Abstract
Background and Aims
FABP4, a fatty acid-binding protein, is predominantly expressed in adipose tissue (AT) and has been shown to be elevated in patients with chronic kidney disease (CKD). ...Although elevated levels of FABP4 have been linked to cardiovascular disease in end-stage renal disease (ESRD) patients, the cause of this increase is unclear. The aim of this study was to evaluate the expression of AT FABP4 under uremic conditions and its impact on the function of macrophages and vascular smooth muscle cells (VSMC).
Method
We measured the levels of FABP4 in the blood and urine of CKD patients. The expression of AT FABP4 under uremic conditions was analyzed using omental AT obtained from healthy kidney donors and patients with ESRD who received peritoneal catheter insertion. The effect of FABP4 on the function of macrophages and VSMC was also assessed.
Results
The levels of FABP4 in the blood and urine of CKD patients were inversely correlated with their estimated glomerular filtration rate (eGFR). An increase in FABP4 in the blood was detected before its increase in the urine. FABP4 expression was found to be higher in mature adipocytes in visceral AT compared to the stromal vascular fraction (SVF). Adipocytes treated with p-cresol and adipocytes isolated from CKD patients showed higher levels of FABP4 expression compared to healthy individuals. Single-cell RNA sequencing of SVF showed increased FABP4 expression in progenitor cells and macrophages from CKD patients. In THP-1 cells, FABP4 induced more foam cells and increased levels of inflammatory mediators in the presence of palmitic acid. VSMC treated with p-cresol or VSMC isolated from CKD mice induced by an adenine diet showed a pro-calcific phenotype, as indicated by increased calcium content and bone-related gene expression, which was further enhanced by FABP4.
Conclusion
The elevated levels of FABP4 in CKD patients are not solely a result of decreased renal clearance but also due to increased production in AT. These higher levels of circulating FABP4 may be associated with dysfunction in vascular cells.
Recent advances have led to greater recognition of the role of mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD). There has been evidence that CKD is also associated with ...dysbiosis. Here, we aimed to evaluate whether probiotic supplements can have protective effects against kidney injury via improving mitochondrial function.
An animal model of CKD was induced by feeding C57BL/6 mice a diet containing 0.2% adenine. KBL409, a strain of Lactobacillus acidophilus, was administered via oral gavage at a dose of 1 × 10
CFU daily. To clarify the underlying mechanisms by which probiotics exert protective effects on mitochondria in CKD, primary mouse tubular epithelial cells stimulated with TGF-β and p-cresyl sulfate were administered with butyrate.
In CKD mice, PGC-1α and AMPK, key mitochondrial energy metabolism regulators, were down-regulated. In addition, mitochondrial dynamics shifted toward fission, the number of fragmented cristae increased, and mitochondrial mass decreased. These alterations were restored by KBL409 administration. KBL409 supplementation also improved defects in fatty acid oxidation and glycolysis and restored the suppressed enzyme levels involved in TCA cycle. Accordingly, there was a concomitant improvement in mitochondrial respiration and ATP production assessed by mitochondrial function assay. These favorable effects of KBL409 on mitochondria ultimately decreased kidney fibrosis in CKD mice. In vitro analyses with butyrate recapitulated the findings of animal study.
This study demonstrates that administration of the probiotic Lactobacillus acidophilus KBL409 protects against kidney injury via improving mitochondrial function.
Abstract
Background and Aims
Recent evidences has shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular and renal outcomes of type 2 diabetes mellitus (T2DM) patients. ...However, the mechanisms by which SGLT2 inhibitors improve clinical outcomes are unclear. Mitochondrial dysfunction plays a principal role in the pathophysiology of T2DM and its complications. We hypothesized empagliflozin, an SGLT2 inhibitor improves mitochondrial dysfunction in T2DM patients.
Method
We prospectively recruited healthy volunteers (n = 22) and SGLT2 naïve T2DM patients (n = 21). Copy numbers of urinary and serum mitochondrial DNA (mtDNA) nicotinamide adenine dinucleotide dehydrogenase subunit-1 (mtND-1) and cytochrome-c oxidase 3 (mtCOX-3) were measured using quantitative polymerase chain reaction in healthy volunteers and T2DM patients at baseline and in T2DM patients after 3 months of treatment with empagliflozin (10 mg, n = 17 or 25 mg, n = 4).
Results
Patients with T2DM were older than healthy volunteers and had higher body mass index and systolic blood pressure, but lower estimated glomerular filtration rate. Urinary mtND-1 and mtCOX-3 copy numbers were significantly higher in the T2DM group than in healthy volunteers. Urinary mtDNA copy numbers were correlated with diabetes duration (8.74 ± 7.60 years, r = 0.54, P = 0.01 for mtND-1, r = 0.50, P = 0.02 for mtCOX-3). Urinary copy numbers of mtND-1 and mtCOX-3 decreased after empagliflozin treatment. The amount of reduction of urinary mtDNA copy number did not differ according to empagliflozin dose (P = 0.897 for mtND-1, P = 0.462 for mtCOX-3).
Conclusion
In this study, we found that T2DM is associated with elevated urinary mtND-1 and mtCOX-3 copy numbers. Empagliflozin reduces the elevated urinary mtND-1 and mtCOX-3 copy numbers in patients with T2DM. Our results suggest that empagliflozin could attenuate mitochondrial damage in the kidney cells of T2DM patients.
The aim of this study is to elucidate the effects of warfarin use in patients with atrial fibrillation undergoing dialysis using a population-based Korean registry.
Data were extracted from the ...Health Insurance Review and Assessment Service, which is a nationwide, mandatory social insurance database of all Korean citizens enrolled in the National Health Information Service between 2009 and 2013. Thromboembolic and hemorrhagic outcomes were analyzed according to warfarin use. Overall and propensity score-matched cohorts were analyzed by Cox proportional hazards models.
Among 9974 hemodialysis patients with atrial fibrillation, the mean age was 66.6±12.2 years, 5806 (58.2%) were men, and 2921 (29.3%) used warfarin. After propensity score matching to adjust for all described baseline differences, 5548 subjects remained, and differences in baseline variables were distributed equally between warfarin users and nonusers. During a mean follow-up duration of 15.9±11.1 months, ischemic and hemorrhagic stroke occurred in 678 (6.8%) and 227 (2.3%) patients, respectively. In a multiple Cox model, warfarin use was significantly associated with an increased risk of hemorrhagic stroke (hazard ratio, 1.44; 95% confidence interval, 1.09-1.91;
=0.010) in the overall cohort. Furthermore, a significant relationship between warfarin use and hemorrhagic stroke was found in propensity-matched subjects (hazard ratio, 1.56; 95% confidence interval, 1.10-2.22;
=0.013). However, the ratios for ischemic stroke were not significantly different in either the propensity-matched (hazard ratio, 0.95; 95% confidence interval, 0.78-1.15;
=0.569) or overall cohort (hazard ratio, 1.06; 95% confidence interval, 0.90-1.26;
=0.470).
Our findings suggest that warfarin should be used carefully in hemodialysis patients, given the higher risk of hemorrhagic events and the lack of ability to prevent thromboembolic complications.
Serum hemoglobin (Hb) level affects the viscosity of blood. Several studies have reported that Hb level is associated with adverse cardiovascular outcome. However, there is a paucity of evidence on ...the association between serum Hb level and the risk of subclinical atherosclerosis. Thus, the objective of this study was to investigate the relationship between Hb level and risk of carotid plaque in a health checkup cohort.
This retrospective study analyzed a total of 3,805 individuals without history of cardiovascular disease (CVD) who underwent carotid ultrasonography (USG) between January 2016 and June 2018. Participants were divided into 4 groups based on Hb quartiles in each of male and female. Carotid plaque score was calculated based on USG reports. Multivariable logistic regression analysis was performed for each index of quartile groups regarding the risk of carotid plaque.
Of 3,805 individuals (mean age, 52.62±10.25 years; 2,674 70.28% males), mean Hb level was 15.11±0.75 g/dL in male and 13.35±0.74 g/dL in female. When the Q1 group was compared to the Q4, increasing quartile of Hb was associated with the presence of significant carotid plaque (plaque score ≥3) in male (adjusted odds ratio OR, 1.538; 95% confidence interval CI, 1.182-2.001;
=0.001) and female (adjusted OR, 1.749; 95% CI, 1.058-2.676;
=0.01).
A high Hb level is associated with an increased risk of carotid plaques in individuals without history of CVD. This finding may support the need for early screening of CVD in individuals with high Hb levels.
Objective: Obesity is an independent risk factor for chronic kidney disease. Recently, urinary mitochondrial DNA (mtDNA) has been used as a surrogate marker of mitochondrial damage in various kidney ...diseases. However, there are no data regarding its use in patients with obesity or the change in urinary mtDNA copy number after surgery. Design: We prospectively recruited age- and sex-matched healthy volunteers and patients with obesity (n = 22 in each group: nine men and 13 women). The copy number of urinary and serum mtDNA nicotinamide adenine dinucleotide dehydrogenase subunit-1 (mtND-1) and cytochrome-c oxidase 3 (mtCOX-3) was measured using quantitative PCR. We measured urinary mtDNA and body weight and carried out laboratory tests, 6 months after surgery. Results: Urinary mtND-1 copy number was significantly higher in the obese group than in healthy volunteers. However, urinary mtCOX-3 and serum ND-1 copy numbers in the obese group did not differ from that in the healthy volunteers. When patients with obesity were divided into two groups, according to their baseline mtND-1 copy number, bariatric surgery reduced the mtND-1 copy number (P = 0.006) in the high baseline mtDNA copy-number group. The change in urinary mtND-1 copy number was correlated with a change in urinary albumin (r = 0.478, P = 0.025). Conclusions: Obesity is associated with elevated urinary mtND-1 copy number. Bariatric surgery reduces the elevated urinary mtND-1 copy number in patients with obesity. This suggests that bariatric surgery could attenuate mitochondrial damage in the kidney cells of patients with obesity. (J Clin Endocrinol Metab 104: 2257-2266, 2019)
The risk of delayed AKI (AKI development beyond the perioperative period) in patients undergoing colorectal surgery is greater than that in patients undergoing other major operations. However, the ...characteristics of and risk factors for delayed AKI are unclear.
We investigated 683 patients who underwent colorectal surgery with intestinal resection at a single tertiary hospital. All patients were followed-up for a year postoperatively. The primary outcome was the development of AKI during follow-up.
AKI occurred in 177 (25.9%) during the first postoperative year. Patients who developed AKI were significantly older, showed a lower body mass index, and significantly lower preoperative hemoglobin and serum albumin levels. AKI occurred most commonly during the first 3 months postoperatively. However, AKI occurred persistently even after this initial period. Older age, lower preoperative serum albumin levels, and late ostomy closure were independently associated with a higher risk of delayed AKI.
AKI commonly occurs beyond the perioperative period. Careful risk stratification and modification of risk factors may prevent delayed AKI in patients undergoing colorectal cancer surgery.
•Patients undergoing colorectal surgery are vulnerable to occurrence of post-operative acute kidney injury (AKI).•The characteristics of and risk factors for delayed AKI (AKI development beyond the perioperative period) are unclear.•Analysis of the incidence of and risk factors for delayed AKI in patients undergoing colorectal surgery.•AKI occurred most commonly during the first 3 months after surgery, however AKI occurred persistently even after this period.•Older age, lower albumin levels, and late ostomy closure were independently associated with a higher risk of delayed AKI.
A genotype-phenotype correlation is known to be associated with Alport syndrome (AS). Identifying novel mutations can expand the knowledge about the natural course of AS.
The first patient was ...a-15-year-old boy detected with proteinuria during the school health check-up. The second case was a-29-year-old woman, who visited the outpatient clinic for edema.
We performed targeted next-generation sequencing to identify the mutations associated with AS. Results were confirmed by Sanger sequencing and multiplex ligation-dependent probe amplification. Missense mutation (c.2332G>C, p.Gly778Arg) was identified in the first case and an exon 16 deletion was also identified in the second case.
We treated both cases with angiotensin receptor blocker (ARB).
The amount of proteinuria in the first case did not change after ARB therapy, during the follow-up period (1 year). Proteinuria in the woman decreased to half of the baseline level, 1 year after treatment. Glomerular filtration rate was also maintained during the follow-up.
We identified novel mutations in Koreans with an X-linked AS mutation in the COL4A5 gene and an individual phenotype. This is the first report of AS patients with a novel missense mutation and copy number variation.
Vitamin D deficiency is associated with renal progression in chronic kidney disease. Moreover, improvement of clinical outcomes after vitamin D supplementation has been reported in the diabetic and ...chronic kidney disease population.
We investigated the association between renal hyperfiltration (RHF) and vitamin D status in a relatively healthy population.
Data were retrieved from the Korean NHANES, a nationwide population-based cross-sectional study from 2008 to 2015. Overall, 33,210 subjects with normal renal function were included in the final analysis. Severe vitamin D deficiency was defined as serum 25-hydroxyvitamin D concentration <10 ng/mL. RHF was defined as estimated glomerular filtration rate with residual in the >95th percentile after adjustment for age, sex, height, weight, and history of hypertension or diabetes.
The mean ± SD age of subjects was 48.1 ± 15.9 y, and the number of women was 18,779 (56.5%). Estimated glomerular filtration rate was negatively associated with serum 25-hydroxyvitamin D concentrations in multivariable linear regression analysis (β: −0.02; 95% CI: −0.02, −0.01; P < 0.001). Furthermore, 1637 (4.9%) subjects were categorized into the RHF group, and the prevalence of RHF was significantly higher in the severe vitamin D deficiency group than in the sufficiency group (5.8% compared with 5.0%, P < 0.001). In a multivariable logistic regression model, severe vitamin D deficiency was a significant risk factor for RHF (OR: 2.41; 95% CI, 1.72, 3.43; P < 0.001).
Severe vitamin D deficiency is significantly associated with increasing prevalence of RHF in a relatively healthy adult population.
PDF
