPS), modified GPS (mGPS), neutrophil-lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), prognostic index (PI) and prognostic nutritional index (PNI)], which have been established as a useful scoring system in cancer patients. We enrolled 339 patients on regular HD (age: 64 ± 13 years; time on HD: 129 ± 114 months; males/females = 253/85) and followed them for 42 months. The area under the receiver-operating characteristics curve was used to determine which scoring system was more predictive of mortality. Results: Elevated GPS, mGPS, NLR, PLR, PI and PNI were all associated with total mortality, independent of covariates. If GPS was raised, mGPS, NLR, PLR and PI were also predictive of all-cause mortality and/or hospitalization. GPS and PNI were associated with poor nutritional status. Using overall mortality as an endpoint, the area under the curve (AUC) was significant for a GPS of 0.701 (95% CI: 0.637-0.765; p < 0.01) and for a PNI of 0.616 (95% CI: 0.553-0.768; p = 0.01). However, AUC for hypoalbuminemia (<3.5 g/dl) was comparable to that of GPS (0.695, 95% CI: 0.632-0.759; p < 0.01). Conclusion: GPS, based on serum albumin and highly sensitive C-reactive protein, has the most prognostic power for mortality prediction among the prognostic scores in HD patients. However, as the determination of serum albumin reflects mortality similarly to GPS, other composite combinations are needed to provide additional clinical utility beyond that of albumin alone in HD patients.

Alogliptin improves steroid-induced hyperglycemia in treatment-naïve Japanese patients with chronic kidney disease by decrease of plasma glucagon levels

Background Chronic kidney disease (CKD) is a risk factor for end-stage renal failure and cardiovascular disease, and a strategy to counteract CKD must be established. CKD caused by immunological abnormalities is treated by steroids, frequently resulting in steroid diabetes. Although insulin is the most effective drug against steroid diabetes, administering it to patients can be difficult. Dipeptidyl peptidase-4 (DPP-4) inhibitors were developed for diabetes mellitus with a new mechanism of action. However, their efficacies and mechanisms of action for steroid diabetes are unclear. Material/Methods We studied 11 CKD patients treated with steroids admitted to our hospital (3 men and 8 women; age, 66.0±15.9 years). DPP-4 inhibitor alogliptin was administered for steroid diabetes. Levels of markers related to glucose metabolism were measured before alogliptin treatment and after alogliptin treatment, before the prednisolone dose was reduced. Results Alogliptin treatment significantly increased plasma glucagon-like peptide-1 (GLP-1) levels from 1.16±1.71 pmol/L to 4.48±1.53 pmol/L and significantly reduced levels of plasma glucose recorded 2 h after lunch and hemoglobin A1c (HbA1c). No significant differences were seen in insulin secretory ability of homeostasis model assessment (HOMA) (HOMA-β) and insulin resistance index of HOMA (HOMA-R) before and after alogliptin treatment. In contrast, alogliptin treatment significantly decreased plasma glucagon levels, from 116.1±38.7 pg/mL to 89.6±17.3 pg/mL. Moreover, there were significant correlations among HbA1c, GLP-1, and glucagon levels. Conclusions Alogliptin improves steroid-induced hyperglycemia by decrease of glucagon levels through an increase in plasma GLP-1 levels.

Serum Creatinine Modifies Associations between Body Mass Index and Mortality and Morbidity in Prevalent Hemodialysis Patients

Background High body mass index (BMI) is paradoxically associated with better outcomes in hemodialysis (HD) patients. This study aimed to examine whether serum creatinine (Cr), a marker of muscle mass, could modify the association between BMI, and mortality and morbidity in prevalent HD patients. Methods A retrospective study was conducted using a nationwide database from the registry of the Japanese Society for Dialysis Therapy. A total of 119,099 patients were selected (age: 65±12 years; median time on HD: 5.6 years; male: 62%), and we examined the association of basal BMI with mortality and morbidity after a 1-year period. Patients were stratified either by BMI into 4 groups or by serum Cr levels into 3 tertiles. Odds ratio (OR) [95% confidence interval] was calculated by multivariate logistic regression analysis. Results Higher BMI did not predict a higher 1-year total mortality. However, when we stratified the patients by serum Cr levels, the risk of cardiac death became significantly higher in obese patients with the lowest Cr levels, in both males (OR 2.82 [1.51–5.27], p<0.01) and females (OR 2.00 [1.03–3.90], p<0.05). The risk of new cerebral infarction was also higher in obese male patients within the lowest Cr tertile. In contrast, there was a significantly lower risk of cardiac, cerebrovascular, and infection-related death in non-obese patients with higher levels of Cr. Higher serum Cr was also related to a lower risk of cardiovascular events and hip fracture in non-obese HD patients. Conclusions The obesity paradox was found to be present in HD patients only when obesity was defined by BMI. Decreased serum Cr levels were found to be positively associated with clinical poor outcomes in all BMI groups. Thus, irrespective of BMI, the evaluation of serum Cr levels is important to predict mortality and morbidity in patients receiving regular HD.

Analysis of intra-GBM microstructures in a SLE case with glomerulopathy associated with podocytic infolding

BackgroundSystemically podocytic infolding into the GBM which causes nonargyrophilic holes in the GBM in association with intra-GBM microstructures has been considered as a new pathological entity. However, its pathomechanisms are largely unknown.MethodsWe analyzed intra-GBM microstructures in an SLE patient with glomerulopathy associated with podocytic infolding by immunoelectron microscopy for vimentin (a marker for both podocyte and endothelium) and C5b-9 and by 3D reconstruction of transmission electron microscopy (TEM) images by computer tomography method.ResultsImmunofluorescent study showed immunoglobulin deposition in a diffuse, capillary pattern; however, electron-dense deposits like stage 3 membranous nephropathy could be found only in some capillary loops by TEM in spite of the systemic existence of podocytic infolding and the intra-GBM microstructures. Three-dimensional reconstructed images of the TEM images revealed that some of the intra-GBM microstructures made connections with the podocyte. The clustered microstructures underneath the podocyte and their surroundings looked as a whole like the degraded part of podocyte in 3D reconstructed images. Immunoelectron microscopy showed that vimentin was positive in most intra-GBM microstructures. C5b-9 was positive along the entire epithelial side of the GBM and in some microstructures, suggesting that the podocytes may be attacked by C5b-9 and that the microstructures may contain C5b-9 bound cellular membranes.ConclusionIntra-GBM microstructures may be originated mainly from the podocyte. Podotyte and GBM injuries caused by C5b-9 attack to podocytes might contribute in part to podocytic infolding and intra-GBM microstructures in this case.

Augmented circadian rhythm of the intrarenal renin-angiotensin systems in anti-thymocyte serum nephritis rats.

We report that disturbance to the circadian rhythm of urinary angiotensinogen (AGT) excretion may lead to renal damage, hypertension and diurnal blood pressure (BP) variations. We aim to clarify the circadian rhythm of the intrarenal renin–angiotensin system (RAS) and its contribution to renal damage, hypertension and BP variations, and to evaluate whether the administration of RAS blockers influences the circadian rhythms of intrarenal RAS components. Anti-thymocyte serum (ATS) nephritis rats were used as a chronic progressive glomerulonephritis model (group A) and compared with control rats (group C). Other rats with ATS nephritis received olmesartan medoxomil (an angiotensin II (AngII) type 1 receptor (AT1R) blocker; group AO) or hydralazine (a vasodilator; group AH). The levels of intrarenal RAS components were evaluated every 6 h. The expression levels of intrarenal AGT, AngII and AT1R were increased in group A and peaked at the same time as BP and urinary protein excretion during the rest phase. The amplitude of the circadian fluctuation of these proteins was more increased in group A than in group C. The circadian fluctuation of these proteins was reduced in groups AO and AH. However, renal function, proteinuria and augmentation of intrarenal RAS components were reduced only in group AO. Intrarenal RAS components, such as AGT, AngII and AT1R proteins, were increased and the amplitude of the oscillations of these proteins was augmented in ATS nephritis rats. Interestingly, renal damage may be linked to the activation of the intrarenal RAS independent of the amplitude of its oscillations and BP.

Relationship between ghrelin, Helicobacter pylori and gastric mucosal atrophy in hemodialysis patients.

AIM To investigate the relationship between plasma ghrelin level, Helicobacter pylori (H. pylori) infection status and the severity of atrophy in hemodialysis patients. METHODS One hundred eights patients who received hemodialysis and 13 non-hemodialysis H. pylori-negative controls underwent gastroduodenoscopy to evaluate the severity of gastric atrophy. Serum levels of pepsinogen (PG) were measured as serum markers of gastric atrophy. H. pylori infection was evaluated by anti-H. pylori IgG antibody, rapid urease test and culture test. We classified H. pylori infection status as non-infection, present infection and past infection. In addition, plasma acyl-ghrelin and desacyl-ghrelin levels were measured by enzyme-linked immunosorbent assay. RESULTS Infection rate of H. pylori was 45.4% (49/108). Acyl-ghrelin level in the non-infection group (39.4 ± 23.0 fmol/mL) was significantly higher than in the past (23.4 ± 19.9 fmol/mL, P = 0.005) and present infection groups (19.5 ± 14.0 fmol/mL, P < 0.001). Furthermore, desacyl-ghrelin level in the non-infection group (353.2 ± 190.2 fmol/mL) was significantly higher than those in the past (234.9 ± 137.5 fmol/mL, P = 0.008) and present infection groups (211.8 ± 124.2 fmol/mL, P < 0.001). Acyl-ghrelin was positively correlated with the PG I level and PG I/II ratio (|R| = 0.484, P < 0.001 and |R| = 0.403, P < 0.001, respectively). Both ghrelins were significantly decreased in accordance with the progress of endoscopic atrophy (both P < 0.001) and acyl-ghrelin was significantly lower in patients with mild, moderate and severe atrophy (24.5 ± 23.1 fmol/mL, 20.2 ± 14.9 fmol/mL and 18.3 ± 11.8 fmol/mL) than in those with non-atrophy (39.4 ± 22.2 fmol/mL, P = 0.039, P = 0.002 and P < 0.001, respectively). CONCLUSION In hemodialysis patients, plasma ghrelin level was associated with the endoscopic and serological severity of atrophy related to H. pylori infection.

Severity of Gastric Mucosal Atrophy Is the Major Determinant of Plasma Ghrelin Level in Hemodialysis Patients

Background: Ghrelin, an orexigenic hormone, has multiple favorable functions including protein anabolism enhancement, anti-inflammatory actions, and cardiovascular protection. A low plasma ghrelin level is associated with increased mortality in patients treated with hemodialysis (HD). However, it is unclear whether the plasma ghrelin level in HD patients correlates with the severity of gastric mucosal atrophy and Helicobacter pylori status. Methods: Seventy-eight maintenance HD patients and 51 non-dialysis patients with chronic kidney disease were evaluated for severity of gastric mucosal atrophy by gastroduodenoscopy and for H. pylori status using an anti-H. pylori-antibody and rapid urease test. Plasma acyl and des-acyl ghrelin levels were measured and their associations with relevant clinical parameters were investigated. Results: Des-acyl ghrelin level in HD patients was significantly higher than that in patients with kidney function preserved. Although acyl and des-acyl ghrelin levels were similar between current H. pylori positive and negative HD patients, both levels decreased significantly with the progress of endoscopic gastric mucosal atrophy in HD patients. Serum pepsinogen (PG) I level and PG I/II ratio decreased significantly according to the severity of atrophy in HD patients and positively significantly correlated with both ghrelin levels. Multiple regression analysis showed significant positive correlations between acyl ghrelin and PG I levels (β = 0.738, p < 0.001) and significant negative correlations between ghrelin and age, albumin, and creatinine levels. Conclusions: Gastric atrophy is the major determinant of ghrelin level in HD patients. Management practices, such as H. pylori eradication, before advanced atrophy may be required to prevent the decrease of ghrelin levels and improve the prognosis of HD patients.

Methoxy polyethylene glycol-epoetin beta for anemia with chronic kidney disease.

Chronic kidney disease (CKD) is a risk factor for end-stage renal failure and cardiovascular events. In patients with CKD, anemia is often caused by decreased erythropoietin production relative to hemoglobin levels. As correction of anemia is associated with improved cardiac and renal function and quality of life, erythropoiesis-stimulating agents (ESAs) are standard therapy for anemia in CKD patients. However, traditional ESAs such as epoetin or darbepoetin have short half-lives and require frequent administration, dose changes, and close monitoring of hemoglobin concentration to maintain target hemoglobin levels. Methoxy polyethylene glycol-epoetin beta (MPG-EPO) is the only ESA that is generated by chemical modification of glycosylated erythropoietin through the integration of one specific, long, linear chain of polyethylene glycol. This ESA induces continuous erythropoietin receptor activation and has a long half-life (approximately 130 hours). Subcutaneous or intravenous administration of MPG-EPO once every 2 weeks or monthly achieved a high hemoglobin response rate in patients with anemia associated with CKD, regardless of whether the patient was undergoing dialysis. According to data from an observational time and motion study, MPG-EPO maintains hemoglobin levels when the same dose is administered, however infrequently. This suggests that compared with the use of traditional ESAs, administration of MPG-EPO reduces the overall time and cost associated with the management of anemia in CKD patients undergoing dialysis. MPG-EPO is generally well tolerated and most adverse events are of mild to moderate severity. The most commonly reported adverse effects are hypertension, nasopharyngitis, and diarrhea. Subcutaneous injection of MPG-EPO is significantly less painful than subcutaneous injection of darbepoetin. In conclusion, MPG-EPO is as effective and safe as traditional ESAs in managing renal anemia, irrespective of whether the patient is undergoing dialysis.

Water intoxication induced by low-dose oral cyclophosphamide in a patient with anti-neutrophil cytoplasmic antibody-related glomerulonephritis.

We reported the case of a 70-year-old woman with moderate renal failure due to anti-neutrophil cytoplasmic antibody-related glomerulonephritis who developed symptomatic water intoxication (serum Na: 108 mEq/L) following treatment with oral low-dose cyclophosphamide (CY) (50mg/day). Estimated glomerular filtration rate was 29.5 mL/min/1.73 m2. She had drunk >2 L of fluid in 12 h prior to the development of cerebral oedema. This rare case suggests that oral low-dose CY could be an occult cause of water intoxication in patients with chronic kidney disease taking large fluid volumes.