ω-3 Polyunsaturated Fatty Acids Improve the Blood-Brain-Barrier Integrity in Contrast-Induced Blood-Brain-Barrier Injury in Uremic Mice.

In patients with chronic kidney disease, the need for examinations using contrast media (CM) increases because of underlying diseases. Although contrast agents can affect brain cells, the blood-brain barrier (BBB) protects against brain-cell damage in vivo. However, uremia can disrupt the BBB, increasing the possibility of contrast-agent-induced brain-cell damage in patients with chronic kidney disease (CKD). ω-3 polyunsaturated fatty acids (PUFAs) have shown protective effects on various neurological disorders, including uremic brain injury. This study examined whether ω-3 PUFAs attenuate damage to the BBB caused by uremia and contrast agents in a uremic mouse model and evaluated its associated mechanisms. C57BL/6 mice (eight weeks old, male) and fat-1 mice (b6 background/eight weeks old, male) were divided into groups according to uremic induction, CM, and ω-3 PUFA administration. Uremia was induced via 24 h ischemia-reperfusion (IR) renal injury. One day after CM treatment, the brain tissue, kidney tissue, and blood were collected. The expression levels of glial fibrillary acidic protein (GFAP), claudin 5, CD31, laminin α4, and laminin α5 increased in ω-3 PUFA + CM-treated uremic mice and the brain of fat-1 + CM-treated uremic mice compared with those in the brains of CM-treated uremic mice. The pro-apoptotic protein expression decreased, whereas the anti-apoptotic proteins increased in ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with CM-treated uremic mice. In addition, the brain-expression levels of p-JNK, p-P53, and p-P38 decreased in the ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with those in wild-type uremic mice. Our results confirm that uremic toxin and CM damage the BBB and cause brain-cell death. ω-3 PUFAs play a role in BBB protection caused by CM in uremic mice.

Mitochondrial Dysfunction in Podocytes Caused by CRIF1 Deficiency Leads to Progressive Albuminuria and Glomerular Sclerosis in Mice.

Recent studies have implicated mitochondrial disruption in podocyte dysfunction, which is a characteristic feature of primary and diabetic glomerular diseases. However, the mechanisms by which primary mitochondrial dysfunction in podocytes affects glomerular renal diseases are currently unknown. To investigate the role of mitochondrial oxidative phosphorylation (OxPhos) in podocyte dysfunction, glomerular function was examined in mice carrying a loss of function mutation of the gene encoding CR6-interacting factor-1 (CRIF1), which is essential for intramitochondrial production and the subsequent insertion of OxPhos polypeptides into the inner mitochondrial membrane. Homozygotic deficiency of CRIF1 in podocytes resulted in profound and progressive albuminuria from 3 weeks of age; the CRIF1-deficient mice also developed glomerular and tubulointerstitial lesions by 10 weeks of age. Furthermore, marked glomerular sclerosis and interstitial fibrosis were observed in homozygous CRIF1-deficient mice at 20 weeks of age. In cultured mouse podocytes, loss of CRIF1 resulted in OxPhos dysfunction and marked loss or abnormal aggregation of F-actin. These findings indicate that the OxPhos status determines the integrity of podocytes and their ability to maintain a tight barrier and control albuminuria. Analyses of the glomerular function of the podocyte-specific primary OxPhos dysfunction model mice demonstrate a link between podocyte mitochondrial dysfunction, progressive glomerular sclerosis, and tubulointerstitial diseases.

Collecting Duct-Specific CR6-Interacting Factor-1-Deletion Aggravates Renal Inflammation and Fibrosis Induced by Unilateral Ureteral Obstruction.

Although inflammation and fibrosis, which are key mechanisms of chronic kidney disease, are associated with mitochondrial damage, little is known about the effects of mitochondrial damage on the collecting duct in renal inflammation and fibrosis. To generate collecting duct-specific mitochondrial injury mouse models, CR6-interacting factor-1 (CRIF1) flox/flox mice were bred with Hoxb7-Cre mice. We evaluated the phenotype of these mice. To evaluate the effects on unilateral ureteral obstruction (UUO)-induced renal injury, we divided the mice into the following four groups: a CRIF1flox/flox (wild-type (WT)) group, a CRIF1flox/flox-Hob7 Cre (CRIF1-KO) group, a WT-UUO group, and a CRIF1-KO UUO group. We evaluated the blood and urine chemistries, inflammatory and fibrosis markers, light microscopy, and electron microscopy of the kidneys. The inhibition of Crif1 mRNA in mIMCD cells reduced oxygen consumption and membrane potential. No significant differences in blood and urine chemistries were observed between WT and CRIF1-KO mice. In UUO mice, monocyte chemoattractant protein-1 and osteopontin expression, number of F4/80 positive cells, transforming growth factor-ß and α-smooth muscle actin staining, and Masson's trichrome staining were significantly higher in the kidneys of CRIF1-KO mice compared with the kidneys of WT mice. In sham mice, urinary 8-hydroxydeoxyguanosine (8-OHDG) was higher in CRIF1-KO mice than in WT mice. Moreover, CRIF1-KO sham mice had increased 8-OHDG-positive cell recruitment compared with WT-sham mice. CRIF1-KO-UUO kidneys had increased recruitment of 8-OHDG-positive cells compared with WT-UUO kidneys. In conclusion, collecting duct-specific mitochondrial injury increased oxidative stress. Oxidative stress associated with mitochondrial damage may aggravate UUO-induced renal injury.

Omega-3 Polyunsaturated Fatty Acid Attenuates Uremia-Induced Brain Damage in Mice.

Although the cause of neurological disease in patients with chronic kidney disease (CKD) has not been completely identified yet, recent papers have identified accumulated uremic toxin as its main cause. Additionally, omega-3 polyunsaturated fatty acid (ω-3 PUFA) plays an important role in maintaining normal nerve function, but its protective effects against uremic toxin is unclear. The objective of this study was to identify brain damage caused by uremic toxicity and determine the protective effects of ω-3 PUFA against uremic toxin. We divided mice into the following groups: wild-type (wt) sham (n = 8), ω-3 PUFA sham (n = 8), Fat-1 sham (n = 8), ischemia-reperfusion (IR) (n = 20), and ω-3 PUFA+IR (n = 20) Fat-1+IR (n = 20). Brain tissue, kidney tissue, and blood were collected three days after the operation of mice (sham and IR operation). This study showed that Ki67 and neuronal nuclei (NeuN) decreased in the brain of uremic mice as compared to wt mice brain, but increased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. The pro-apoptotic protein expressions were increased, whereas anti-apoptotic protein expression decreased in the brain of uremic mice as compared to wt mice brain. However, apoptotic protein expression decreased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. Furthermore, the brain of ω-3 PUFA-treated uremic mice and uremic Fat-1 mice showed increased expression of p-PI3K, p-PDK1, and p-Akt as compared to the brain of uremic mice. We confirm that uremic toxin damages the brain and causes cell death. In these injuries, ω-3 PUFA plays an important role in neuroprotection through PI(3)K-Akt signaling.

Artery-to-Fistula Diameter Ratio as a Predictor of Early Re-Occlusion of Immature Right Radio-Cephalic Arteriovenous Fistula after Primary PTA.

Percutaneous transluminal angioplasty (PTA) is widely performed for arteriovenous fistula (AVF) that fails to mature after initial formation. We observed that some immature AVFs re-occlude earlier than others. We sought to investigate the predictors for early post-intervention failure of immature fistulas after primary PTA. We retrospectively reviewed the records and angiographic images of patients who had immature fistulas and thereby received PTA between 2013 and 2019 at our center. We investigated the short-term post-intervention outcomes of the patients within 90 days post-PTA. Patients who had re-occlusion within the period were defined as the early failure group and the rest as the patent group. We investigated factors associated with early failure. There were 80 eligible patients with 22 brachio-cephalic (BC) and 58 radio-cephalic (RC) AVFs. The median age of the patients was 64 years [range, 38-87]. There were 51 (63%) males and 29 (36%) females. Among the 58 RC AVFs, 10 (17%) patients had early failure. Logistic regression analysis showed that a larger artery to fistula (A/F) diameter ratio was the sole independent predictor of early failure after primary PTA (odd ratio 2.29 [1.023-5.147], p value = 0.044). Although further studies on a larger scale are required to confirm the clinical significance, a larger A/F diameter ratio was a potential predictor of early re-occlusion in immature fistulas after primary PTA.

Serum Growth Differentiation Factor-15/Albumin Ratio as a 2-Year Survival Marker of End-Stage Renal Disease Patients Initiating Maintenance Hemodialysis.

It is important to identify risk factors related to mortality in end-stage renal disease (ESRD) patients starting renal replacement therapy. Recently, several studies proposed that growth-differentiation factor-15 (GDF-15) is a possible biomarker for the prognosis of patients on maintenance hemodialysis. Here, we investigated the predictive value of serum GDF-15/Albumin ratio on two-year mortality in ESRD patients initiating maintenance hemodialysis. The study was a single center, retrospective study on ESRD patients starting maintenance hemodialysis with a follow-up of two years. All patients completed laboratory test and bioimpedance spectroscopy prior to the initiation of the first dialysis. The patients were stratified into quartiles according to the quartiles of serum GDF-15/Albumin ratio. Among the 159 patients, the mean age was 61.78 ± 12.52 years and median survival was 20.03 ± 7.73 months. The highest GDF-15/Albumin quartile was significantly more associated with the increased risk of all-cause mortality than other quartiles (unadjusted hazard ratio (HR): 8.468, 95% CI 2.981-24.054, p < 0.001). Older age and a higher overhydration state were associated with GDF-15/Albumin ratio. The ROC analysis confirmed that the ability of the GDF-15/Albumin ratio to predict mortality was superior to GDF-15 or albumin alone. In conclusion, the GDF-15/Albumin ratio measured at the initial maintenance hemodialysis is an independent prognostic marker of two-year mortality in ESRD patients.

Body Fat Plays an Important Role in of Bioimpedance Spectroscopy-Based Dry Weight Measurement Error for Patients with Hemodialysis.

Accurate dry weight (DW) estimation is important for hemodialysis patients. Although bioimpedance spectroscopy (BIS) is commonly used to measure DW, the BIS-based DW frequently differs from the clinical DW. We analyzed the characteristics of patients whose BIS-based DWs were over- and underestimated. In this retrospective cohort study, we evaluated 1555 patients undergoing maintenance hemodialysis in Chungnam National University Hospital. The gap (DWCP-BIS) was calculated by comparing the BIS and clinical DWs. We analyzed the clinical characteristics of patients with positive (n = 835) and negative (n = 720) gaps. Compared with other patients, the DWCP-BIS-positive group had higher extracellular water (ECW) level and extracellular/intracellular water index (E/I) and had lower weight, body mass index (BMI), lean tissue index (LTI), fat tissue index (FTI), fat mass (FAT), and adipose tissue mass (ATM). The DWCP-BIS-negative group exhibited elevated BMI, FTI, FAT, and ATM; however, it had lower height, ECW, and E/I. Linear regression analysis revealed that FAT significantly predicted DWCP accuracy. The clinical DW of patients with a low fat mass tended to be underestimated, while the clinical DW of patients with comparatively large fat reserves tended to be overestimated. These characteristics will aid in the reduction of BIS-based DW errors.

Genetic polymorphism of the serum proteins of horses in Jeju.

The study was carried out to investigate the genetic polymorphism of the serum proteins of horses in Cheju. They were assigned to three groups; 45 Cheju native horses(CNH), 60 Cheju racing horses(CRH) and 60 Thoroughbreds(TB). We analyzed the phenotypes and gene frequencies of serum proteins which were albumin (Alb), vitamin-D binding protein(GC), esterase (ES), A1B glycoprotein(A1B) and transferrin(TF) loci using horizontal polyacrylamide gel electrophoresis (HPAGE). All of the loci, except A1B in TB, showed polymorphisms and different allelic and phenotypic frequencies in all three groups. ESS and TFF1 were not observed in CNH. Allelic frequencies of AlbB, ESI, TFD and TFF1 were high in TB. All of the loci, except ES locus in CRH, appeared to be in a state of Hardy-Weinberg equilibrium from goodness-of-fit test in all three groups. Heterozygosity estimates at Alb, ES and TF loci were high, but GC and A1B loci were low in all three groups. Average heterozygosities in CNH, CRH and TB were 0.3535, 0.3555 and 0.2726, respectively. Results showed differences in the frequencies of alleles and phenotypes of several serum protein loci between CNH and CRH, suggested that CRH might be crossed with other breeds of horses in some degree.