Association of Admission Functional Status and Body Mass Index with Mortality in Patients Receiving Chronic Dialysis: A Nationwide Observational Cohort Study.

Introduction: Chronic kidney disease (CKD) significantly affects activities of daily living (ADLs) before and after the initiation of dialysis, particularly in elderly individuals. However, the impact of admission functional status on dialysis patients' outcome is not fully understood. This study aimed to investigate the effect of the number of ADL disabilities usually measured for all patients hospitalized in Japan on in-hospital outcome for dialysis patients. Methods: Using an inpatient administrative claims database, we included 104,557 admissions of patients undergoing chronic dialysis aged 65 years and above from 2012 to 2014. The primary outcome was in-hospital all-cause mortality (evaluated using logistic regression models), and the secondary outcomes were length of stay and care cost. Results: The mean age of the participants was 74.0 ± 6.2 years, the mean body mass index (BMI) was 21.8 ± 3.9, 31% needed assistance for one or more of five basic ADLs (feeding, transferring, going to toilet, dressing, and bathing) at admission, and 3.5% (n = 3,701) died after hospitalization. After adjusting for confounding factors, the odds ratios (ORs) (95% confidence intervals) of death for 1, 2, 3, 4, and 5 ADL disabilities were 1.43 (1.19-1.70), 2.04 (1.71-2.45), 2.58 (2.19-3.04), 3.74 (3.35-4.17), and 6.83 (6.29-7.41) versus a complete independence, respectively. The increasing number of ADL disabilities was also associated with greater length of stay and costs. Risk stratification by age, admission functional status, and BMI showed an 18-mortality risk matrix with a maximal risk of a 15.5-higher OR for lean patients aged ≥75 years with severe ADL disability compared with that for patients aged <75 years with middle BMI and no ADL disability on admission. Conclusions: Admission functional status decline significantly increases in-hospital mortality, length of stay, and costs. Routine assessment of functional status can facilitate the risk prediction of dialysis patients.

Chronic kidney disease causes blood-brain barrier breakdown via urea-activated matrix metalloproteinase-2 and insolubility of tau protein.

Chronic kidney disease (CKD) causes cognitive impairment and contributes to the overall global burden of dementia. However, mechanisms through which the kidneys and brain communicate are not fully understood. We established a CKD mouse model through adenine-induced tubulointerstitial fibrosis. Novel object recognition tests indicated that CKD decreased recognition memory. Sarkosyl-insoluble-proteomic analyses of the CKD mouse hippocampus revealed an accumulation of insoluble MAPT (microtubule-associated protein tau) and RNA-binding proteins such as small nuclear ribonucleoprotein U1 subunit 70 (SNRNP70). Additionally, there was an accumulation of Immunoglobulin G (IgG), indicating blood-brain barrier (BBB) breakdown. We identified that expressions of essential tight-junction protein claudin-5 and adherens-junction protein platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) were decreased in the brain endothelial cells of CKD mice. We determined urea as a major uremic solute that dose dependently decreased both claudin-5 and PECAM-1 expression in the mouse brain endothelial cell line bEnd.3 cells. Gelatin zymography indicated that the serum of CKD mice activated matrix metalloproteinase-2 (MMP2), while marimastat ameliorated the reduction of claudin-5 expression by urea in bEnd.3 cells. This study established a brain proteomic signature of CKD indicating BBB breakdown and insolubility of tau protein, which are pathologically linked to Alzheimer's disease. Urea-mediated activation of MMP2 was partly responsible for BBB breakdown in CKD.

Circulating Extracellular Vesicle-Propagated microRNA Signature as a Vascular Calcification Factor in Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) accelerates vascular calcification via phenotypic switching of vascular smooth muscle cells (VSMCs). We investigated the roles of circulating small extracellular vesicles (sEVs) between the kidneys and VSMCs and uncovered relevant sEV-propagated microRNAs (miRNAs) and their biological signaling pathways. METHODS AND RESULTS: We established CKD models in rats and mice by adenine-induced tubulointerstitial fibrosis. Cultures of A10 embryonic rat VSMCs showed increased calcification and transcription of osterix (Sp7), osteocalcin (Bglap), and osteopontin (Spp1) when treated with rat CKD serum. sEVs, but not sEV-depleted serum, accelerated calcification in VSMCs. Intraperitoneal administration of a neutral sphingomyelinase and biogenesis/release inhibitor of sEVs, GW4869 (2.5 mg/kg per 2 days), inhibited thoracic aortic calcification in CKD mice under a high-phosphorus diet. GW4869 induced a nearly full recovery of calcification and transcription of osteogenic marker genes. In CKD, the miRNA transcriptome of sEVs revealed a depletion of 4 miRNAs, miR-16-5p, miR-17~92 cluster-originated miR-17-5p/miR-20a-5p, and miR-106b-5p. Their expression decreased in sEVs from CKD patients as kidney function deteriorated. Transfection of VSMCs with each miRNA-mimic mitigated calcification. In silico analyses revealed VEGFA (vascular endothelial growth factor A) as a convergent target of these miRNAs. We found a 16-fold increase in VEGFA transcription in the thoracic aorta of CKD mice under a high-phosphorus diet, which GW4869 reversed. Inhibition of VEGFA-VEGFR2 signaling with sorafenib, fruquintinib, sunitinib, or VEGFR2-targeted siRNA mitigated calcification in VSMCs. Orally administered fruquintinib (2.5 mg/kg per day) for 4 weeks suppressed the transcription of osteogenic marker genes in the mouse aorta. The area under the curve of miR-16-5p, miR-17-5p, 20a-5p, and miR-106b-5p for the prediction of abdominal aortic calcification was 0.7630, 0.7704, 0.7407, and 0.7704, respectively. CONCLUSIONS: The miRNA transcriptomic signature of circulating sEVs uncovered their pathologic role, devoid of the calcification-protective miRNAs that target VEGFA signaling in CKD-driven vascular calcification. These sEV-propagated miRNAs are potential biomarkers and therapeutic targets for vascular calcification.

Ruptured infected aneurysm of the thoracic aorta associated with tunneled dialysis catheter-related methicillin-resistant Staphylococcus aureus bacteremia in a hemodialysis patient.

Patients with an indwelling tunneled dialysis catheter (TDC) for hemodialysis access are at a high risk of developing methicillin-resistant Staphylococcus aureus (MRSA) infection. MRSA bacteremia complications rarely include infected aneurysm. Here, we report the first case of an infected thoracic aneurysm associated with TDC-related MRSA bacteremia. An 86-year-old Japanese male with a TDC for hemodialysis access developed TDC-related MRSA bacteremia. Intravenous vancomycin was initiated, and the TDC was removed on day 3. Despite removal of the catheter and initiation of vancomycin treatment, MRSA bacteremia persisted. Chest computed tomography (CT) showed no aneurysm; however, calcification of the thoracic aorta was detected on admission. The patient subsequently developed hemosputum. CT revealed a thoracic aneurysm, which turned out to be caused by MRSA bacteremia. The patient eventually died because of the rupture of the infected aneurysm, as confirmed by autopsy. This report demonstrates TDC management in a patient with TDC-related MRSA bacteremia and the importance of investigating a metastatic infection to a calcified artery if bacteremia persists.