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

Angiotensin II Type 1 Receptor Blockers Reduce Urinary Angiotensinogen Excretion and the Levels of Urinary Markers of Oxidative Stress and Inflammation in Patients with Type 2 Diabetic Nephropathy

Objective To demonstrate that the administration of an angiotensin (Ang) II type 1 receptor (AT1R) blocker (ARB) inhibits the vicious cycle of high glucose (HG)-reactive oxygen species (ROS)-angiotensinogen (AGT)-Ang II-AT1R-ROS by suppressing ROSs and inflammation, thus ameliorating diabetic nephropathy (DN). Research Design and Methods Thirteen hypertensive DN patients were administered ARBs, and the following parameters were evaluated before and 16 weeks after the treatment: urinary AGT (UAGT), albumin (albumin-creatinine ratio: ACR), 8-hydroxydeoxyguanosine (8-OHdG), 8-epi-prostaglandin F2α (8-epi-PGF2α), monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, and IL-10. Results ARB treatment reduced the blood pressure and urinary levels of AGT, ACR, 8-OHdG, 8-epi-PGF2α, MCP-1, and IL-6 but increased the urinary levels of IL-10. The reduction rate of UAGT correlated with the reduction rate of blood pressure; the reduction rates of the urinary ACR, 8-OHdG, 8-epi-PGF2α, MCP-1, and IL-6 levels; and the increase rate of the urinary IL-10 levels. Moreover, subjects who had high UAGT values at baseline exhibited higher reduction rates of urinary albumin excretion. Conclusions ARB-induced blockade of the abovementioned vicious cycle contributes to the renoprotective effects of ARBs in DN. The urinary levels of AGT could represent a predictive factor for reduced ACR in patients receiving ARB treatment

The Amelioration of Renal Damage in Skp2-Deficient Mice Canceled by p27 Kip1 Deficiency in Skp2−/− p27−/− Mice

SCF-Skp2 E3 ubiquitin ligase (Skp2 hereafter) targets several cell cycle regulatory proteins for degradation via the ubiquitin-dependent pathway. However, the target-specific physiological functions of Skp2 have not been fully elucidated in kidney diseases. We previously reported an increase in Skp2 in progressive nephropathy and amelioration of unilateral ureteral obstruction (UUO) renal injury associated with renal accumulation of p27 in Skp2−/− mice. However, it remains unclear whether the amelioration of renal injury in Skp2−/− mice is solely caused by p27 accumulation, since Skp2 targets several other proteins. Using Skp2−/−p27−/− mice, we investigated whether Skp2 specifically targets p27 in the progressive nephropathy mediated by UUO. In contrast to the marked suppression of UUO renal injury in Skp2−/− mice, progression of tubular dilatation associated with tubular epithelial cell proliferation and tubulointerstitial fibrosis with increased expression of collagen and α-smooth muscle actin were observed in the obstructed kidneys in Skp2−/−p27−/− mice. No significant increases in other Skp2 target proteins including p57, p130, TOB1, cyclin A and cyclin D1 were noted in the UUO kidney in Skp2−/− mice, while p21, c-Myc, b-Myb and cyclin E were slightly increased. Contrary to the ameliorated UUO renal injure by Skp2-deficiency, the amelioration was canceled by the additional p27-deficiency in Skp2−/−p27−/− mice. These findings suggest a pathogenic role of the reduction in p27 targeted by Skp2 in the progression of nephropathy in UUO mice

Prevalence of Enhanced Granular Expression of Thrombospondin Type-1 Domain-Containing 7A in the Glomeruli of Japanese Patients with Idiopathic Membranous Nephropathy.

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults. Autoantibodies against M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A), which mainly belong to the IgG4 subclass, were reported as associated antibodies for the development of MN. Although PLA2R is a major target antigen for idiopathic MN, the prevalence of MN patients seropositive for PLA2R in Japan is lower than that in other countries. In this study, we conducted immunohistochemical analysis of the presence of THSD7A and PLA2R in renal specimens of MN patients to estimate the prevalence of THSD7A/PLA2R-related idiopathic MN in Japan. Enhanced granular expression of THSD7A and PLA2R was detected in 9.1% and 52.7%, respectively, of the patients with idiopathic MN. Although none of patients with secondary MN displayed enhanced granular expression of THSD7A, 5.4% of them had enhanced granular expression of PLA2R. In conclusion, the prevalence of enhanced granular expression of THSD7A in the glomeruli of Japanese patients with idiopathic MN was higher than the prevalence of MN patients seropositive for THSD7A in USA and Europe

Decline in Walking Independence and Related Factors in Hospitalization for Dialysis Initiation: A Retrospective Cohort Study

Patients with chronic kidney disease require intervention planning because their physical function declines with worsening disease. Providers can work closely with patients during the induction phase of dialysis. This single-center, retrospective observational study aimed to investigate the rate of decline in walking independence during the induction phase of dialysis and the factors that influence this decline, and to provide information on prevention and treatment during this period. Of the 354 patients who were newly initiated on hemodialysis between April 2018 and January 2022, 285 were included in the analysis. The functional independence measure-walking score was used to sort patients into decreased walking independence (DWI; n = 46) and maintained walking independence (no DWI; n = 239) groups, and patient characteristics were compared. After adjusting for various factors by logistic regression analysis, we observed that age, high Charlson comorbidity index (CCI), C-reactive protein, and emergency dialysis start (EDS) were significant predictors of DWI. Even during the very short period of dialysis induction, as many as 16.1% of patients had DWI, which was associated with older age, higher CCI, higher inflammation, and EDS. Therefore, we recommend the early identification of patients with these characteristics and early rehabilitation

Examples of positive and negative staining for THSD7A, PLA2R, and IgG4.

<p>Positive staining for THSD7A (a, b), PLA2R (e, f), and IgG4 (i, j), and negative staining for THSD7A (c, d), PLA2R (g, h), and IgG4 (k, l) are shown.</p

Characteristics of idiopathic membranous nephropathy (MN) patients with enhanced granular expression of thrombospondin type-1 domain-containing 7A (THSD7A) or M-type phospholipase A2 receptor (PLA2R) in the glomeruli.

<p>Characteristics of idiopathic membranous nephropathy (MN) patients with enhanced granular expression of thrombospondin type-1 domain-containing 7A (THSD7A) or M-type phospholipase A2 receptor (PLA2R) in the glomeruli.</p

Immunohistochemical analysis for thrombospondin type-1 domain-containing 7A (THSD7A) and M-type phospholipase A2 receptor (PLA2R).

<p>Immunostaining for THSD7A (a, c, e) and PLA2R (b, d, f) in patients with idiopathic membranous nephropathy (a–d) and secondary membranous nephropathy (e, f). Original magnification: ×400. Inset, enhanced granular expression of THSD7A (a) and PLA2R (d) shown at a higher magnification (arrows). Abbreviations: THSD7A, Thrombospondin type-1 domain-containing 7A; PLA2R, M-type phospholipase A2 receptor; MN, membranous nephropathy.</p