Impact of obesity on renal function in elderly Korean adults: a national population-based cohort study.

Background: Obesity is a well-known risk factor for chronic kidney disease and its progression. However, the impact of obesity on the renal function of the elderly population is uncertain. We investigated the association between obesity and renal outcomes in the elderly. Methods: We analyzed 130,504 participants from the Korean National Health Insurance Service-Senior cohort. Obesity was classified according to body mass index (BMI), sex-specific waist circumference (WC), and the presence of metabolic syndrome. The primary outcome was renal function decline, defined as a decline in the estimated glomerular filtration rate (eGFR) of at least 50% from baseline or new-onset end-stage renal disease. Results: During a follow-up period of 559,531.1 person-years (median, 4.3 years), 2,486 participants (19.0%; incidence rate of 4.44 per 1,000 person-years) showed renal function decline. A multivariate Cox proportional hazards model revealed that BMI/WC was not associated with renal function decline. However, the group with metabolic syndrome had a significantly increased risk of renal function decline compared to the group without metabolic syndrome (adjusted hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.13-1.36). Compared with the non-metabolic syndrome group, the adjusted HRs (95% CI) for participants with one through five components were 0.96 (0.84-1.11), 1.10 (0.96-1.27), 1.24 (1.06-1.45), 1.37 (1.12-1.66), and 1.99 (1.42-2.79), respectively (p for trend < 0.001). Conclusion: In elderly Korean adults, metabolic syndrome and the number of its components were associated with a higher risk of renal function decline, but BMI or WC was not significant.

Spontaneous Remission of Minimal Change Disease in a Colon Cancer Patient: A Case Report.

Introduction: Minimal change disease (MCD) is most often primary but may occur secondary to other systemic diseases such as malignancy. In secondary MCD, spontaneous remission of nephrotic syndrome after the treatment of related diseases without steroid therapy is rare. Case Presentation: A 78-year-old man visited the outpatient clinic with foamy urine and generalized edema that had persisted for 2 months. The patient had nephrotic syndrome. Before a kidney biopsy, he underwent several tests to determine the secondary cause of the nephrotic syndrome. The serum CEA was slightly elevated, and colon cancer was detected in the sigmoid colon. MCD was diagnosed from a kidney biopsy. He immediately underwent surgery for colon cancer. Complete remission of the MCD was achieved within 2 weeks after surgery. Conclusion: Here, we report a rare case of a patient with secondary MCD who successfully achieved spontaneous remission after colon cancer surgery.

Idiopathic Spontaneous Rupture of a Subcostal Artery in a Patient Undergoing Hemodialysis: A Case Report.

The spontaneous rupture of a subcostal (12th intercostal) artery is exceptionally rare and could be fatal, requiring early diagnosis and treatment. Only one case of intercostal artery (ICA) bleeding in a patient undergoing hemodialysis (HD) has been reported. We additionally describe a 41-year-old man undergoing HD who presented with a spontaneous hemoperitoneum and shock resulting from a subcostal artery rupture. He initially complained of diffuse abdominal pain and dizziness at the emergency room. His abdomen was bloated, and there was tenderness in the right upper quadrant area. Enhanced computed tomography and arteriography revealed a rupture of the right subcostal artery. After the super-selection of the bleeding artery by a microcatheter, embolization was performed using a detachable coil and gelfoam. In a subsequent arteriogram, additional contrast leakage was no longer detected, and his blood pressure was restored to normal. The patient was discharged without any sequelae. He was followed up at our HD center without recurrence of ICA bleeding. To the best of our knowledge, this is the second case in the English literature documenting a spontaneous ICA rupture in a patient undergoing HD. This case indicates that injury to ICA should be suspected when patients undergoing HD complain of abdominal or chest pain and dizziness, although it is very rare.

CRISPR-based identification of N-terminal acetylation in synucleinopathies.

A recent study by Kumar et al. identified several biological pathways that regulate the levels of endogenous alpha-synuclein (α-synuclein). They specifically highlighted the N-terminal acetylation (NTA) pathway as an important factor in maintaining the stability of endogenous α-synuclein, suggesting targeting the NTA pathway as a potential therapeutic approach.

Association between dementia diagnosis at dialysis initiation and mortality in older patients with end-stage kidney disease in South Korea.

Background: The prevalence of dementia is 2- to 7-fold higher among patients with end-stage kidney disease (ESKD) than among the general population; however, its clinical implications in this population remain unclear. Therefore, this study aimed to determine whether comorbid dementia increases mortality among older patients with ESKD undergoing newly initiated hemodialysis. Methods: We analyzed data from the Korean Society of Geriatric Nephrology retrospective cohort, which included 2,736 older ESKD patients (≥70 years old) who started hemodialysis between 2010 and 2017. Kaplan-Meier survival and Cox regression analyses were used to examine all-cause mortality between the patients with and without dementia in this cohort. Results: Of the 2,406 included patients, 8.3% had dementia at the initiation of dialysis; these patients were older (79.6 ± 6.0 years) than patients without dementia (77.7 ± 5.5 years) and included more women (male:female, 89:111). Pre-ESKD diagnosis of dementia was associated with an increased risk of overall mortality (hazard ratio, 1.503; p < 0.001), and this association remained consistent after multivariate adjustment (hazard ratio, 1.268; p = 0.009). In subgroup analysis, prevalent dementia was associated with mortality following dialysis initiation in female patients, those aged <85 years, those with no history of cerebrovascular accidents or severe behavioral disorders, those not residing in nursing facilities, and those with no or short-term hospitalization. Conclusion: A pre-ESKD diagnosis of dementia is associated with mortality following dialysis initiation in older Korean population. In older patients with ESKD, cognitive assessment at dialysis initiation is necessary.

Importance of dialysis specialists in early mortality in elderly hemodialysis patients: a multicenter retrospective cohort study.

The early mortality rate in elderly patients undergoing hemodialysis is more than twice that in young patients, requiring more specialized healthcare. We investigated whether the number of professional dialysis specialists affected early mortality in elderly patients undergoing hemodialysis. This multicenter retrospective cohort study analyzed data from 1860 patients aged ≥ 70 years who started hemodialysis between January 2010 and December 2017. Study regions included Seoul, Gyeonggi-do, Gangwon-do, Daejeon/Chungcheong-do, Daegu/Gyeongsangbuk-do, and Busan/Ulsan/Gyeongsangnam-do. The number of patients undergoing hemodialysis per dialysis specialist was calculated using registered data from each hemodialysis center. Early mortality was defined as death within 6 months of hemodialysis initiation. Gangwon-do (28.3%) and Seoul (14.5%) showed the highest and lowest early mortality rate, respectively. Similarly, Gangwon-do (64.6) and Seoul (43.9) had the highest and lowest number of patients per dialysis specialist, respectively. Relatively consistent results were observed for the regional rankings of early mortality rate and number of patients per dialysis specialist. Multivariate Cox regression analysis-adjusted for previously known significant risk factors-revealed that the number of patients per dialysis specialist was an independent risk factor for early mortality (hazard ratio: 1.031, p < 0.001). This study underscores the growing need for dialysis specialists for elderly hemodialysis patients in Korea.

Targeted degradation of SNCA/α-synuclein aggregates in neurodegeneration using the AUTOTAC chemical platform.

Parkinson disease (PD) characterized by dopaminergic neuronal loss is caused by aggregation of misfolded SNCA/α-synuclein. We recently developed autophagy-targeting chimera (AUTOTAC), a targeted protein degradation (TPD) technology based on the macroautophagy/autophagy-lysosome pathway (ALP). In this study, we employed AUTOTAC to synthesize ATC161, a chimeric compound that adopts Anle138b as target-binding ligand (TBL) for SNCA aggregates. The autophagy-targeting ligand (ATL) of ATC161 was designed to allosterically activate the autophagy receptor SQSTSM1/p62 (sequestosome 1), a key step for targeting SNCA aggregates to the phagophore. The lysosomal degradation of SNCA aggregates by ATC161 acutely occurs at DC50 of 100-500 nM with no significant off-target degradation of monomeric SNCA. ATC161 protects cells from DNA and mitochondrial damage by SNCA aggregates. In PD model mice, oral administration of ATC161 decreases the level of SNCA aggregates and their propagation across brain regions, which mitigates glial inflammatory responses and improves muscle strength and locomotive activity. An Investigational New Drug (IND) was approved by the Korean Food and Drug Administration for a phase 1 clinical trial to treat PD, Alzheimer disease (AD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). We suggest that AUTOTAC provides a platform for drug discovery in proteinopathies and other diseases.

Membrane reciprocation and quorum quenching: An innovative combination for fouling control and energy saving in membrane bioreactors.

Membrane bioreactors (MBRs) play a crucial role in wastewater treatment, but they face considerable challenges due to fouling. To tackle this issue, innovative strategies are needed. This study investigated the effectiveness of membrane reciprocation and quorum quenching (QQ) to control fouling in MBRs. The study compared MBRs using membrane reciprocation (30 rpm) and QQ (injecting media containing 100 or 200 mg/L BH4) with conventional MBRs employing different air-scouring intensities. The results demonstrated that combining membrane reciprocation (30 rpm) with QQ (200 mg/L BH4) significantly extended the service time of MBRs, making it approximately six times longer than conventional methods. Moreover, this approach reduced physically reversible resistance. The reduction in signal molecules related to biofouling due to QQ showcased its critical role in controlling biofouling, even under high shear caused by membrane reciprocation. However, the impact of QQ on microbial community structure appeared relatively insignificant when compared to factors such as operation time, aeration intensity, and membrane reciprocation. By combining membrane reciprocation and QQ, the study achieved a remarkable 81 % energy saving compared to extensive aeration (103 s-1 in velocity gradient), in addition to the extended service time. Importantly, this combined antifouling approach did not negatively affect microbial characteristics and wastewater treatment, emphasizing its effectiveness in MBRs. Overall, the findings of this study offer valuable insights for developing synergistic fouling control strategies in MBRs, significantly improving the energy efficiency of the wastewater treatment process.

Effect of low-density lipoprotein level and mortality in older incident statin-naïve hemodialysis patients.

BACKGROUND: This study aimed to analyze low-density lipoprotein cholesterol (LDL-C) levels and their relationship with mortality in order to identify the appropriate lipid profile for older Korean hemodialysis patients. METHODS: We enrolled a total of 2,732 incident hemodialysis patients aged > 70 years from a retrospective cohort of the Korean Society of Geriatric Nephrology from 2010 Jan to 2017 Dec, which included 17 academic hospitals in South Korea. Of these patients, 1,709 were statin-naïve, and 1,014 were analyzed after excluding those with missing LDL-C level data. We used multivariate Cox regression analysis to select risk factors from 20 clinical variables among the LDL-C groups. RESULTS: The mean age of the entire patient population was 78 years, with no significant differences in age between quartiles Q1 to Q4. However, the proportion of males decreased as the quartiles progressed towards Q4 (p < 0.001). The multivariate Cox regression analysis, which included all participants, showed that low LDL-C levels were associated with all-cause mortality. In the final model, compared to Q1, the hazard ratios (95% confidence interval) were 0.77 (0.620-0.972; p = 0.027), 0.85 (0.676-1.069; p = 0.166), and 0.65 (0.519-0.824; p < 0.001) for Q2, Q3, and Q4, respectively, after adjusting for covariates, such as conventional and age-specific risk factors. The final model demonstrated that all-cause mortality increased as LDL-C levels decreased, as confirmed by a restrictive cubic spline plot. CONCLUSIONS: In older hemodialysis patients who had not previously received dyslipidemia treatment, elevated LDL-C levels were not associated with increased all-cause mortality. Intriguingly, lower LDL-C levels appear to be associated with an unfavorable effect on all-cause mortality among high-risk hemodialysis patients.

Psoralen Alleviates Renal Fibrosis by Attenuating Inflammasome-Dependent NLRP3 Activation and Epithelial-Mesenchymal Transition in a Mouse Unilateral Ureteral Obstruction Model.

The role of psoralen (PS), a major active component extracted from Psoralea corylifolia L. seed, in renal fibrosis is still unclear. Thus, the objective of this study was to evaluate the effects of PS on the development and progression of renal fibrosis induced by unilateral ureteral obstruction (UUO) in a mouse model. Mice were divided into four groups: PS (20 mg/kg, i.g., n = 5), PS + sham (n = 5), UUO (n = 10), and PS + UUO (n = 10). PS was intragastrically administered 24 h before UUO and continued afterwards for 7 days. All mice were killed 7 days post UUO. Severe tubular atrophy, tubular injury, and tubulointerstitial fibrosis (TIF) were significantly developed in UUO mice. A higher expression of transforming growth factor-ß1 (TGF-ß1) was accompanied by elevated levels of α-smooth muscle actin (α-SMA) and phosphorylated Smad2/3 (pSmad2/3) at 7 days post UUO. However, PS treatment reduced tubular injury, interstitial fibrosis, and the expression levels of TGF-ß1, α-SMA, and pSmad2/3. Furthermore, the levels of macrophages (represented by F4/80 positive cells) and the inflammasome, reflected by inflammasome markers such as nucleotide-binding and oligomerization domain-like receptors protein 3 (NLRP3) and cleaved caspase1 (cCASP-1), were significantly decreased by PS treatment. These results suggest that PS merits further exploration as a therapeutic agent in the management of chronic kidney disease (CKD).

Changes in oligodendroglial subpopulations in Parkinson's disease.

Parkinson's disease (PD) is characterized by a selective loss of dopaminergic neurons. While most research on PD conducted to date has focused on neurons and, to a certain extent, glia, few studies have investigated changes in oligodendroglia. Here, we investigated the heterogeneity of oligodendrocytes from PD patients compared with those of control cases by analyzing single-nuclei transcriptomes. These analyses revealed the presence of distinct oligodendrocyte populations in PD patients indicative of corresponding variations in molecular features, notably including activation of inflammatory responses, response to protein folding stress, and myelination abnormalities. We confirmed myelination abnormalities in an α-synuclein preformed fibril-injection mouse model of PD. These results suggest that oligodendrocytes acquire disease-associated phenotypes in PD and may contribute to the accompanying neurodegeneration.

IgA nephropathy with minimal change disease associated with primary Sjögren's syndrome: A case report.

RATIONALE: Only 1 case of IgA nephropathy (IgAN) with minimal change disease (MCD) associated with primary Sjögren's syndrome (SS) has been reported. We additionally describe IgAN with MCD associated with primary SS. PATIENT CONCERNS: A 80-year-old woman visited our hospital complaining of generalized edema that had started 4 weeks prior. She reported a sense of thirst and dry eye for the last 5 years. DIAGNOSES: Her initial laboratory findings were compatible with nephrotic syndrome; both the antinuclear antibody (1:80) and anti-SS-A (Ro) antibody (200 U/mL) tests were positive. A salivary gland scan revealed markedly decreased uptake for both the parotid and submandibular glands. The Schirmer test was positive. The random urine protein/creatinine ratio was 10 mg/mg. Renal biopsy was compatible with IgAN with superimposed MCD. INTERVENTIONS: Furosemide was intravenously administered with intermittent albumin infusion for her edema control. She was started on prednisone 40mg daily for 6 weeks, which was tapered to 5 mg for another 6 months after starting prednisolone. OUTCOMES: Over the next 6 months, her edema improved and the proteinuria decreased significantly. LESSONS: Physician should suspect IgA with MCD when patient with SS clinically showed nephrotic syndrome, and perform renal biopsy for pathologically diagnosis and appropriate treatment.

Targeted degradation of ⍺-synuclein aggregates in Parkinson's disease using the AUTOTAC technology.

BACKGROUND: There are currently no disease-modifying therapeutics for Parkinson's disease (PD). Although extensive efforts were undertaken to develop therapeutic approaches to delay the symptoms of PD, untreated α-synuclein (α-syn) aggregates cause cellular toxicity and stimulate further disease progression. PROTAC (Proteolysis-Targeting Chimera) has drawn attention as a therapeutic modality to target α-syn. However, no PROTACs have yet shown to selectively degrade α-syn aggregates mainly owing to the limited capacity of the proteasome to degrade aggregates, necessitating the development of novel approaches to fundamentally eliminate α-syn aggregates. METHODS: We employed AUTOTAC (Autophagy-Targeting Chimera), a macroautophagy-based targeted protein degradation (TPD) platform developed in our earlier studies. A series of AUTOTAC chemicals was synthesized as chimeras that bind both α-syn aggregates and p62/SQSTM1/Sequestosome-1, an autophagic receptor. The efficacy of Autotacs was evaluated to target α-syn aggregates to phagophores and subsequently lysosomes for hydrolysis via p62-dependent macroautophagy. The target engagement was monitored by oligomerization and localization of p62 and autophagic markers. The therapeutic efficacy to rescue PD symptoms was characterized in cultured cells and mice. The PK/PD (pharmacokinetics/pharmacodynamics) profiles were investigated to develop an oral drug for PD. RESULTS: ATC161 induced selective degradation of α-syn aggregates at DC50 of ~ 100 nM. No apparent degradation was observed with monomeric α-syn. ATC161 mediated the targeting of α-syn aggregates to p62 by binding the ZZ domain and accelerating p62 self-polymerization. These p62-cargo complexes were delivered to autophagic membranes for lysosomal degradation. In PD cellular models, ATC161 exhibited therapeutic efficacy to reduce cell-to-cell transmission of α-syn and to rescue cells from the damages in DNA and mitochondria. In PD mice established by injecting α-syn preformed fibrils (PFFs) into brain striata via stereotaxic surgery, oral administration of ATC161 at 10 mg/kg induced the degradation of α-syn aggregates and reduced their propagation. ATC161 also mitigated the associated glial inflammatory response and improved muscle strength and locomotive activity. CONCLUSION: AUTOTAC provides a platform to develop drugs for PD. ATC161, an oral drug with excellent PK/PD profiles, induces selective degradation of α-syn aggregates in vitro and in vivo. We suggest that ATC161 is a disease-modifying drug that degrades the pathogenic cause of PD.

Metabolomic profiling in kidney cells treated with a sodium glucose-cotransporter 2 inhibitor.

We aimed to determine the metabolomic profile of kidney cells under high glucose conditions and following sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment. Targeted metabolomics using the Absolute IDQ-p180 kit was applied to quantify metabolites in kidney cells stimulated with high glucose (25 and 50 mM) and treated with SGLT2 inhibitor, dapagliflozin (2 µM). Primary cultured human tubular epithelial cells and podocytes were used to identify the metabolomic profile in high glucose conditions following dapagliflozin treatment. The levels of asparagine, PC ae C34:1, and PC ae C36:2 were elevated in tubular epithelial cells stimulated with 50 mM glucose and were significantly decreased after 2 µM dapagliflozin treatment. The level of PC aa C32:0 was significantly decreased after 50 mM glucose treatment compared with the control, and its level was significantly increased after dapagliflozin treatment in podocytes. The metabolism of glutathione, asparagine and proline was significantly changed in tubular epithelial cells under high-glucose stimulation. And the pathway analysis showed that aminoacyl-tRNA biosynthesis, arginine and proline metabolism, glutathione metabolism, valine, leucine and isoleucine biosynthesis, phenylalanine, tyrosine, and tryptophan biosynthesis, beta-alanine metabolism, phenylalanine metabolism, arginine biosynthesis, alanine, aspartate and glutamate metabolism, glycine, serine and threonine metabolism were altered in tubular epithelial cells after dapagliflozin treatment following 50 mM glucose compared to those treated with 50 mM glucose.

Association between physical activity and risk of renal function decline and mortality in community-dwelling older adults: a nationwide population-based cohort study.

BACKGROUND: Physical activity (PA) is an important risk factor associated with health outcomes. However, the relationship between PA and kidney function decline in older adults remains unclear. We examined the influence of PA on kidney function decline and mortality in community-dwelling older adults. METHODS: Adults aged ≥ 65 years with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 who had available health checkup data from 2009 to 2010 were included. The cohort was followed annually through December 2015 for anthropometric, sociodemographic, and medical information including outcomes and biennially for laboratory information from the health checkup. We divided these patients into three groups according to self-reported PA (Inactive group: no leisure-time PA, Active group: vigorous activity for at least 80 min/week or a sum of moderate-intensity activity and walking for at least 300 min/week, Low-active group: level of PA between the definitions of the other two groups). Associations between the intensity of PA and death, cardiovascular death, and ≥ 50% eGFR decline were investigated. RESULTS: Among 102,353 subjects, 32,984 (32.23%), 54,267 (53.02%), and 15,102 (14.75%) were classified into the inactive, low-active, and active groups, respectively. The active group was younger, contained a higher proportion of men, and had higher frequencies of hypertension, diabetes mellitus, drinking, and smoking than the other groups. The active group had significantly lower incidence rates of mortality, cardiovascular mortality, and kidney function decline than the other groups (all p < 0.001). The active group also showed lower all-cause (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.70-0.82) and cardiovascular mortality (HR, 0.64; 95% CI, 0.53-0.78) and protection against ≥ 50% eGFR decline (HR, 0.81; 95% CI, 0.68-0.97) compared with the inactive group in the fully adjusted Cox proportional hazards regression model. CONCLUSIONS: High PA was an independent modifiable lifestyle factor for reducing mortality and protecting against declines in kidney function in older adults.

Inflammation promotes synucleinopathy propagation.

The clinical progression of neurodegenerative diseases correlates with the spread of proteinopathy in the brain. The current understanding of the mechanism of proteinopathy spread is far from complete. Here, we propose that inflammation is fundamental to proteinopathy spread. A sequence variant of α-synuclein (V40G) was much less capable of fibril formation than wild-type α-synuclein (WT-syn) and, when mixed with WT-syn, interfered with its fibrillation. However, when V40G was injected intracerebrally into mice, it induced aggregate spreading even more effectively than WT-syn. Aggregate spreading was preceded by sustained microgliosis and inflammatory responses, which were more robust with V40G than with WT-syn. Oral administration of an anti-inflammatory agent suppressed aggregate spreading, inflammation, and behavioral deficits in mice. Furthermore, exposure of cells to inflammatory cytokines increased the cell-to-cell propagation of α-synuclein. These results suggest that the inflammatory microenvironment is the major driver of the spread of synucleinopathy in the brain.