From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease.

This article provides a thorough overview of the biomarkers, pathophysiology, and molecular pathways involved in the transition from acute kidney injury (AKI) and acute kidney disease (AKD) to chronic kidney disease (CKD). It categorizes the biomarkers of AKI into stress, damage, and functional markers, highlighting their importance in early detection, prognosis, and clinical applications. This review also highlights the links between renal injury and the pathophysiological mechanisms underlying AKI and AKD, including renal hypoperfusion, sepsis, nephrotoxicity, and immune responses. In addition, various molecules play pivotal roles in inflammation and hypoxia, triggering maladaptive repair, mitochondrial dysfunction, immune system reactions, and the cellular senescence of renal cells. Key signaling pathways, such as Wnt/ß-catenin, TGF-ß/SMAD, and Hippo/YAP/TAZ, promote fibrosis and impact renal function. The renin-angiotensin-aldosterone system (RAAS) triggers a cascade leading to renal fibrosis, with aldosterone exacerbating the oxidative stress and cellular changes that promote fibrosis. The clinical evidence suggests that RAS inhibitors may protect against CKD progression, especially post-AKI, though more extensive trials are needed to confirm their full impact.

Impact of SGLT2 inhibitors on patient outcomes: a network meta-analysis.

BACKGROUND: A comprehensive network meta-analysis comparing the effects of individual sodium-glucose cotransporter 2 (SGLT2) inhibitors on patients with and without comorbidities including diabetes mellitus (DM), heart failure (HF), and chronic kidney disease (CKD) has not been previously conducted. METHODS: We searched PubMed, Embase, Cochrane, and ClinicalTrials.gov for randomized controlled trials up to March 28, 2023. Network meta-analysis using a random-effects model was conducted to calculate risk ratios (RRs). Risk of Bias tool 2.0 was used to assess bias, and CINeMA to assess the certainty of evidence. In the subgroup analysis, the SGLT2 inhibitors were classified into highly (dapagliflozin, empagliflozin, and ertugliflozin) and less selective SGLT2 inhibitors (canagliflozin and sotagliflozin). RESULTS: A total of fourteen trials with 75,334 patients were analyzed. Among these, 40,956 had taken SGLT2 inhibitors and 34,378 had not. One of the main results with particular findings was empagliflozin users had a significantly lower risk of all-cause death compared to dapagliflozin users in DM population (RR: 0.81, 95% CI 0.69-0.96). In HF population, sotagliflozin users had a borderline significantly lower risk of CV death or hospitalization for HF (HHF) than dapagliflozin users (RR: 0.90, 95% CI 0.80-1.01). In non-HF population, those who used canagliflozin had a significantly lower risk of CV death or HHF compared with those who used dapagliflozin (RR: 0.75, 95% CI 0.58-0.98). At last, for HF patients, those who used less selective SGLT2 inhibitors had a significantly lower risk of MACEs compared to those who used highly selective SGLT2 inhibitors (RR: 0.75, 95% CI 0.62-0.90). CONCLUSIONS: Our network meta-analysis revealed that empagliflozin users with diabetes experienced a lower risk of dying from any cause than those using dapagliflozin. Additionally, canagliflozin users demonstrated a reduced risk of cardiovascular death or HHF compared to dapagliflozin users in those without HF. In HF patients, less selective SGLT2 inhibitors showed superior CV composite outcomes, even surpassing the performance of highly selective SGLT2 inhibitors. TRIAL REGISTRATION: PROSPERO [CRD42022361906].

Acute kidney injury in patients with COVID-19 compared to those with influenza: a systematic review and meta-analysis.

Background: COVID-19 and influenza can both lead to acute kidney injury (AKI) as a common complication. However, no meta-analysis has been conducted to directly compare the incidence of AKI between hospitalized patients with COVID-19 and influenza. The objective of our study aims to investigate the incidence and outcomes of AKI among hospitalized patients between these two groups. Materials and methods: A systematic search of PubMed, Embase, and Cochrane databases was conducted from December 2019 to August 2023 to identify studies examining AKI and clinical outcomes among hospitalized patients with COVID-19 and influenza. The primary outcome of interest was the incidence of AKI, while secondary outcomes included in-hospital mortality, recovery from AKI, hospital and ICU stay duration. The quality of evidence was evaluated using Cochrane and GRADE methods. Results: Twelve retrospective cohort studies, involving 17,618 hospitalized patients with COVID-19 and influenza, were analyzed. COVID-19 patients showed higher AKI incidence (29.37% vs. 20.98%, OR: 1.67, 95% CI 1.56-1.80, p < 0.01, I2 = 92.42%), and in-hospital mortality (30.95% vs. 5.51%, OR: 8.16, 95% CI 6.17-10.80, p < 0.01, I2 = 84.92%) compared to influenza patients with AKI. Recovery from AKI was lower in COVID-19 patients (57.02% vs., 80.23%, OR: 0.33, 95% CI 0.27-0.40, p < 0.01, I2 = 85.17%). COVID-19 patients also had a longer hospital stay (SMD: 0.69, 95% CI 0.65-0.72, p < 0.01, I2 = 98.94%) and longer ICU stay (SMD: 0.61, 95% CI 0.50-0.73, p < 0.01, I2 = 94.80%) than influenza patients. In our study, evidence quality was high (NOS score 7-9), with low certainty for AKI incidence and moderate certainty for recovery form AKI by GRADE assessment. Conclusion: COVID-19 patients had higher risk of developing AKI, experiencing in-hospital mortality, and enduring prolonged hospital/ICU stays in comparison to influenza patients. Additionally, the likelihood of AKI recovery was lower among COVID-19 patients.

Impact of type of dialyzable beta-blockers on subsequent risk of mortality in patients receiving dialysis: A systematic review and meta-analysis.

BACKGROUND: Beta-blockers has been reported to improve all-cause mortality and cardiovascular mortality in patients receiving dialysis, but type of beta-blockers (i.e., high vs. low dialyzable) on patient outcomes remains unknown. This study aimed at assessing the outcomes of patients receiving dialyzable beta-blockers (DBBs) compared to those receiving non-dialyzable beta-blockers (NDBBs). METHODS: We searched the databases including PubMed, Embase, Cochrane, and ClinicalTrials.gov until 28 February 2022 to identify articles investigating the impact of DBBs/NDBBs among patients with renal failure receiving hemodialysis/peritoneal dialysis (HD/PD). The primary outcome was risks of all-cause mortality, while the secondary outcomes included risk of overall major adverse cardiac event (MACE), acute myocardial infarction (AMI) and heart failure (HF). We rated the certainty of evidence (COE) by Cochrane methods and the GRADE approach. RESULTS: Analysis of four observational studies including 75,193 individuals undergoing dialysis in hospital and community settings after a follow-up from 180 days to six years showed an overall all-cause mortality rate of 11.56% (DBBs and NDBBs: 12.32% and 10.7%, respectively) without significant differences in risks of mortality between the two groups [random effect, aHR 0.91 (95% CI, 0.81-1.02), p = 0.11], overall MACE [OR 1.03 (95% CI, 0.78-1.38), p = 0.82], and AMI [OR 1.02 (95% CI, 0.94-1.1), p = 0.66]. Nevertheless, the pooled odds ratio of HF among patients receiving DBBs was lower than those receiving NDBB [random effect, OR 0.87 (95% CI, 0.82-0.93), p<0.001]. The COE was considered low for overall MACE, AMI and HF, while it was deemed moderate for all-cause mortality. CONCLUSIONS: The use of dialyzable and non-dialyzable beta-blockers had no impact on the risk of all-cause mortality, overall MACE, and AMI among dialysis patients. However, DBBs were associated with significant reduction in risk of HF compared with NDBBs. The limited number of available studies warranted further large-scale clinical investigations to support our findings.

Distinct Effects of a High Fat Diet on Bone in Skeletally Mature and Developing Male C57BL/6J Mice.

Increased risks of skeletal fractures are common in patients with impaired glucose handling and type 2 diabetes mellitus (T2DM). The pathogenesis of skeletal fragility in these patients remains ill-defined as patients present with normal to high bone mineral density. With increasing cases of glucose intolerance and T2DM it is imperative that we develop an accurate rodent model for further investigation. We hypothesized that a high fat diet (60%) administered to developing male C57BL/6J mice that had not reached skeletal maturity would over represent bone microarchitectural implications, and that skeletally mature mice would better represent adult-onset glucose intolerance and the pre-diabetes phenotype. Two groups of developing (8 week) and mature (12 week) male C57BL/6J mice were placed onto either a normal chow (NC) or high fat diet (HFD) for 10 weeks. Oral glucose tolerance tests were performed throughout the study period. Long bones were excised and analysed for ex vivo biomechanical testing, micro-computed tomography, 2D histomorphometry and gene/protein expression analyses. The HFD increased fasting blood glucose and significantly reduced glucose tolerance in both age groups by week 7 of the diets. The HFD reduced biomechanical strength, both cortical and trabecular indices in the developing mice, but only affected cortical outcomes in the mature mice. Similar results were reflected in the 2D histomorphometry. Tibial gene expression revealed decreased bone formation in the HFD mice of both age groups, i.e., decreased osteocalcin expression and increased sclerostin RNA expression. In the mature mice only, while the HFD led to a non-significant reduction in runt-related transcription factor 2 (Runx2) RNA expression, this decrease became significant at the protein level in the femora. Our mature HFD mouse model more accurately represents late-onset impaired glucose tolerance/pre-T2DM cases in humans and can be used to uncover potential insights into reduced bone formation as a mechanism of skeletal fragility in these patients.

Room-Temperature Chemical Solution Treatment for Flexible ZnS(O,OH)/Cu(In,Ga)Se2 Solar Cell: Improvements in Interface Properties and Metastability.

We demonstrate an effective room-temperature chemical solution treatment, by using thioacetamide (S treatment) or thioacetamide-InCl3 (In-S treatment) solution, on Cu(In,Ga)Se2 (CIGSe) surface to engineer the ZnS(O,OH)/CIGSe interface and junction quality, leading to enhanced efficiency and minimized metastability of flexible solar cells. The control device without treatment reveals a relatively low efficiency of 8.15%, which is significantly improved to 9.74% by In-S treatment, and 10.39% by S treatment. Results of X-ray photoelectron spectroscopy suggest that S is incorporated into CIGSe surface forming CIGSSe by S treatment, whereas a thin In-S layer is formed on CIGSe surface by In-S treatment with reduced amount of S diffusing into CIGSe. PL spectra and TRPL lifetime further reveal that S incorporation into CIGS surface may substitute the OSe and/or directly occupy the vacant anion site (VSe), resulting in the effective passivation of the recombination centers at CIGSe surface. Moreover, reducing the concentrations of VSe may thereby decrease the density of (VCu-VSe) acceptors, which can minimize the metastability of ZnS(O,OH)/CIGSe solar cells. With S treatment, the light soaking (LS) time of ZnS(O,OH)/CIGSe device is reduced approximately to one-half of control one. Our approach can be potentially applied for alternative Cd-free buffer layers to achieve high efficiency and low metastability.

ß-catenin is essential for ethanol metabolism and protection against alcohol-mediated liver steatosis in mice.

UNLABELLED: The liver plays a central role in ethanol metabolism, and oxidative stress is implicated in alcohol-mediated liver injury. ß-Catenin regulates hepatic metabolic zonation and adaptive response to oxidative stress. We hypothesized that ß-catenin regulates the hepatic response to ethanol ingestion. Female liver-specific ß-catenin knockout (KO) mice and wild-type (WT) littermates were fed the Lieber-Decarli liquid diet (5% ethanol) in a pairwise fashion. Liver histology, biochemistry, and gene-expression studies were performed. Plasma alcohol and ammonia levels were measured using standard assays. Ethanol-fed (EtOH) KO mice exhibited systemic toxicity and early mortality. KO mice exhibited severe macrovesicular steatosis and 5 to 6-fold higher serum alanine aminotransferase and aspartate aminotransferase levels. KO mice had a modest increase in hepatic oxidative stress, lower expression of mitochondrial superoxide dismutase (SOD2), and lower citrate synthase activity, the first step in the tricarboxylic acid cycle. N-Acetylcysteine did not prevent ethanol-induced mortality in KO mice. In WT livers, ß-catenin was found to coprecipitate with forkhead box O3, the upstream regulator of SOD2. Hepatic alcohol dehydrogenase and aldehyde dehydrogenase activities and expression were lower in KO mice. Hepatic cytochrome P450 2E1 protein levels were up-regulated in EtOH WT mice, but were nearly undetectable in KO mice. These changes in ethanol-metabolizing enzymes were associated with 30-fold higher blood alcohol levels in KO mice. CONCLUSION: ß-Catenin is essential for hepatic ethanol metabolism and plays a protective role in alcohol-mediated liver steatosis. Our results strongly suggest that integration of these functions by ß-catenin is critical for adaptation to ethanol ingestion in vivo.

Liver-specific ß-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis.

UNLABELLED: Beta-catenin plays important roles in liver physiology and hepatocarcinogenesis. While studying the role of ß-catenin in diet-induced steatohepatitis, we recently found that liver-specific ß-catenin knockout (KO) mice exhibit intrahepatic cholestasis. This study was undertaken to further characterize the role of ß-catenin in biliary physiology. KO mice and wild-type (WT) littermates were fed standard chow or a diet supplemented with 0.5% cholic acid for 2 weeks. Chow-fed KO mice had higher serum and hepatic total bile acid levels and lower bile flow rate than WT mice. Expression levels of bile acid biosynthetic genes were lower and levels of major bile acid exporters were similar, which therefore could not explain the KO phenotype. Despite loss of the tight junction protein claudin-2, KO mice had preserved functional integrity of tight junctions. KO mice had bile canalicular morphologic abnormalities as evidenced by staining for F-actin and zona occludens 1. Electron microscopy revealed dilated and tortuous bile canaliculi in KO livers along with decreased canalicular and sinusoidal microvilli. KO mice on a cholic acid diet had higher hepatic and serum bile acid levels, bile ductular reaction, increased pericellular fibrosis, and dilated, misshapen bile canaliculi. Compensatory changes in expression levels of several bile acid transporters and regulatory genes were found in KO livers. CONCLUSION: Liver-specific loss of ß-catenin leads to defective bile canalicular morphology, bile secretory defect, and intrahepatic cholestasis. Thus, our results establish a critical role for ß-catenin in biliary physiology.

Transcriptional regulation of CXC-ELR chemokines KC and MIP-2 in mouse pancreatic acini.

Neutrophils and their chemoattractants, the CXC-ELR chemokines keratinocyte cytokine (KC) and macrophage inflammatory protein-2 (MIP-2), play a critical role in pancreatitis. While acute pancreatitis is initiated in acinar cells, it is unclear if these are a source of CXC-ELR chemokines. KC and MIP-2 have NF-κB, activator protein-1 (AP-1) sites in their promoter regions. However, previous studies have shown increased basal and reduced caerulein-induced AP-1 activation in harvested pancreatic tissue in vitro, which limits interpreting the caerulein-induced response. Moreover, recent studies suggest that NF-κB silencing in acinar cells alone may not be sufficient to reduce inflammation in acute pancreatitis. Thus the aim of this study was to determine whether acinar cells are a source of KC and MIP-2 and to understand their transcriptional regulation. Primary overnight-cultured murine pancreatic acini were used after confirming their ability to replicate physiological and pathological acinar cell responses. Upstream signaling resulting in KC, MIP-2 upregulation was studied along with activation of the transcription factors NF-κB and AP-1. Cultured acini replicated critical responses to physiological and pathological caerulein concentrations. KC and MIP-2 mRNA levels increased in response to supramaximal but not to physiological caerulein doses. This upregulation was calcium and protein kinase C (PKC), but not cAMP, dependent. NF-κB inhibition completely prevented upregulation of KC but not MIP-2. Complete suppression of MIP-2 upregulation required dual inhibition of NF-κB and AP-1. Acinar cells are a likely source of KC and MIP-2 upregulation during pancreatitis. This upregulation is dependent on calcium and PKC. MIP-2 upregulation requires both NF-κB and AP-1 in these cells. Thus dual inhibition of NF-κB and AP-1 may be a more successful strategy to reduce inflammation in pancreatitis than targeting NF-κB alone.

Liver-specific beta-catenin knockout mice exhibit defective bile acid and cholesterol homeostasis and increased susceptibility to diet-induced steatohepatitis.

Although the role of Wnt/beta-catenin signaling in liver growth and development is well established, its contribution in non-neoplastic hepatic pathologies has not been investigated. Here, we examine the role of beta-catenin in a murine model of diet-induced liver injury. Mice with hepatocyte-specific beta-catenin deletion (KO) and littermate controls were fed the steatogenic methionine and choline-deficient (MCD) diet or the corresponding control diet for 2 weeks and characterized for histological, biochemical, and molecular changes. KO mice developed significantly higher steatohepatitis and fibrosis on the MCD diet compared with wild-type mice. Both wild-type and KO livers accumulated triglyceride on the MCD diet but, unexpectedly, higher hepatic cholesterol levels were observed in KO livers on both control and MCD diets. Gene expression analysis showed that hepatic cholesterol accumulation in KO livers was not attributable to increased synthesis or uptake. KO mice had lower expression of bile acid synthetic enzymes but exhibited higher hepatic bile acid and serum bilirubin levels, suggesting defects in bile export. Therefore, loss of beta-catenin in the liver leads to defective cholesterol and bile acid metabolism in the liver and increased susceptibility to developing steatohepatitis in the face of metabolic stress.