Changes in erythropoiesis-stimulating agent responsiveness after transfer to combined therapy with peritoneal dialysis and hemodialysis for patients on peritoneal dialysis: A prospective multicenter study in Japan.

INTRODUCTION: Inadequate dialysis and fluid overload are corrected after starting combined therapy with peritoneal dialysis (PD) and hemodialysis (HD). However, the effects on anemia management has not been elucidated. METHODS: We conducted a prospective, multicenter, observational cohort study of 40 PD patients (age, 60 ± 10 years; male, 88%; median PD duration, 28 months) starting combined therapy and investigated changes in several clinical parameters, including erythropoiesis-stimulating agent (ESA) resistance index (ERI). RESULTS: ERI decreased significantly during 6 months after switching to combined therapy (from 11.8 [IQR 8.0-20.4] units/week/kg/(g/dL) to 7.8 [IQR 3.9-18.6] units/week/kg/(g/dL), p = 0.047). Body weight, urinary volume, serum creatinine and the dialysate-to-plasma creatinine ratio (D/P Cr) decreased, whereas hemoglobin and serum albumin increased. In subgroup analysis, the changes in ERI were not affected by cause for starting combined therapy, PD holiday and D/P Cr. CONCLUSION: Although detailed mechanism was unclear, ESA responsiveness improved after switching from PD alone to combined therapy.

Pleiotropic effect of erythropoiesis-stimulating agents on circulating endothelial progenitor cells in dialysis patients.

BACKGROUND: Recent studies have suggested that erythropoiesis-stimulating agents (ESAs) may accelerate not only angiogenesis but also vasculogenesis, beyond erythropoiesis. METHODS: We conducted a 12-week prospective study in 51 dialysis patients; 13 were treated with recombinant human erythropoietin (EPO, 5290.4 ± 586.9 IU/week), 16 with darbepoetin (DA, 42.9 ± 4.3 µg/week), 12 with epoetin ß pegol (CERA, 40.5 ± 4.1 µg/week) and 10 with no ESAs. Vascular mediators comprising endothelial progenitor cells (EPCs), vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), and high-sensitivity C-reactive protein (hs-CRP) were measured at 0 and 12 weeks. EPCs were measured by flow cytometry as CD45lowCD34+CD133+ cells. RESULTS: The EPC count increased significantly to a greater extent in the EPO group than in the other three group, and increased significantly from 0 to 12 weeks in a EPO dose-dependent manner. In both the DA and CERA groups, the EPC count did not change at 12 weeks. Serum levels of VEGF, MMP-2 and hs-CRP were not affected by ESA treatment in all groups. In the CERA group, serum ferritin decreased significantly compared to the no-ESA group and correlated with CERA dose, although use of iron was permitted if required during the prospective study period of 12 weeks. CONCLUSIONS: When patients on dialysis were treated with clinical doses of various ESAs, only EPO induced a significant increase of circulating EPCs from bone marrow, whereas, DA and CERA had no effect.

Modulation of circulating endothelial progenitor cells by erythropoiesis-stimulating agents in patients with chronic kidney disease stage G5 and 5D
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AIMS: Circulating endothelial progenitor cells (EPCs) play a pivotal role in vasculogenesis and promote angiogenesis by secreting growth factors. Recent studies have suggested that erythropoietin (EPO) may accelerate not only angiogenesis but also vasculogenesis, beyond erythropoiesis. The aim of this study was to investigate whether two erythropoiesis-stimulating agents (ESAs) modulate vascular-related factors and EPC mobilization in patients with chronic kidney disease stage G5 and dialysis (CKD G5 and 5D). MATERIALS AND METHODS: We conducted a 12-week prospective study in 63 patients; 21 patients received recombinant human erythropoietin (rhEPO) (EPO group, 4,565.5 ± 1,994.4 IU/week), 21 patients received darbepoetin (DA) (DA group, 40.1 ± 13.8 µg/week), and 21 patients received no ESAs (no-ESA group). Vascular mediators, including EPCs, vascular endothelial growth factor, matrix metalloproteinase-2 (MMP-2), high-sensitivity C-reactive protein, and asymmetric dimethyl arginine, were measured at 0 and 12 weeks. EPCs were measured by flow cytometry as CD45lowCD34+CD133+ cells. We also performed a subanalysis of dialysis (5D) patients (n = 32) in the three groups. RESULTS: In the EPO group, EPC count increased significantly from 0 to 12 weeks in a dose-dependent manner (r = 0.62, p = 0.005), and the increase was more conspicuous in the subgroup of dialysis 5D patients. In the DA group, the EPC number did not change at 12 weeks. Neither rhEPO nor DA affected the serum levels of the aforementioned biomarkers other than EPC. ;Conclusion: We speculate that the pleiotropic effects of rhEPO and DA beyond their hematopoietic effects may differ between CKD G5 and 5D patients.
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Establishment and characterization of a novel VEGF-producing HHV-8-unrelated PEL-like lymphoma cell line, OGU1.

Primary effusion lymphoma (PEL) is a rare B-cell lymphoma subtype that is characterized by lymphomatous effusion without the presence of masses, and it typically occurs in human immunodeficiency virus (HIV)-infected individuals. Lymphoma cells are universally positive for human herpesvirus 8 (HHV-8). Recently, a cavity-based effusion lymphoma that is similar to PEL without HHV-8 infection, called HHV-8-unrelated PEL-like lymphoma, has been reported in non-HIV-infected individuals. However, the pathophysiology of this lymphoma is largely undefined. We established a novel B-cell line OGU1 derived from a patient with HHV-8-unrelated PEL-like lymphoma. Notably, OGU1 cells produced vascular endothelial growth factor (VEGF) and expressed VEGF receptor 1, whose inhibitors retarded cell growth. Because VEGF acts as a vascular permeability and growth factor, it could play a role, at least in part, in the pathogenesis of this unique lymphoma. Thus, the OGU1 cell line is useful for the investigation of HHV-8-unrelated PEL-like lymphoma.

The Prevalence of the Risk Factors for Atherosclerosis among Type 2 Diabetic Patients Is Greater in the Progressive Stages of Chronic Kidney Disease.

BACKGROUND/AIMS: The prevalence of the risk factors for atherosclerosis, other than diabetes mellitus, among type 2 diabetic patients with different stages of chronic kidney disease (CKD) determined by glomerular filtration rate (GFR) was investigated. METHODS: The prevalence of ten risk factors (age ≥65 years, history of smoking, male gender, obesity, albuminuria, hypertension, hypercholesterolemia, hypo-HDL-cholesterolemia, hyperuricemia and anemia) was determined in 2,107 Japanese type 2 diabetic patients with different stages of CKD (six stages according to GFR). RESULTS: The risk factors for age ≥65 years and male gender were found in 49 and 62% of the study subjects, respectively. The percentages of subjects with a current history of smoking, obesity, albuminuria, hypertension, hypercholesterolemia, hypo-HDL-cholesterolemia, hyperuricemia and anemia were 35, 44, 47, 70, 61, 13, 21 and 26%, respectively. The prevalence of age ≥65 years, male gender, albuminuria, hypertension, hypo-HDL-cholesterolemia, hyperuricemia and anemia was greater in the later stages of GFR, whereas the prevalence of hypercholesterolemia and obesity did not differ between stages. The prevalence of a current history of smoking was lower in the later stages of GFR. The cumulative number of risk factors increased from 3.1 to 6.8 in the later stages of GFR. CONCLUSION: Among type 2 diabetic patients with CKD, the total number of risk factors increases with the progression of renal dysfunction. It is important to pay attention to newly recognized risk factors for hyperuricemia and anemia, in addition to hypertension, albuminuria and hypo-HDL-cholesterolemia, in monitoring diabetic patients with later stages of CKD.

Randomized controlled open-label trial of vitamin E-bonded polysulfone dialyzer and erythropoiesis-stimulating agent response.

BACKGROUND AND OBJECTIVES: A 1-year multicenter prospective randomized controlled study was conducted on the effects of vitamin E-bonded polysulfone dialyzers on erythropoiesis-stimulating agent response in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Major inclusion criteria were use of high-flux polysulfone dialyzers with 50-70 ml/min ß2-microglobulin clearance over 3 months, transferrin saturation over 20%, same erythropoiesis-stimulating agent for over 3 months, and hemoglobin at 10-12 g/dl. Hemodialysis patients were placed in four interventional groups: two hemoglobin ranges (10.0-10.9 or 11.0-11.9 g/dl) and two dialyzers. Patients were randomly assigned by central registration to a vitamin E-bonded polysulfone dialyzers or polysulfone control group. Primary end point was relative erythropoiesis resistance index at baseline between groups at 12 months. Erythropoiesis resistance index was defined as total weekly erythropoiesis-stimulating agent dose divided by hemoglobin. RESULTS: There were no statistically significant differences in age or sex. There was no significant difference in relative erythropoiesis resistance index between vitamin E-bonded polysulfone dialyzers and control groups at 12 months (vitamin E-bonded polysulfone dialyzers: 1.1, control: 1.3). The vitamin E-bonded polysulfone dialyzers group showed better relative erythropoiesis resistance index than the control group at 11.0-11.9 g/dl hemoglobin (vitamin E-bonded polysulfone dialyzers: 1.0, control: 1.4 at 12 months, significant difference) but no difference at 10.0-10.9 g/dl hemoglobin. CONCLUSIONS: The overall relative erythropoiesis resistance index showed no difference between the vitamin E-bonded polysulfone dialyzers and control groups, although the change in relative erythropoiesis resistance index differed according to hemoglobin level.

[Clinicopathological analysis of malignant nephrosclerosis].

BACKGROUND: Although pathological changes in the vascular lesions of malignant nephrosclerosis have been quantified, little is understood about interstitial changes. We quantified pathological changes such as glomerular damage (glomerular sclerosis and collapse), vascular patency and interstitial fibrosis to determine statistical correlations with clinical data. METHODS: We examined 25 patients who were diagnosed with malignant hypertension and investigated correlations among age, urinary protein, SUN, 1/Cre, systolic BP and diastolic BP (from medical charts), interstitial fibrosis, glomerular damage, acute tubular damage (semiquantified by scoring) and arterial and arteriolar patency (from renal biopsies). RESULTS: Interstitial fibrosis inversely correlated with 1/Cre (p=0.0114), interlobular arterial patency (p= 0.0139) and total vascular patency (p = 0.0499). Glomerular damage tended to correlate with urinary protein, but the values did not reach the level of statistical significance (p=0.0666). On the other hand, glomerular damage correlated with neither interstitial fibrosis nor vascular patency. Acute tubular damage closely correlated with both diastolic (p= 0.0086) and systolic (p = 0.0075) BP. CONCLUSIONS: Interstitial damage increases with decreasing interlobular arterial patency and renal function decreases with increasing interstitial damage. Since acute tubular damage that can progress to chronic interstitial damage closely correlates with BP, the control of BP might indirectly influence the prognosis of renal function.

[Histological investigation of renal pathological changes in MPO-ANCA-related nephritis using repeat renal biopsies].

We compared the histological changes before and after treatment in 14 cases of myeloperoxidase antineutrophil cytoplasmic autoantibodies (MPO-ANCA) related nephritis in whom we were able to perform two renal biopsies. The results show that the clinical findings and acute glomerular and tubulointerstitial injuries decreased, while chronic glomerular injuries increased. No changes were seen in minor glomerular abnormalities(MGAs) or chronic tubulointerstitial injuries between the first and second biopsies. In the vascular system, no treatment related aggravation of arteriosclerosis occurred and it was found that fibrinoid necrosis disappeared with treatment. Finally, in MPO-ANCA related nephritis, the care given between the first and second biopsies caused acute glomerular injuries to become chronic glomerular injuries, but no changes were detected in the MGA. We believe that the changes in acute tubulointerstitial injuries reflected an improvement in renal function, since the acute tubulointerstitial injuries obviously improved in response to PSL, contributing to the improved renal function. In other words, MPO ANCA-related nephritis is a condition that involves "acute glomerulonephritis+ acute tubulointerstitial nephritis + angiitis," and it is thought that the characteristics of each are independent. We believe that the renal function improved as the acute tubulointerstitial nephritis improved, while the acute glomerular injuries developed into chronic glomerular injuries.

Expression of matrix metalloproteinase-9 associated with ets-1 proto-oncogene in rat tubulointerstitial cells.

BACKGROUND: Ets-1 proto-oncogene exhibits multiple activities in the transcriptional regulation of numerous genes including metalloproteinase (MMP)-1, -3 and -9. MMPs play an important role in the remodelling of extracellular matrix in various renal diseases. However, the role of the Ets-1-MMP axis in advanced renal diseases is uncertain. In the present study, we investigated whether Ets-1 is involved in interleukin (IL)-1-mediated expression of MMPs in tubulointerstitial cells. METHODS: Rat renal fibroblasts (NRK-49F) and tubular epithelial cells (NRK-52E) were cultured and allocated to an IL-1beta-treated group (10 ng/ml), a platelet-derived growth factor (PDGF)-BB-treated group (25 ng/ml) and a control group. Protein and mRNA were extracted after 1, 6, 12 and 24 h of treatment. Parallel flasks were treated with 2 muM ets-1 antisense oligodeoxynucleotides (ODNs) before exposure to IL-1beta. The expression of Ets-1 protein was evaluated by western blotting. The activities of MMPs were evaluated by gelatin zymography. The expression of ets-1 and/or MMP-9 mRNA was evaluated semiquantitatively by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In NRK-49F cells, Ets-1 protein increased significantly by 6.8-fold at 6 h, and MMP-9 activity increased significantly by 9.9-fold at 12 h in the IL-1beta-treated group compared with controls. MMP-2 and -3 activities also increased significantly in the IL-1beta-treated group. In NRK-52E cells, Ets-1 protein was 3.1 times higher at 1 h, and the latent form of MMP-9 activity increased 3.4-fold at 6 h in the IL-1beta group compared with controls. However, MMP-2 or MMP-3 activities were not markedly altered by IL-1beta treatment compared with controls. When the cells were treated with ets-1 antisense ODNs before IL-1beta treatment, Ets-1 protein expression decreased at least 50%, and MMP-9 activity was clearly inhibited in both cells. We also confirmed that MMP-9 activity was upregulated on days 21 and 28 in renal cortex of rat crescentic glomerulonephritis. CONCLUSIONS: The Ets-1 transcriptional factor may participate in IL-1beta-mediated MMP-9 expression in tubulointerstitial cells.