Clinical and Experimental Nephrology最新文献

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: Encapsulating peritoneal sclerosis (EPS) is one of the most serious complications of peritoneal dialysis (PD). Although the incidence and severity of EPS are said to have decreased with the widespread adoption of biocompatible neutral PD solutions, the overall prevalence in Japan remains unclear.

Methods: We extracted patients with EPS from 2012 to 2022 using the Web-based Analysis of Dialysis Data Archives (WADDA) system of the Japanese Society for Dialysis Therapy. EPS was defined as present in patients with a history of PD treatment presenting with symptoms of ileus due to intestinal adhesion. Patients with only ascites, calcification of the intestine or bloody PD effluent were not defined as having EPS. We collected data from patients with EPS including sex, age, dialysis modality, dialysis duration, cause of end-stage kidney disease and cause of death among deceased patients.

Results: Approximately 700 patients with EPS were identified (60-65% males; mean age, 61-66 years), accounting for 5% of the sum of PD patients and patients on other dialysis modalities with experience of PD. The majority received hemodialysis or hemodiafiltration, with a mean dialysis duration of 12-14 years. The crude death rate was approximately 5% and death from ileus was more frequent than in the total cohort of dialysis patients.

Conclusions: The present study using a nationwide database of Japanese dialysis patients revealed a large number of patients with EPS. We plan to conduct a longitudinal study to clarify outcomes for patients with EPS.

Background: Numerous kidney diseases progress to end-stage kidney disease (ESKD); however, a limited number of cohort studies have evaluated the underlying kidney diseases through kidney biopsy (KB).

Methods: We retrospectively evaluated all patients who initiated dialysis at Toranomon Hospital, Japan, from 1985 to 2019, and whose underlying kidney disease had been diagnosed by KB. The data on histopathological diagnosis and various clinical characteristics were collected and analyzed for 357 patients.

Results: The most prevalent underlying diseases, which constituted the primary endpoint of this study, were diabetic nephropathy (DN; n = 100, 28.0%), IgA nephropathy (IgAN; n = 99, 27.7%), and focal segmental glomerulosclerosis (n = 34, 9.5%). Benign nephrosclerosis (BNS; n = 1, 0.3%), that is, arteriosclerosis/arteriolosclerosis without distinct glomerulopathy, was rare. As the secondary endpoint, Cox regression analysis revealed that lower eGFR (p < 0.0001), higher proteinuria (p < 0.0001), older age (p = 0.005) and presence of DN (p = 0.008) were significant independent risk factors for early dialysis initiation. In the subgroup analysis, when comparing DN and IgAN, significantly earlier dialysis initiation was observed in DN than in IgAN by log-rank analysis (p < 0.0001), as well as after adjustment for baseline clinical characteristics using propensity score matching (n = 45 each) (p = 0.023).

Conclusions: We identified a list of kidney diseases that were at risk for ESKD at the time of KB through a long-term follow-up. DN and IgAN are the two primary causes of ESKD, whereas BNS is an infrequent direct cause of ESKD in patients requiring kidney biopsy.

Background: Inquiries by community pharmacists to physicians regarding prescriptions for patients with impaired renal function are an important part of pharmaceutical care. However, such inquiries remain infrequent in Japan. To address this, we conducted a study to assess the effects of an educational program aimed at improving pharmacists' understanding of renal function assessment and prescription management.

Methods: We evaluated the changes in knowledge and awareness of pharmacists at 14 community pharmacies. The participants watched five instructional videos between September 12 and 18, 2022, and a questionnaire survey was administered immediately before and after the program. In addition, we analyzed pharmacy-level changes in the number of inquiries made to physicians regarding prescriptions related to renal function. The study was performed from June 6 to December 25, 2022. Changes were evaluated using interrupted time series (ITS) analysis.

Results: A total of 43 pharmacists viewed the educational videos. The median number of correct answers increased significantly from seven before the intervention to nine afterwards (p < 0.001). During the study period, 64 inquiries related to renal function were recorded. ITS analysis showed no significant change in the number of inquiries following the intervention.

Conclusion: Although the educational program improved the knowledge of the pharmacists, it did not lead to an increase in the number of inquiries made to physicians. Further larger scale studies are needed to validate the program's effectiveness.

Background: Cardiovascular disease remains a significant cause of death in kidney transplant recipients. While several studies have demonstrated the association of aortoiliac calcification with cardiovascular disease and mortality, few have reported the association between segmental (especially internal iliac artery) aortoiliac calcification and prognosis. This study evaluated the association between segmental aortoiliac calcification scores and cardiovascular disease incidence and mortality after kidney transplantation.

Methods: This retrospective study included 104 primary living-donor kidney transplant recipients at our hospital between 2009 and 2023 who underwent preoperative computed tomography. The aortoiliac calcification quantification was performed on non-contrast computed tomography using the Agatston score. The aortoiliac artery was divided into four segments: distal aorta, common iliac artery, external iliac artery, and internal iliac artery.

Results: The median follow-up period was 61 months; 15 recipients died, and 28 experienced cardiovascular disease. The ability to distinguish cardiovascular disease was the best for the internal iliac artery, followed by the common iliac artery (area under the curve: 0.75 and 0.73, respectively). The high calcification group, classified by the internal iliac artery and common iliac artery calcification scores, was associated with a poorer prognosis for cardiovascular disease-free and patient survival. Multivariate analysis revealed that internal iliac artery calcification and age were independent risk factors for cardiovascular disease (hazard ratio: 5.08 and 5.74, respectively) and patient survival (hazard ratio: 4.67 and 7.61, respectively).

Conclusion: The internal iliac artery calcification score was more closely associated with cardiovascular disease onset and mortality than other segment calcification scores.

Background: The proteinuria selectivity index (SI) is a valuable marker of glomerular permeability. Traditionally, SI has been calculated using the clearance ratio of immunoglobulin G (IgG) to transferrin-SI (Tf)-due to historical limitations in albumin measurement accuracy. However, recent advances have enabled precise quantification of albumin, raising the possibility of using an albumin-based SI-SI (Alb)-in clinical practice. This study aimed to evaluate the correlation between SI (Alb) and SI (Tf) and to compare their diagnostic utility in patients with proteinuria.

Methods: We retrospectively analyzed 265 patients with proteinuria > 0.15 g/g·Cr who visited Ehime University Hospital between January 2014 and April 2024. SI (Alb) and SI (Tf) were calculated as the clearance ratios of IgG to albumin and IgG to transferrin, respectively. Linear regression was used to assess their correlation. Diagnostic performance for minimal change disease (MCD) in patients with nephrotic-range proteinuria (≥ 3.5 g/g·Cr) was evaluated using ROC curves, and AUCs were compared using DeLong's test.

Results: SI (Alb) strongly correlated with SI (Tf) in patients with proteinuria ≥ 3.5 and < 3.5 g/g·Cr. Among patients with nephrotic-range proteinuria, both indices effectively identified MCD, yielding comparable areas under the ROC curve. Sensitivity and specificity at optimal thresholds were similarly high.

Conclusion: SI (Alb) shows a high degree of concordance with SI (Tf) and offers comparable diagnostic accuracy for identifying MCD. Given its practical advantages, SI (Alb) may serve as a reliable and convenient alternative to SI (Tf) for assessing glomerular selectivity in patients with proteinuria.

Background: Uremic pruritus (UP) is a distressing condition in hemodialysis patients with unclear mechanisms. This study investigates the role of LCN2 in pruritus, focusing on its interaction with GRP/GRPR signaling and astrocyte activation.

Methods: Clinical skin biopsy samples from CKD patients with and without UP were analyzed for LCN2 expression. A chronic renal failure mouse model (UP model) was established through surgical kidney ablation, while a morphine-induced itch model was generated via intrathecal morphine injection. LCN2 knockout (LCN2^-/-) mice were used to evaluate its functional role in itch modulation. Scratching behavior was recorded, and Western blot, qRT-PCR, immunohistochemistry, immunofluorescence, and ELISA were performed to assess LCN2 expression, GRP/GRPR signaling, and inflammatory cytokines in the spinal cord. Additionally, RC-3095 (a GRPR inhibitor) and GRP were administered to evaluate their effects on pruritus.

Results: LCN2 expression was elevated in CKD patients with UP and positively correlated with itch severity. Similarly, UP model mice showed increased spinal LCN2 levels, while LCN2 deficiency (LCN2^-/- mice) reduced scratching behavior. Mechanistically, LCN2 promoted pruritus by enhancing GRP/GRPR signaling and astrocyte activation. Blocking GRP/GRPR with RC-3095 reduced pruritus in both UP and morphine-induced models, confirming LCN2's role in itch transmission.

Conclusion: LCN2 mediates pruritus by promoting GRP/GRPR signaling, astrocyte activation, and neuroinflammation, making it a potential therapeutic target for CKD-related and opioid-induced pruritus.

Background: Sepsis, a systemic inflammatory disease, often leads to severe complications, including septic acute kidney injury (AKI). Despite its prevalence, effective treatments for septic AKI remain elusive. MicroRNAs (miRNAs) are critical regulators of gene expression and play essential roles in sepsis pathogenesis. This study investigates the function and regulatory pathway of miR-760 in septic AKI.

Methods: Septic AKI models were developed using lipopolysaccharide (LPS)-treated mice and HK-2 renal tubular epithelial cells. Renal pathology was assessed via H&E staining, while renal function was assessed through the measurement of blood urea nitrogen (BUN) and creatinine levels. Apoptosis, inflammation, and oxidative stress markers were analyzed using functional assays, ELISA, and flow cytometry. Bioinformatics analysis, RT-qPCR, and dual luciferase reporter assays were used to identify and validate miR-760's target, enkurin domain containing 1 (ENKD1).

Results: Database analysis and experimental validation revealed markedly decreased level of miR-760-3p levels in LPS-induced septic AKI mice model. MiR-760-3p overexpression in vivo ameliorated renal damage, improved kidney function, and reduced tubular apoptosis, inflammation, and oxidative stress. In vitro, miR-760 mimics enhanced cell proliferation while inhibiting apoptosis, inflammation, and oxidative stress in LPS-stimulated HK-2 cells. Mechanistically, ENKD1 was identified as a direct target of miR-760. ENKD1 overexpression negated the protective effects of miR-760, exacerbating renal injury, apoptosis, and inflammatory responses.

Conclusion: This study demonstrates that miR-760 alleviates septic AKI by targeting ENKD1, reducing apoptosis, inflammation, and oxidative stress. The miR-760/ENKD1 axis offers a promising therapeutic avenue to address septic AKI.