Takuya Fujimaru

Background and Objective: Neutrophil extracellular trap (NET) formation has been proposed as a potential component of the inflammatory response associated with hemodialysis (HD). However, direct assessment of NET formation by neutrophils during HD has been limited. This study evaluated NET-associated signals in neutrophils during HD using flow cytometry and compared these findings with circulating NET-associated biomarkers. Methods: Ten clinically stable outpatients receiving regular HD with H₂-enriched dialysate (H₂-HD) participated in a prospective within-subject repeated-measures exploratory study. Patients underwent H₂-HD for 1 week (phase 1), standard HD (SHD) for 1 week (phase 2), and H₂-HD again for 1 week (phase 3). Blood samples were obtained immediately before and after the third HD session in each phase. NET-associated signals were assessed in isolated polymorphonuclear leukocyte preparations by flow cytometry using SYTOX Green and anti-myeloperoxidase (MPO) staining. Plasma cell-free DNA (cfDNA) and MPO-DNA complexes were also measured. Results: The proportion of SYTOX Green/MPO double-positive events in the predefined extracellular fraction increased significantly after HD during phase 2 (SHD), whereas no significant increase was observed during phases 1 or 3 (H₂-HD). Changes in the NET-associated signal did not differ significantly among the three phases. The change in the NET-associated signal was strongly correlated with the change in MPO-positive events (r=0.966, P2-HD on NET formation remains uncertain.

Background: Mean corpuscular volume (MCV) is routinely measured in patients with chronic kidney disease (CKD) and anemia; however, its prognostic significance, particularly in the context of erythropoiesis-stimulating agent (ESA) therapy, remains unclear. Methods: We conducted a post hoc analysis of the BRIGHTEN study, a multicenter, prospective trial that enrolled 1219 ESA-naïve patients with non-dialysis-dependent CKD who initiated darbepoetin alfa. Patients were categorized based on changes in MCV from baseline to week 16 as either increased or decreased. The primary outcome was renal function decline, defined as the initiation of dialysis, kidney transplantation, ≥ 50% reduction in estimated glomerular filtration rate (eGFR), or an eGFR ≤ 6 mL/min/1.73 m ² within 96 weeks. Results: MCV decreased in 778 (63.8%) patients during the study period. Changes in MCV were not correlated with baseline MCV values or ESA responsiveness. Over a mean follow-up of 2.46 ± 0.78 years, renal function decline occurred in 304 (39.1%) and 140 (31.7%) patients in the decreased and increased MCV groups, respectively. After adjusting for age, sex, baseline eGFR, albumin, high-sensitivity CRP, proteinuria, ferritin, transferrin saturation and ESA responsiveness, increased MCV remained independently associated with a reduced risk of renal function decline (adjusted hazard ratio 0.67; 95% confidence interval 0.53–0.85; p < 0.001). Conclusion: In ESA-naïve patients with non-dialysis-dependent CKD, an increase in MCV following ESA treatment was associated with a significantly lower risk of renal function decline. Monitoring MCV dynamics may serve as a simple, adjunctive tool for risk stratification and individualized CKD management.

A 47-year-old man with nephrotic syndrome and stage 4 chronic kidney disease was diagnosed with C1q nephropathy presenting with focal segmental glomerulosclerosis (FSGS) on a renal biopsy. A genetic analysis performed because of a family history of microscopic hematuria and lamellar glomerular basement membranes identified a heterozygous COL4A4 variant, leading to a genetic diagnosis of autosomal dominant Alport syndrome (ADAS). Despite immunosuppressive therapy, the patient progressed to end-stage kidney disease much earlier than in previously reported cases of C1q nephropathy. This case suggests that the synergistic effects of C1q nephropathy-induced podocyte damage and abnormal glomerular basement membrane due to ADAS may promote rapid progression of FSGS.

This article is part of a review series on water and electrolyte disorders, based on the annual “Electrolyte Winter Seminar” for early-career nephrologists in Japan. The seminar features interactive case-based discussions, some of which are included as self-assessment questions. The fifth installment addresses the management of hyperkalemia. Hyperkalemia frequently occurs in patients with chronic kidney disease (CKD) and can become life-threatening when severe, necessitating prompt treatment regardless of its underlying cause. Renin–angiotensin system inhibitors (RASi) are a recognized risk factor for hyperkalemia in CKD; however, discontinuing RASi in response to elevated potassium levels may adversely affect patient outcomes. Although there are no formal criteria distinguishing acute from chronic hyperkalemia, symptoms presentation and potassium levels offer a practical guide for clinical management. This review covers standard treatment strategies for severe (symptomatic or acute) hyperkalemia in emergency and inpatient settings and discusses how to manage mild-to-moderate (asymptomatic or chronic) cases in CKD patients while continuing RASi therapy.

This review article series on water and electrolyte disorders is based on the “Electrolyte Winter Seminar” that is held annually for young nephrologists in Japan. This seminar includes lively discussions based on cases, which have been partly included in this series as self-assessment questions. In this fourth article of the series, we have focused on the pathophysiology of potassium and the diagnosis of hyperkalemia. Hyperkalemia is associated with increased overall mortality, cardiovascular mortality, hospitalization, and progression to end-stage renal disease. Although most patients with hyperkalemia exhibit impaired kidney function, some exhibit normal kidney function. Therefore, accurately diagnosing the underlying cause of hyperkalemia is crucial for its appropriate management. In this review, we have first discussed the pathophysiology of potassium regulation. We have then highlighted the causes of hyperkalemia other than chronic kidney disease, including pseudohyperkalemia, which is often overlooked in clinical practice, and hypoaldosteronism, which can cause hyperkalemia even in patients with normal or mildly impaired kidney function. Finally, we have shared practical “Tips and Pearls” on hyperkalemia for clinicians that are applicable in daily practice.

Background Unplanned intensive care unit (ICU) transfers owing to clinical deterioration contribute to in-hospital mortality. The risk factors for unplanned ICU transfers among the general population have been investigated, whereas those among patients undergoing hemodialysis remain unclear. Therefore, this study aimed to examine the risk factors for clinical deterioration in hospitalized patients undergoing hemodialysis. Methods We conducted a single-center, retrospective, observational cohort study, focusing on hospitalized adult patients receiving maintenance hemodialysis between January 2003 and December 2020. Age, sex, planned or emergency hospitalization type, hemodialysis duration, vital signs, quick sequential organ failure assessment score, serum albumin levels, and comorbid conditions (diabetes mellitus, coronary artery disease [CAD], peripheral artery disease, cerebrovascular disease, intradialytic hypotension, and cancer) were considered as predictors. For all predictors, data at admission were used. Outcomes measured included clinical deterioration, unplanned ICU transfers within 72 h to 30 days after admission, and sudden death within 30 days. Results Among the 389 enrolled patients (median age: 73.1 years, 64.3% male), 40 patients experienced clinical deterioration: 37 (9.5%) underwent unplanned ICU transfers, and 3 (0.8%) experienced sudden deaths in general wards. In-hospital mortality was significantly higher in the deterioration group than in the non-deterioration group (62.5% vs 5.4%, p < 0.001, respectively). Cox regression analysis identified CAD as an independent risk factor for clinical deterioration (hazard ratio: 2.11; 95% confidence interval: 1.05–4.24). Conclusions CAD is a risk factor for clinical deterioration in hospitalized patients undergoing hemodialysis.

This review article series on water and electrolyte disorders is based on the ‘Electrolyte Winter Seminar’ held annually for young nephrologists in Japan. This is the third article in this series that focuses on water and electrolyte disturbances caused by novel pharmacological agents for kidney disease and cancer. The advent of novel pharmacological agents in cardiorenal medicine and oncology has introduced both therapeutic benefits and challenges in managing medication-induced water and electrolyte disturbances. These medications, including sodium–glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (ns-MRAs), and immune checkpoint inhibitors (ICIs), significantly impact water and electrolyte homeostasis. SGLT2 inhibitors used widely in diabetes mellitus, heart failure, and chronic kidney disease mitigate hyperkalemia and hypomagnesemia but increase the risk of hypernatremia in patients on fluid restriction. Conversely, they are beneficial for managing hyponatremia in the syndrome of inappropriate antidiuresis (SIAD). ns-MRAs, prescribed for diabetic kidney disease, exhibit a high risk of hyperkalemia, particularly when combined with renin–angiotensin system inhibitors. ICIs, a breakthrough in oncology, frequently induce hyponatremia through immune-related adverse events, such as hypophysitis and non-immune-related adverse events like SIAD. Understanding the pathophysiology of these disturbances and implementing timely interventions, including hormone replacement and water and electrolyte management, is critical for optimizing treatment outcomes.

This review article series on water and electrolyte disorders is based on the ‘Electrolyte Winter Seminar’ held annually for young nephrologists in Japan. The seminar features dynamic case-based discussions, some of which are included as self-assessment questions in this series. The second article in this series focuses on treatment of hyponatremia, a common water and electrolyte disorder frequently encountered in clinical practice. Hyponatremia presents diagnostic challenges due to its various etiologies and the presence of co-morbidities that affect water and electrolyte homeostasis. Furthermore, limited evidence, including a lack of robust randomized controlled trials, complicates treatment decisions and increases the risk of poor outcomes from inappropriate management of both acute and chronic hyponatremia. This review provides a comprehensive overview of treatment of hyponatremia for better comprehension and improved clinical practice.

This review article series on water and electrolyte disorders is based on the 'Electrolyte Winter Seminar' held annually for young nephrologists in Japan. The seminar includes lively discussions based on cases, which are also partly included in this series as self-assessment questions. The first article in this series focuses on pathophysiology, symptoms, outcomes, and evaluation of hyponatremia, a common water and electrolyte disorder in clinical practice. Diagnosing the root cause(s) of hyponatremia can be challenging due to various etiologies and co-morbidities that affect water and electrolyte homeostasis, which can result in inappropriate management and worse outcomes in acute and chronic hyponatremia. This review provides an overview of pathophysiology, symptoms, outcomes, and evaluation of hyponatremia for better comprehension and improved clinical practice.

Background: There are limited data on the long-term outcomes and risk factors for non-recovery after development of rituximab (RTX)-associated persistent hypogammaglobulinaemia among children with idiopathic nephrotic syndrome (NS). Methods: A nationwide Japanese survey was conducted to determine the prognosis of patients with childhood-onset idiopathic NS who developed persistent hypogammaglobulinaemia after RTX administration. Specifically, predictors of IgG level recovery and risk factors for serious infection were examined. Results: The cohort comprised 118 patients (66.1% boys; median age at initial RTX administration, 7.5 years). Among the 121 patients diagnosed with persistent hypogammaglobulinaemia, only 31 (26.3%) recovered within a median observation period of 2.8 years; approximately 70% of patients continued to exhibit persistent hypogammaglobulinaemia. Among the patients who recovered from hypogammaglobulinaemia, the median time to recovery was 14.1 months. Patients with a history of steroid-resistant NS were less likely to recover from persistent hypogammaglobulinaemia (hazard ratio 0.28; 95% confidence interval 0.09–0.87). In addition, of the 118 eligible patients, 18 (15.3%) developed serious infections requiring hospitalization, and the main risk factor for infection during hypogammaglobulinaemia was agranulocytosis (a well-known adverse effect of RTX in children). Conclusions: A significant portion of patients with RTX-associated persistent hypogammaglobulinaemia did not exhibit recovery even after 1 year. Moreover, the data indicate that patients with a history of steroid-resistant NS have a significantly lower probability of recovering from this condition. Agranulocytosis under hypogammaglobulinaemia was significantly associated with an elevated risk of serious infections.