Fluctuating risk of acute kidney injury-related mortality for four weeks after exposure to air pollution: A multi-country time-series study in 6 countries.

BACKGROUND: Recent studies have reported that air pollution is related to kidney diseases. However, the global evidence on the risk of death from acute kidney injury (AKI) owing to air pollution is limited. Therefore, we investigated the association between short-term exposure to air pollution-particulate matter ≤ 2.5 µm (PM2.5), ozone (O3), and nitrogen dioxide (NO2)-and AKI-related mortality using a multi-country dataset. METHODS: This study included 41,379 AKI-related deaths in 136 locations in six countries during 1987-2018. A novel case time-series design was applied to each air pollutant during 0-28 lag days to estimate the association between air pollution and AKI-related deaths. Moreover, we calculated AKI deaths attributable to non-compliance with the World Health Organization (WHO) air quality guidelines. RESULTS: The relative risks (95% confidence interval) of AKI-related deaths are 1.052 (1.003, 1.103), 1.022 (0.994, 1.050), and 1.022 (0.982, 1.063) for 5, 10, and 10 µg/m3 increase in lag 0-28 days of PM2.5, warm-season O3, and NO2, respectively. The lag-distributed association showed that the risk appeared immediately on the day of exposure to air pollution, gradually decreased, and then increased again reaching the peak approximately 20 days after exposure to PM2.5 and O3. We also found that 1.9%, 6.3%, and 5.2% of AKI deaths were attributed to PM2.5, warm-season O3, and NO2 concentrations above the WHO guidelines. CONCLUSIONS: This study provides evidence that public health policies to reduce air pollution may alleviate the burden of death from AKI and suggests the need to investigate the several pathways between air pollution and AKI death.

Hypoglycemia and Mortality Risk in Incident Hemodialysis Patients.

OBJECTIVE: Hypoglycemia is a frequent occurrence in chronic kidney disease patients due to alterations in glucose and insulin metabolism. However, there are sparse data examining the predictors and clinical implications of hypoglycemia including mortality risk among incident hemodialysis patients. DESIGN AND METHODS: Among 58,304 incident hemodialysis patients receiving care from a large national dialysis organization over 2007-2011, we examined clinical characteristics associated with risk of hypoglycemia, defined as a blood glucose concentration <70 mg/dL, in the first year of dialysis using expanded case-mix + laboratory logistic regression models. We then examined the association between hypoglycemia during the first year of dialysis with all-cause mortality using expanded case-mix + laboratory Cox models. RESULTS: In the first year of dialysis, hypoglycemia was observed among 16.8% of diabetic and 6.9% of nondiabetic incident hemodialysis patients. In adjusted logistic regression models, clinical characteristics associated with hypoglycemia included younger age, female sex, African-American race, presence of a central venous catheter, lower residual renal function, and longer dialysis session length. In the overall cohort, patients who experienced hypoglycemia had a higher risk of all-cause mortality risk (reference: absence of hypoglycemia): adjusted hazard ratio (95% confidence interval) 1.08 (1.04, 1.13). In stratified analyses, hypoglycemia was also associated with higher mortality risk in the diabetic and nondiabetic subgroups: adjusted hazard ratios (95% confidence interval's) 1.08 (1.04-1.13), and 1.17 (0.94-1.45), respectively. CONCLUSIONS: Hypoglycemia was a frequent occurrence among both diabetic and nondiabetic hemodialysis patients and was associated with a higher mortality risk. Further studies are needed to identify approaches that reduce hypoglycemia risk in the hemodialysis population.

Effects of sitagliptin on peritoneal membrane: The potential role of mesothelial cell tight junction proteins.

BACKGROUND: The roles of tight junction (TJ) proteins in peritoneal membrane transport and peritoneal dialysis (PD) require further characterisation. Dipeptidyl peptidase-4 is expressed in mesothelial cells, and its activity may affect peritoneal membrane function and morphology. METHODS: Human peritoneal mesothelial cells (HPMCs) were isolated and cultured from omentum obtained during abdominal surgery, and paracellular transport functions were evaluated by measuring transmesothelial electrical resistance (TMER) and dextran flux. Sprague-Dawley rats were infused daily with 4.25% peritoneal dialysate with and without sitagliptin administration for 8 weeks. At the end of this period, rat peritoneal mesothelial cells (RPMCs) were isolated to evaluate TJ protein expression. RESULTS: In HPMCs, the protein expression of claudin-1, claudin-15, occludin and E-cadherin was decreased by TGF-ß treatment but reversed by sitagliptin co-treatment. TMER was decreased by TGF-ß treatment but improved by sitagliptin co-treatment. Consistent with this, dextran flux was increased by TGF-ß treatment and reversed by sitagliptin co-treatment. In the animal experiment, sitagliptin-treated rats had a lower D2/D0 glucose ratio and a higher D2/P2 creatinine ratio than PD controls during the peritoneal equilibration test. Protein expression of claudin-1, claudin-15 and E-cadherin decreased in RPMCs from PD controls but was not affected in those from sitagliptin-treated rats. Peritoneal fibrosis was induced in PD controls but ameliorated in sitagliptin-treated rats. CONCLUSION: The expression of TJ proteins including claudin-1 and claudin-15 was associated with transport function both in HPMCs and in a rat model of PD. Sitagliptin prevents peritoneal fibrosis in PD and can potentially restore peritoneal mesothelial cell TJ proteins.

Fructose might be a clue to the origin of preeclampsia insights from nature and evolution.

Preeclampsia is a hypertensive disorder of pregnancy and is due to abnormal placentation. The pathogenesis remains unclear. Fructose is biologically distinct from glucose and has a critical role in fetal growth in early pregnancy. Many species, including humans, produce fructose in their placenta during the first trimester to assist fetal growth and survival during a time when hypoxia is significant. Fructose is preferred over glucose in hypoxic tissues, and in the developing fetus, fructose has a critical role in stimulating the production of nucleic acids, lipids and glycosaminoglycans. Fructose production normally decreases significantly following the establishment of maternal-fetal circulation following placentation. However, if there is impaired placentation, local hypoxia will continue to drive fructose production. Excessive fructose metabolism drives endothelial dysfunction, oxidative stress, elevated blood pressure, insulin resistance, fatty liver, and a rise in uric acid and vasopressin levels, all of which are features of the preeclamptic state. In addition to fructose production, dietary fructose, for example, from soft drinks, would be additive and has been reported to be a strong independent risk factor for preeclampsia. Uric acid-associated endothelial dysfunction disturbs the invasion of the spiral artery, leading to placental ischemia and further placental hypoxia. Here, we summarize the previous literature regarding the physiological and pathological roles of fructose in pregnancy and propose studies to further investigate the pathogenesis of preeclampsia. Fructose might be a Clue to the Origin of Preeclampsia Insights from Nature and Evolution Preeclampsia is a hypertensive disorder of pregnancy. The pathogenesis remains unclear. Fructose has a critical role in fetal growth in early pregnancy, and might be a key role to developing preeclampsia. Here, we summarize the previous literatures regarding the physiological andpathological roles of fructose in pregnancy to propose studies to further investigate the pathogenesis of preeclampsia.

Early fluid management affects short-term mortality in patients with end-stage kidney disease undergoing chronic hemodialysis and requiring continuous renal replacement therapy.

BACKGROUND: Early fluid management is considered a key element affecting mortality in critically ill patients requiring continuous renal replacement therapy (CRRT). Most studies have primarily focused on patients with intrinsic acute kidney injury requiring CRRT, although end-stage kidney disease (ESKD) patients generally exhibit greater vulnerability. We investigated the association between fluid balance and short-term mortality outcomes in ESKD patients undergoing chronic hemodialysis and requiring CRRT. METHODS: This retrospective study included 110 chronic hemodialysis patients who received CRRT between 2017 and 2019 at Ewha Womans University Mokdong Hospital. The amounts of daily input and output, and cumulative 3-day and 7-day input and output, were assessed from the initiation of CRRT. The participants were classified into two groups based on 7-day and 14-day mortalities. Cox regression analyses were carried out on the basis of the amounts of daily input and output, cumulative input and output, and cumulative fluid balance. RESULTS: During follow-up, 7-day and 14-day mortalities were observed in 24 (21.8%) and 34 (30.9%) patients. The patients were stratified into two groups (14-day survivors vs. non-survivors), and there were no significant differences in demographic characteristics between the two groups. However, diabetes mellitus was more common among survivors than among non-survivors. Univariate analyses showed that the amounts of daily output at 48, and 72 h, and 3-day cumulative input and output, were significantly associated with 7-day mortality risk regardless of the cumulative fluid balance (HR: 0.28, 95% CI: 0.12-0.70, p = 0.01 for daily output at 48 h; HR: 0.34, 95% CI: 0.13-0.85, p = 0.02 for daily output at 72 h.; HR: 0.72, 95% CI: 0.61-0.86, p = 0.01 for 3-day cumulative input; HR: 0.65, 95% CI: 0.41-0.90, p = 0.01 for 3-day cumulative output). Adjusted multivariate analyses showed that the lower 3-day cumulative output is an independent risk factor for 7-day and 14-day mortality. CONCLUSIONS: In our study, increased cumulative output were significantly associated with reduced short-term mortality risk in chronic hemodialysis patients undergoing CRRT regardless of cumulative fluid balance. Further prospective studies to investigate the association between fluid balance and mortality in ESRD patients requiring CRRT are warranted.

Association between exposure to fine particulate matter and kidney function: Results from the Korea National Health and Nutrition Examination Survey.

BACKGROUND: The incidence and prevalence of chronic kidney disease (CKD) are increasing worldwide. Recent studies have shown that air pollution is associated with poorer kidney function. We evaluated the association of long-term exposure to air pollutants with kidney function, and with risk of CKD using data from the seventh Korean National Health and Nutrition Examination Survey (KNHANES). METHODS: KNHANES data from 2016 through 2018 and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation were used to calculate estimated glomerular filtration rates (eGFRs) and define the CKD patients with eGFRs <60 mL/min/1.73 m2. After applying the sampling weights based on the complex survey design, we conducted multivariate linear regression and logistic regression analyses to examine the association of air pollutant exposure with kidney function and CKD risk, after adjusting for covariates, including gender, body mass index, education level, household income, smoking status, alcohol consumption, comorbidities, and serum triglyceride. RESULTS: A total of 15,983 adults aged ≥20 years were included in the analysis. Long-term exposure to PM2.5, PM10, NO2, and CO was associated with decreases in eGFR levels (PM2.5: -4.67, 95% confidence interval (CI): -6.16, -3.18; PM10: -2.19, 95% CI: -2.84, -1.54; NO2: -1.56, 95% CI: -2.16, -0.97; CO: -1.34, 95% CI: -1.96, -0.71). Long-term exposure to PM2.5 (odds ratio (OR): 1.97, 95% CI: 1.14, 3.42) and PM10 (OR: 1.45, 95% CI: 1.10, 1.91) was associated with an increased the risk of CKD. CONCLUSIONS: Annual exposure to PM2.5, PM10, NO2, and CO was significantly associated with decreased eGFR. Long-term exposure to PM2.5 and PM10 was associated with an increased risk of CKD.

Revisiting glomerular hyperfiltration and examining the concept of high dietary protein-related nephropathy in athletes and bodybuilders.

PURPOSE OF REVIEW: High-protein diets (HPDs) are popular but their consequences for kidney health, especially among athletes and bodybuilders who typically maintain a high protein intake for a long time, have not been investigated. This review focused on recent studies of the association of HPD with long-term kidney health and the concept of high dietary protein-related nephropathy. RECENT FINDINGS: Several long-term observational studies including large populations have reinforced the notion that HPDs are associated with a rapid decline of kidney function. An increase in renal blood flow and glomerular hyperfiltration caused by vasodilation, and increased levels of endocrine and paracrine factors (glucagon, IGF-1, prostanoids, and nitric oxide), facilitates the excretion of protein-derived nitrogenous waste. Inhibition of tubule-glomerular feedback and increased proximal tubular Na+ reabsorption after a HPD augment glomerular hyperfiltration and may trigger synthesis of proinflammatory cytokines and receptor for advanced glycation end-products (RAGE). Focal segmental glomerulosclerosis reported in association with anabolic steroid may indeed be a HPD nephropathy given that HPD results in progressive glomerulosclerosis, especially in remnant glomeruli or in diabetic kidney disease but can happen in any high-risk situation, such as solitary kidney and polycystic kidneys. SUMMARY: HPD among athletes and bodybuilders in an extreme way across a long-term period may pose a risk to renal health including high incidence of HPD nephropathy.

Fructose in the kidney: from physiology to pathology.

The Warburg effect is a unique property of cancer cells, in which glycolysis is activated instead of mitochondrial respiration despite oxygen availability. However, recent studies found that the Warburg effect also mediates non-cancer disorders, including kidney disease. Currently, diabetes or glucose has been postulated to mediate the Warburg effect in the kidney, but it is of importance that the Warburg effect can be induced under nondiabetic conditions. Fructose is endogenously produced in several organs, including the kidney, under both physiological and pathological conditions. In the kidney, fructose is predominantly metabolized in the proximal tubules; under normal physiologic conditions, fructose is utilized as a substrate for gluconeogenesis and contributes to maintain systemic glucose concentration under starvation conditions. However, when present in excess, fructose likely becomes deleterious, possibly due in part to excessive uric acid, which is a by-product of fructose metabolism. A potential mechanism is that uric acid suppresses aconitase in the Krebs cycle and therefore reduces mitochondrial oxidation. Consequently, fructose favors glycolysis over mitochondrial respiration, a process that is similar to the Warburg effect in cancer cells. Activation of glycolysis also links to several side pathways, including the pentose phosphate pathway, hexosamine pathway, and lipid synthesis, to provide biosynthetic precursors as fuel for renal inflammation and fibrosis. We now hypothesize that fructose could be the mediator for the Warburg effect in the kidney and a potential mechanism for chronic kidney disease.

Myostatin/Appendicular Skeletal Muscle Mass (ASM) Ratio, Not Myostatin, Is Associated with Low Handgrip Strength in Community-Dwelling Older Women.

BACKGROUND/AIMS: Elevated levels of serum myostatin have been proposed as a biomarker for sarcopenia. Recent studies have shown that elevated level of serum myostatin was associated with physical fitness and performance. This study aimed to examine the significance of myostatin in the association between muscle mass and physical performance in the elderly. METHODS: This cross-sectional study is based on the Korean Frailty and Aging Cohort study involving 1053 people aged 70 years or over. Anthropometric, physical performance, and laboratory data were collected. RESULTS: The mean age of the participants was 75.8 years, and 50.7% of them were female. Serum myostatin levels in men (3.7 ± 1.2 vs. 3.2 ± 1.1 ng/mL, p < 0.001) were higher compared with that in women. Serum myostatin level was associated with appendicular skeletal muscle mass (ASM) index and eGFR by cystatin C. Serum myostatin/ASM ratio was associated with handgrip strength in women. CONCLUSION: Higher serum myostatin levels were related with higher muscle mass and better physical performances in the elderly. Serum myostatin/ASM ratio may be a predictor for physical performance rather than myostatin.

Comparison of Different Types of Oral Adsorbent Therapy in Patients with Chronic Kidney Disease: A Multicenter, Randomized, Phase IV Clinical Trial.

PURPOSE: Oral adsorbents delay disease progression and improve uremic symptoms in patients with chronic kidney disease (CKD). DW-7202 is a newly developed oral adsorbent with high adsorptive selectivity for uremic toxins. We evaluated patient preference for and adherence to DW-7202 versus AST-120 therapy and compared treatment efficacy and safety in patients with pre-dialysis CKD. MATERIALS AND METHODS: A seven-center, randomized, open-label, two-way crossover, active-controlled, phase IV clinical trial was conducted. Patients with stable CKD were randomly assigned to receive DW-7202 (capsule type) or AST-120 (granule type) for 12 weeks. The groups then switched to the other adsorbent and took it for the next 12 weeks. Patient preference was the primary outcome. Secondary outcomes included changes in estimated glomerular filtration rate (eGFR) and serum creatinine, cystatin C, and indoxyl sulfate (IS) levels. RESULTS: Significantly more patients preferred DW-7202 than AST-120 (p<0.001). Patient adherence improved after switching from AST-120 to DW-7202; there was no apparent change in adherence after switching from DW-7202 to AST-120. Changes in eGFR and serum creatinine, cystatin C, and IS levels were not significantly different according to adsorbent type. There was also no significant difference in the incidences of adverse events during treatment with DW-7202 and AST-120. CONCLUSION: DW-7202 can be considered as an alternative to AST-120 in patients who cannot tolerate or show poor adherence to granule type adsorbents. Further studies to evaluate factors affecting patient preferences and improved adherence are warranted (Clinical trial registration No. NCT02681952).

Loosening of the mesothelial barrier as an early therapeutic target to preserve peritoneal function in peritoneal dialysis.

Phenotype transition of peritoneal mesothelial cells (MCs) including the epithelial-to-mesenchymal transition (EMT) is regarded as an early mechanism of peritoneal dysfunction and fibrosis in peritoneal dialysis (PD), producing proinflammatory and pro-fibrotic milieu in the intra-peritoneal cavity. Loosening of intercellular tight adhesion between adjacent MCs as an initial process of EMT creates the environment where mesothelium and submesothelial tissue are more vulnerable to the composition of bio-incompatible dialysates, reactive oxygen species, and inflammatory cytokines. In addition, down-regulation of epithelial cell markers such as E-cadherin facilitates de novo acquisition of mesenchymal phenotypes in MCs and production of extracellular matrices. Major mechanisms underlying the EMT of MCs include induction of oxidative stress, pro-inflammatory cytokines, endoplasmic reticulum stress and activation of the local renin-angiotensin system. Another mechanism of peritoneal EMT is mitigation of intrinsic defense mechanisms such as the peritoneal antioxidant system and anti-fibrotic peptide production in the peritoneal cavity. In addition to use of less bio-incompatible dialysates and optimum treatment of peritonitis in PD, therapies to prevent or alleviate peritoneal EMT have demonstrated a favorable effect on peritoneal function and structure, suggesting that EMT can be an early interventional target to preserve peritoneal integrity.

Eosinophil count and mortality risk in incident hemodialysis patients.

BACKGROUND: Eosinophils are traditionally known as moderators of allergic reactions; however, they have now emerged as one of the principal immune-regulating cells as well as predictors of vascular disease and mortality in the general population. Although eosinophilia has been demonstrated in hemodialysis (HD) patients, associations of eosinophil count (EOC) and its changes with mortality in HD patients are still unknown. METHODS: In 107 506 incident HD patients treated by a large dialysis organization during 2007-11, we examined the relationships of baseline and time-varying EOC and its changes (ΔEOC) over the first 3 months with all-cause mortality using Cox proportional hazards models with three levels of hierarchical adjustment. RESULTS: Baseline median EOC was 231 (interquartile range 155-339) cells/µL and eosinophilia (>350 cells/µL) was observed in 23.4% of patients. There was a gradual increase in EOC over time after HD initiation with a median ΔEOC of 5.1 (IQR -53-199) cells/µL, which did not parallel the changes in white blood cell count. In fully adjusted models, mortality risk was highest in subjects with lower baseline and time-varying EOC (<100 cells/µL) and was also slightly higher in patients with higher levels (≥550 cells/µL), resulting in a reverse J-shaped relationship. The relationship of ΔEOC with all-cause mortality risk was also a reverse J-shape where both an increase and decrease exhibited a higher mortality risk. CONCLUSIONS: Both lower and higher EOCs and changes in EOC over the first 3 months after HD initiation were associated with higher all-cause mortality in incident HD patients.

Hyperuricemia in Kidney Disease: A Major Risk Factor for Cardiovascular Events, Vascular Calcification, and Renal Damage.

Kidney disease, especially when it is associated with a reduction in estimated glomerular filtration rate, can be associated with an increase in serum urate (uric acid), suggesting that hyperuricemia in subjects with kidney disease may be a strictly secondary phenomenon. Mendelian randomization studies that evaluate genetic scores regulating serum urate also generally have not found evidence that serum urate is a causal risk factor in chronic kidney disease. Nevertheless, this is countered by a large number of epidemiologic, experimental, and clinical studies that have suggested a potentially important role for uric acid in kidney disease and cardiovascular disease. Here, we review the topic in detail. Overall, the studies strongly suggest that hyperuricemia does have an important pathogenic role that likely is driven by intracellular urate levels. An exception may be the role of extracellular uric acid in atherosclerosis and vascular calcification. One of the more striking findings on reviewing the literature is that the primary benefit of lowering serum urate in subjects with CKD is not by slowing the progression of renal disease, but rather by reducing the incidence of cardiovascular events and mortality. We recommend large-scale clinical trials to determine if there is a benefit in lowering serum urate in hyperuricemic subjects in acute and chronic kidney disease and in the reduction of cardiovascular morbidity and mortality in subjects with end-stage chronic kidney disease.

Association of Mineral Bone Disorder With Decline in Residual Kidney Function in Incident Hemodialysis Patients.

Abnormalities of mineral bone disorder (MBD) parameters have been suggested to be associated with poor renal outcome in predialysis patients. However, the impact of those parameters on decline in residual kidney function (RKF) is uncertain among incident hemodialysis (HD) patients. We performed a retrospective cohort study in 13,772 patients who initiated conventional HD during 2007 to 2011 and survived 6 months of dialysis. We examined the association of baseline serum phosphorus, calcium, intact parathyroid hormone (PTH), and alkaline phosphatase (ALP) with a decline in RKF. Decline in RKF was assessed by estimated slope of renal urea clearance (KRU) over 6 months from HD initiation. Our cohort had a mean ± SD age of 62 ± 15 years; 64% were men, 57% were white, 65% had diabetes, and 51% had hypertension. The median (interquartile range [IQR]) baseline KRU level was 3.4 (2.0, 5.2) mL/min/1.73 m2 . The median (IQR) estimated 6-month KRU slope was -1.47 (-2.24, -0.63) mL/min/1.73 m2 per 6 months. In linear regression models, higher phosphorus categories were associated with a steeper 6-month KRU slope compared with the reference category (phosphorus 4.0 to <4.5 mg/dL). Lower calcium and higher intact PTH and ALP categories were also associated with a steeper 6-month KRU slope compared with their respective reference groups (calcium 9.2 to <9.5 mg/dL; intact PTH 150 to <250 pg/mL; ALP <60 U/L). The increased number of parameter abnormalities had an additive effect on decline in RKF. Abnormalities of MBD parameters including higher phosphorus, intact PTH, ALP and lower calcium levels were independently associated with decline in RKF in incident HD patients. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Efficacy and Safety of CKD-11101 (Proposed Biosimilar of Darbepoetin-Alfa) Compared with Darbepoetin-Alfa in Patients on Hemodialysis: A Randomized, Double-Blinded, Parallel-Group Phase III Study.

BACKGROUND: Darbepoetin-alfa is an erythropoiesis-stimulating agent (ESA) with a long elimination half-life that achieves better hemoglobin (Hb) stability than short-acting ESAs. OBJECTIVE: We aimed to evaluate the efficacy and safety of intravenous CKD-11101 (a biosimilar of darbepoetin-alfa) compared with those of darbepoetin-alfa in hemodialysis patients. METHODS: The study was performed in 24 centers in Korea between June 2015 and June 2017. The study subjects were randomized in a double-blind manner. The follow-up duration was 24 weeks, which consisted of 20 weeks of maintenance and 4 weeks of evaluation period. All patients underwent a stabilization period to achieve a target baseline Hb of 10-12 g/dL before randomization. Following randomization, patients received darbepoetin-alfa or CKD-11101 weekly or biweekly. RESULTS: A total of 403 patients were randomized into two groups, and a total of 325 patients (80.6%) completed the investigation. The differences between the two groups in terms of change in the average Hb level from baseline to evaluation were not significant. The average administered dose of ESA was similar between the groups. There was no difference in the proportion of patients who maintained the target Hb during the evaluation period [60.4% vs. 66.2% in the CKD-11101 and darbepoetin-alfa groups, respectively (p = 0.3038)]. In addition, the safety analysis, consisting of adverse events and adverse drug reactions, showed comparable results between the two groups. CONCLUSION: The changes in the level of Hb, dose of erythropoietin, and achievement rate of the target Hb during the study period were comparable between the groups. CKD-11101 has an equivalent efficacy and safety compared with darbepoetin-alfa in patients undergoing hemodialysis.

The interactive effects of input and output on managing fluid balance in patients with acute kidney injury requiring continuous renal replacement therapy.

BACKGROUND: The interactive effect of cumulative input and output on achieving optimal fluid balance has not been well elucidated in patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT). This study evaluated the interrelation of fluid components with mortality in patients with AKI requiring CRRT. METHODS: This is a retrospective observational study conducted with a total of 258 patients who were treated with CRRT due to AKI between 2016 and 2018 in the intensive care unit of Ewha Womans University Mokdong Hospital. The amounts of fluid input and output were assessed at 24-h and 72-h from the initiation of CRRT. The study endpoints were 7- and 28-day all-cause mortality. RESULTS: The mean patient age was 64.7 ± 15.8 years, and 165 (64.0%) patients were male. During the follow-up, 7- and 28-day mortalities were observed in 120 (46.5%) and 157 (60.9%) cases. The patients were stratified into two groups (28-day survivors vs. non-survivors), and the cumulative fluid balances (CFBs) at 24 h and 72 h were significantly higher in the 28-day non-survivors compared with the survivors. The increase in 24-h and 72-h CFB was significantly associated with an increase in 7- and 28-day mortality risks. To examine the interactive effect of cumulative input or output on the impact of CFB on mortality, we also stratified patients into three groups based on the tertile of 24-h and 72-h cumulative input or output. The increases in 24-h and 72-h CFBs were still significantly related to the increases in 7-day and 28-day mortality, irrespective of the cumulative input. However, we did not find significant associations between increase in 24-h and 72-h CFB and increase in mortality risk in the groups according to cumulative output tertile. CONCLUSIONS: The impact of cumulative fluid balance on mortality might be more dependent on cumulative output. The physicians need to decrease the cumulative fluid balance of CRRT patients as much as possible and consider increasing patient removal.

Uric acid induced the phenotype transition of vascular endothelial cells via induction of oxidative stress and glycocalyx shedding.

Recent data suggested a causative role of uric acid (UA) in the development of renal disease, in which endothelial dysfunction is regarded as the key mechanism. Endothelial-to-mesenchymal transition (EndoMT) and shedding of the glycocalyx are early changes of endothelial dysfunction. We investigated whether UA induced EndoMT in HUVECs and an animal model of hyperuricemia fed with 2% oxonic acid for 4 wk. UA induced EndoMT in HUVECs with a generation of reactive oxygen species via the activation of membranous NADPH oxidase (from 15 min) and mitochondria (from 6 h) along with glycocalyx shedding (from 6 h), which were blocked by probenecid. GM6001, an inhibitor of matrix metalloproteinase, alleviated UA-induced glycocalyx shedding and EndoMT. Antioxidants including N-acetyl cysteine, apocynin, and mitotempo ameliorated EndoMT; however, they did not change glycocalyx shedding in HUVECs. In the kidney of hyperuricemic rats, endothelial staining in peritubular capillaries (PTCs) was substantially decreased with a de novo expression of α-smooth muscle actin in PTCs. Plasma level of syndecan-1 was increased in hyperuricemic rats, which was ameliorated by allopurinol. UA caused a phenotypic transition of endothelial cells via induction of oxidative stress with glycocalyx shedding, which could be one of the mechanisms of UA-induced endothelial dysfunction and kidney disease.-Ko, J., Kang, H.-J., Kim, D.-A., Kim, M.-J., Ryu, E.-S., Lee, S., Ryu, J.-H., Roncal, C., Johnson, R. J., Kang, D.-H. Uric acid induced the phenotype transition of vascular endothelial cells via induction of oxidative stress and glycocalyx shedding.