Fractal Analysis of Left Ventricular Trabeculae in Patients with End-Stage Renal Disease: A Random Survival Tree Analysis.

BACKGROUND: The complexity of left ventricular (LV) trabeculae is related to the prognosis of several cardiovascular diseases. PURPOSE: To evaluate the prognostic value of LV trabecular complexity in patients with end-stage renal disease (ESRD). STUDY TYPE: Prospective outcome study. POPULATION: 207 participants on maintenance dialysis, divided into development (160 patients from 2 centers) and external validation (47 patients from a third center) cohorts, and 72 healthy controls. FIELD STRENGTH: 3.0T, steady-state free precession (SSFP) and modified Look-Locker imaging sequences. ASSESSMENT: All participants had their trabecular complexity quantified by fractal analysis using cine SSFP images. Patients were followed up every 2 weeks until April 2023, or endpoint events happened. Random Forest (RF) and Cox regression models including age, diabetes, LV mass index, mean basal fractal dimension (FD), and left atrial volume index, were developed to predict major adverse cardiac events (MACE). Patients were divided into low- and high-risk groups based on scores derived from the RF model and survival compared. STATISTICAL TESTS: Receiver operating characteristic curve analysis; Kaplan-Meier survival analysis with log rank tests; Harrel's C-index to assess model performance. A P value <0.05 was considered statistically significant. RESULTS: Fifty-five patients (26.57%) experienced MACE during a median follow-up time of 21.83 months. An increased mean basal FD (≥1.324) was associated with a significantly higher risk of MACE. The RF model (C-index: 0.81) had significantly better discrimination than the Cox regression model (C-index: 0.74). Participants of the external validation dataset classified into the high-risk group had a hazard of experiencing MACE increased by 12.29 times compared to those in the low-risk group. DATA CONCLUSION: LV basal FD was an independent predictor for MACE in patients with ESRD. Reliable risk stratification models could be generated based on LV basal FD and other MRI variables using RF analysis. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Integrative ATAC-seq and RNA-seq analysis associated with diabetic nephropathy and identification of novel targets for treatment by dapagliflozin.

Dapagliflozin (DAPA) are clinically effective in improving diabetic nephropathy (DN). However, whether and how chromatin accessibility changed by DN responds to DAPA treatment is unclear. Therefore, we performed ATAC-seq, RNA-seq, and weighted gene correlation network analysis to identify the chromatin accessibility, the messenger RNA (mRNA) expression, and the correlation between clinical phenotypes and mRNA expression using kidney from three mouse groups: db/m mice (Controls), db/db mice (case group), and those treated with DAPA (treatment group). RNA-Seq and ATAC-seq conjoint analysis revealed many overlapping pathways and networks suggesting that the transcriptional changes of DN and DAPA intervention largely occured dependently on chromatin remodeling. Specifically, the results showed that some key signal transduction pathways, such as immune dysfunction, glucolipid metabolism, oxidative stress and xenobiotic and endobiotic metabolism, were repeatedly enriched in the analysis of the RNA-seq data alone, as well as combined analysis with ATAC-seq data. Furthermore, we identified some candidate genes (UDP glucuronosyltransferase 1 family, Dock2, Tbc1d10c, etc.) and transcriptional regulators (KLF6 and GFI1) that might be associated with DN and DAPA restoration. These reversed genes and regulators confirmed that pathways related to immune response and metabolism pathways were critically involved in DN progression.

Assessment of the Prognostic Value of MRI Left Ventricular Global Function Index (LVGFI) in Patients With End-Stage Renal Disease Under Maintenance Dialysis.

BACKGROUND: Left ventricular global function index (LVGFI) integrates LV volumetric and functional parameters. In patients with end-stage renal disease (ESRD), cardiac injury manifests as LV hypertrophy and dysfunction. However, the prognostic value of LVGFI in this population remains unclear. PURPOSE: To investigate the association of LVGFI with major adverse cardiac events (MACE) in patients with ESRD. STUDY TYPE: Prospective. POPULATION: One hundred fifty-eight ESRD patients (mean age: 54.1 ± 14.4 years; 105 male) on maintenance dialysis. FILED STRENGTH/SEQUENCE: 3.0 T, balanced steady-state free precession (bSSFP) cine and modified Look-Locker inversion recovery (MOLLI) sequences. ASSESSMENT: LV volumetric and functional parameters were determined from bSSFP images. LVGFI was calculated as the ratio of stroke volume to global volume and native T1 was determined from MOLLI T1 maps. MACE was recorded on follow up. Models were developed to predict MACE from conventional risk factors combined with LVGFI, GLS, native T1, and LV mass index (LVMI), respectively. Subgroup analyses were further performed in participants with LVEF above median. STATISTICAL TESTS: Cox proportional hazard regression and log-rank test were used to investigate the association between LVGFI and MACE. The predictive models were evaluated and compared using Harrell's C-statistics and DeLong tests. A P value <0.05 was considered statistically significant. RESULTS: Thirty-four MACE occurred during the median follow-up period of 26 months. The hazard of MACE increased by 114% for each 10% decrease in LVGFI in univariable analysis. The predictive model consisting of LVGFI (C-statistic: 0.724) had significantly better predictive performance than the others (all P < 0.001). These results were consistent in patients (N = 79) with LVEF > median (63.54%). DATA CONCLUSION: LVGFI is a novel marker for MACE risk stratification in patients with ESRD and was better able to predict MACE than native T1 mapping and GLS. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Shear wave elastography parameters adds prognostic value to adverse outcome in kidney transplantation recipients.

INTRODUCTION: The tissue stiffness of donor kidneys in transplantation may increase due to pathological changes such as glomerulosclerosis and interstitial fibrosis, and those changes associate worse outcomes in kidney transplantation recipients. Ultrasound elastography is a noninvasive imaging examination with the ability to quantitatively reflect tissue stiffness. Aim of this study was to evaluate the prognostic value of ultrasound elastography for adverse kidney outcome in kidney transplantation recipients. METHODS: Shear wave elastography (SWE) examinations were performed by two independent operators in kidney transplantation recipients. The primary outcome was a composite of kidney graft deterioration, all-cause re-hospitalization, and all-cause mortality. Survival analysis was calculated by Kaplan-Meier curves with the log-rank test and Cox regression analysis. RESULTS: A total of 161 patients (mean age 46 years, 63.4% men) were followed for a median of 20.1 months. 27 patients (16.77%) reached the primary endpoint. The mean and median tissue stiffness at the medulla (hazard ratio: 1.265 and 1.229, respectively), estimated glomerular filtration rate (eGFR), and serum albumin level were associated with the primary outcome in univariate Cox regression. Adding mean or median medulla SWE to a baseline model containing eGFR and albumin significantly improved its discrimination (C-statistics: 0.736 for the baseline, 0.766 and 0.772 for the model added mean and median medulla SWE, respectively). CONCLUSION: The medullary tissue stiffness of kidney allograft measured by shear wave elastography may provide incremental prognostic value to adverse outcomes in kidney transplantation recipients. Including SWE parameters in kidney transplantation recipients management could be considered to improve risk stratification.

Gene polymorphisms of VEGF and KDR are associated with initial fast peritoneal solute transfer rate in peritoneal dialysis.

BACKGROUND: Peritoneal dialysis (PD) is an effective and successful renal replacement therapy. The baseline peritoneal solute transfer rate (PSTR) is related to local membrane inflammation and may be partially genetically determined. Herein, we focused on vascular endothelial growth factor (VEGF) and its receptor, kinase insert domain containing receptor (KDR). METHODS: This study recruited 200 PD patients from Renji Hospital in Shanghai, China. We analysed the association between the polymorphisms of VEGF and KDR and the 4-hour dialysate-to-plasma ratio for creatinine (4 h D/P Cr), which was measured between one and three months after initiating PD. RESULTS: The CC genotype in VEGF rs3025039 and the AA genotype in KDR rs2071559 were both positively associated with a fast baseline PSTR (VEGF rs3025039 CC vs. TT + TC: 0.65 ± 0.12 vs. 0.61 ± 0.11; P = 0.029; KDR rs2071559 AA vs. GA + GG: 0.65 ± 0.12 vs. 0.62 ± 0.12; P = 0.039). CONCLUSION: Baseline PSTR was partly determined by VEGF and KDR gene polymorphisms.

A novel contrast-induced acute kidney injury mouse model based on low-osmolar contrast medium.

The contrast-induced acute kidney injury (CI-AKI) has been becoming the third common cause of hospital-acquired acute kidney injury. An ideal animal model is essential for understanding the pathophysiology of CI-AKI. Previous CI-AKI studies were mostly performed on rats with high-osmolar contrast medium (HOCM), which is unsuitable for transgenic researches. This study provides a novel, efficient and reproducible CI-AKI model which was developed in mouse by administrating a low-osmolar contrast medium (LOCM). First of all, we applied the frequently used pretreatments (uninephrectomy and water deprivation), which combined with HOCM on rats could induce CI-AKI, on mice with LOCM. Secondly, we attempted to find a novel pretreatment suitable for mouse and LOCM by combining two classic pretreatments(uninephrectomy, water deprivation and furosemide administration). Finally, we evaluate the kidney damage of the novel model. We found that this mouse model possessed a significant reduction in renal function, severe renal tissue damage, and increased renal tubular cells apoptosis, indicating that LOCM is a feasible inducer for CI-AKI mice model. Taken together, we found that uninephrectomy (UPHT) combined with 24 h water deprivation and furosemide administration 20 min before LOCM (iohexol, 10 ml/kg) application is a feasible pretreatment to establish a novel CI-AKI mouse model.

Peritoneal Dialysis as an Option for Unplanned Dialysis Initiation in Patients with End-Stage Renal Disease and Diabetes Mellitus.

AIMS: This study aimed to compare the short-term complications and long-term prognosis between urgent-start peritoneal dialysis (PD) and hemodialysis (HD), and explore the safety and feasibility of PD in end-stage renal disease (ESRD) patients with diabetes. METHODS: This retrospective study enrolled ESRD patients with diabetes who required urgent-start dialysis at a single center from January 2011 to December 2014. Short-term (30-day) dialysis-related complications and patient survival trends were compared between patients receiving PD and HD. RESULTS: Eighty patients were included in the study, including 50 (62.5%) who underwent PD. The incidence of dialysis-related complications and complications requiring reinsertion during the first 30 days was significantly lower in PD patients. Logistic regression identified urgent-start HD as an independent risk factor for dialysis-related complications compared with urgent-start PD. The patient survival rate was higher in the PD compared to that in the HD group. CONCLUSIONS: PD may be acceptable, safe, and feasible for urgent-start dialysis in ESRD patients with diabetes.

Effects of pretransplant peritoneal vs hemodialysis modality on outcome of first kidney transplantation from donors after cardiac death.

BACKGROUND: The effect of pretransplant peritoneal dialysis (PD) or hemodialysis (HD) modality on outcomes of kidney transplantation (KT) for end-stage renal disease (ESRD) is debatable. We evaluated the outcomes these modalities in KT from donor after cardiac death (DCD). METHODS: A cohort of 251 patients on HD, PD or pre-emptive who underwent first KT from DCD between January 2014 and December 2016 were prospectively analyzed to compare for outcomes on recovery of renal function, complications as well as patient and graft survival. The patients were followed till August 2017. Data on 104 HD and 98 PD were available for final comparative outcome analysis, 5 pre-emptive were analyzed as the control group. RESULTS: Both HD and PD group patients were well matched for demographic and baseline characteristics. The follow-up period was 12.5 (3.0, 22.0) months in HD and 12.0 (6.0, 20.0) months in PD patients. Post-transplant renal functions between the two groups showed no differences. Among PD patients, 16 (16.3%) suffered delayed graft function, versus 19 (18.3%) in HD, with no statistical differences (p = 0.715). Complications of acute rejection, infections were comparable between the groups. The patient survival, graft survival and death-censored graft survival were similar for HD and PD after adjusting for other multiple risk factors. CONCLUSIONS: Our results indicate that outcome of first KT from DCD is not affected by pretransplant dialysis modality of PD or HD in aspects of recovery of renal function, complications as well as patient and graft survival.

A case of ureteral myeloid sarcoma post-renal transplantation.

BACKGROUND: Significant attention has been directed toward the high incidence of malignant tumours that occur post-transplantation. However, there are few reports of myeloid sarcomas (MSs) following renal transplantation. CASE PRESENTATION: This case report describes a 26-year-old male patient who presented with repeatedly high creatinine levels and hydronephrosis six months post-renal transplantation. Surgical pathology revealed ureteral MS; however, the tumour recurred following resection. Bone marrow biopsy indicated that the patient also had acute promyelocytic leukaemia. The tumour was treated with local radiotherapy, and the leukaemia was treated with systemic chemotherapy. The patient's conditions were satisfactory at the one-year follow-up. CONCLUSIONS: This report is the first to describe a ureteral MS post-renal transplantation. Our findings suggest that surgical resection combined with radiotherapy and chemotherapy can help control the status of patients with this condition.

Kidney Injury Molecule-1 is Elevated in Nephropathy and Mediates Macrophage Activation via the Mapk Signalling Pathway.

BACKGROUND/AIMS: Kidney injury molecule-1 (KIM-1) is highly expressed in renal tubular cells after injury and is usually regarded as an early biomarker of acute kidney injury(AKI). The aim of this study was to determine the role of KIM-1 in the development of renal tubular injury Methods: Clinical samples, three different animal models and in vitro experiments were utilized to determine the possible mechanism underlying the involvement of KIM-1 in kidney injury. RESULTS: Both plasma and urinary KIM-1 expression levels were significantly higher in AKI and chronic kidney disease (CKD) patients than in healthy volunteers, and urinary KIM-1 expression was significantly higher in CKD patients than in AKI patients. According to the results of our research involving three different mouse models, KIM-1 expression was significantly increased during the early stage of kidney injury and was persistently elevated in renal fibrosis. Our immunofluorescence staining results indicated that KIM-1-positive tubules were surrounded by macrophage infiltrates in regions of kidney injury. Moreover, our transwell, western blotting and real-time PCR data showed that macrophage migration and phenotype transitions were mediated by KIM-1 through the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway inhibition could significantly reverse the effects of KIM-1 with respect to these macrophage phenotype changes and migration. CONCLUSIONS: KIM-1 expression was markedly elevated in both acute and chronic kidney injury and may play a pivotal role in macrophage activation via the MAPK pathway in kidney disease.

The impact of non-dipper circadian rhythm of blood pressure on left ventricular hypertrophy in patients with non-dialysis chronic kidney disease.

Objective The aim of this study was to investigate the correlation between non-dipper circadian rhythm of blood pressure (BP) and left ventricular hypertrophy (LVH) in patients with chronic kidney disease (CKD). Methods and results All 257 patients with stage 1 to 5 CKD were enrolled in the study and classified into a CKD1-3 group and a CKD4-5 group according to renal function. The parameters and circadian rhythm of BP were measured by a GE Marquette Tonoport V Eng dynamic sphygmomanometer, and cardiac structure was examined by echocardiography. The incidence of abnormal circadian BP rhythm (non-dipper rhythm) was quite high (75.4% in all enrolled patients and 71.3% in the patients with normal BP levels) in CKD patients and increased with the deterioration of renal function. Changes of cardiac structure such as LVH in patients with non-dipper BP were more distinct than in patients with dipper BP. The development of left ventricular mass index (LVMI) correlated positively with the incidence of non-dipper BP rhythm. Multiple regression analysis showed that 24-h systolic BP (ß = 0.417, P < 0.01), triglycerides (TG) (ß = -0.132, P = 0.007), Hb (ß = -0.394, P = 0.016) and gender (ß = 0.158, P = 0.039) were independent risk factors of LVMI. Conclusions The incidence of non-dipper circadian rhythm of blood pressure was quite high in CKD patients and increased with the deterioration of renal function. Non-dipper circadian rhythm of BP is closely related with LVMI.

Astragaloside IV suppresses transforming growth factor-ß1 induced fibrosis of cultured mouse renal fibroblasts via inhibition of the MAPK and NF-κB signaling pathways.

Renal fibrosis, a progressive process characterized by the accumulation of extracellular matrix (ECM) leading to organ dysfunction, is a characteristic of chronic kidney diseases. Among fibrogenic factors known to regulate the renal fibrotic process, transforming growth factor-ß (TGF-ß) plays a central role. In the present study, we examined the effect of Astragaloside IV (AS-IV), a component of the traditional Chinese medicinal plant Astragalus membranaceus, on the processes associated with renal fibrosis in cultured mouse renal fibroblasts treated with TGF-ß1. RT-PCR, western blotting, immunofluorescence staining and collagen assays showed that AS-IV suppressed TGF-ß1 induced fibroblast proliferation, transdifferentiation, and ECM production in a dose-dependent manner. Examination of the underlying mechanisms showed that the effect of AS-IV on the inhibition of fibroblast differentiation and ECM formation were mediated by its modulation of the activity of the MAPK and NF-κB signaling pathways. Taken together, our results indicate that AS-IV alleviates renal interstitial fibrosis via a mechanism involving the MAPK and NF-κB signaling pathways and demonstrate the therapeutic potential of AS-IV for the treatment of chronic kidney diseases.

Long-term kidney survival analyses in IgA nephropathy patients under steroids therapy: a case control study.

BACKGROUND: Corticosteroids are preferred to treat patients with active IgA nephropathy (IgAN), and beneficial effects from the short-term use of corticosteroids have been confirmed. However, a large number of patients will progress to end-stage renal disease after a long time follow-up. This study aimed to evaluate kidney disease progression and risk factors on kidney survival in IgAN patients receiving steroids treatment. METHODS: Two hundred biopsy-proven IgAN patients who received corticosteroid therapy were enrolled and followed for a median period of 63.33 months. Risk factors on kidney survival were retrospectively investigated by the Cox proportional hazards model. RESULTS: Of the two hundred patients, twenty patients showed progression of renal impairment at the end of follow-up. The median and interquartile range values for initial serum creatinine were 89.2 and 68.08-121.35 µmol/L, respectively. Multivariate Cox regression analyses revealed that relapse, non-remission, time-averaged eGFR (TA-eGFR), and time-averaged serum albumin (TA-ALB) were independently associated with the kidney progression. Those with TA-ALB levels <35 g/L and TA-eGFR levels <60 mL/min/1.73 m(2) were less likely to recover from kidney progression. Patients were more likely to show kidney function deterioration, when they had non-remission or relapse after corticosteroids treatment. CONCLUSION: This study demonstrated that relapse, non-remission, TA-eGFR, and TA-ALB could serve as independent predictors of long term prognosis of IgAN patients receiving corticosteroid therapy.

Time-averaged albumin predicts the long-term prognosis of IgA nephropathy patients who achieved remission.

BACKGROUND: Primary IgA nephropathy (IgAN) is the most common form of idiopathic glomerulonephritis worldwide. Although most patients are able to achieve remission with the current therapy, a large number of patients will still progress to end-stage renal disease. This study aimed to evaluate kidney disease progression and the risk factors for progression in IgAN patients who achieved remission. METHODS: Patients from a prospective database with IgAN were included in this study. All the subjects had achieved a complete remission (CR) or partial remission (PR) following 6 months of therapy. Renal survival and the relationship between the clinical parameters and composite renal outcomes were assessed. RESULTS: The study comprised 878 IgAN patients recruited between January 2005 and December 2010. Overall, 632 patients were enrolled in this study. The data from the 369 patients who achieved remission were analyzed; the mean follow-up time was 49 months. The median serum creatinine (SCr) concentration at baseline was 91.3 µmol/L, and the time-averaged creatinine (TA-SCr) was 91.8 µmol/L. The mean serum albumin (ALB) level at baseline was 39.4 g/L, and the time-averaged serum albumin (TA-ALB) was 42.1 g/L. Multivariate Cox regression analyses revealed that the TA-ALB and TA-SCr levels were independently associated with the composite renal outcome. The patients with a TA-SCr value > 120 µmol/L and a TA-ALB level < 38 g/L were less likely to recover from renal progression. CONCLUSION: The strong predictive relationship of low TA-ALB and high TA-SCr levels with progression observed in this study suggests that TA-ALB may serve as a marker of the long-term renal prognosis of IgAN patients who have achieved remission.

Heated and humidified CO2 pneumoperitoneum inhibits tumour cell proliferation, migration and invasion in colon cancer.

BACKGROUND: Peritoneal carcinomatosis (PC) arising from colorectal cancer is associated with poor prognosis and few treatment options are currently available. Laparoscopic CO2 insufflation stimulates the progression and metastatic potential of gastrointestinal carcinomas. However, heated and humidified CO2 pneumoperitoneum (HH-CO2) is a promising treatment for PC, although its effects and mechanism of action in human colon cancer cells remain unclear. This study evaluated the anti-tumour effects of HH-CO2 on human colon cancer in vitro. METHODS: Cell viability was assessed using the WST-8 assay in two colon cancer cell lines. Apoptosis was assessed by Annexin V PI flow cytometry, and migration and invasion were examined using wound healing and Transwell® invasion assays. The expressions of Bcl-2, Bax, matrix metalloproteinase-2 (MMP-2), E-cadherin, ICAM-1, and CD44 were detected by western blotting. RESULTS: HH-CO2 significantly inhibited cell proliferation, migration, invasion and adhesion. HH-CO2 induced apoptosis and significantly inhibited the expression of Bcl-2, MMP-2, ICAM-1 and CD44, and increased Bax and E-cadherin expression in colon cancer cells. CONCLUSIONS: HH-CO2 induces apoptosis and inhibits proliferation, migration, invasion and adhesion of human colon cancer cells. Our results suggest that HH-CO2 may serve as a potential candidate for the treatment and/or prevention of peritoneal carcinomatosis from colorectal cancer and warrant further in vivo investigation.

The presence of exudative thickening of Bowman's capsule predict poor prognosis in diabetic kidney disease.

BACKGROUND: The relationship between Bowman's capsule thickening and progression of diabetic kidney disease (DKD) remains uncertain. METHODS: Renal biopsy specimens from 145 DKD patients and 20 control subjects were evaluated for Bowman's capsule thickness. Immunohistochemical staining assessed col4α2, laminin ß1, and albumin expression. In a discovery cohort of 111 DKD patients with eGFR ≥ 30 ml/min/1.73 m2, thickening was classified as fibrotic or exudative. The composite endpoint included CKD stage 5, dialysis initiation, and renal disease-related death. Prognosis was analyzed using Kaplan-Meier and Cox regression analyses. Two validation cohorts were included. RESULTS: Three types of thickening were observed: fibrotic, exudative, and periglomerular fibrosis. Parietal epithelial cell matrix protein accumulation contributed to fibrotic thickening, while albumin was present in exudative thickening. Bowman's capsule was significantly thicker in DKD patients (5.74 ± 2.09 µm) compared to controls (3.38 ± 0.43 µm, P < 0.01). In discovery cohort, the group of exudative thickning had a poorer prognosis(median time 20 months vs 57 months, P = 0.000). Cox multivariate analysis revealed that exudative thickening of Bowman's capsule were associated with a poor prognosis. The validation cohorts confirmed the result. CONCLUSIONS: Various mechanisms contribute to Bowman's capsule thickening in DKD. The proportion of exudative thickening may serve as a valuable prognostic indicator for DKD patients.

Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associatied with increasing effect on the gut microbiota in db/db mice.

Background: The intestinal microbiota disorder gradually aggravates during the progression of diabetes. Dapagliflozin (DAPA) can improve diabetes and diabetic kidney disease(DKD). However, whether the gut microbiota plays a role in the protection of DAPA for DKD remains unclear. Methods: To investigate the effects of DAPA on DKD and gut microbiota composition during disease progression, in our study, we performed 16S rRNA gene sequencing on fecal samples from db/m mice (control group), db/db mice (DKD model group), and those treated with DAPA (treat group) at three timepoints of 14weeks\18weeks\22weeks. Results: We found that DAPA remarkably prevented weight loss and lowered fasting blood glucose in db/db mice during disease progression, eventually delaying the progression of DKD. Intriguingly, the study strongly suggested that there is gradually aggravated dysbacteriosis and increased bile acid during the development of DKD. More importantly, comparisons of relative abundance at the phylum level and partial least squares-discriminant analysis (PLS-DA) plots roughly reflected that the effect of DAPA on modulating the flora of db/db mice increased with time. Specifically, the relative abundance of the dominant Firmicutes and Bacteroidetes was not meaningfully changed among groups at 14 weeks as previous studies described. Interestingly, they were gradually altered in the treat group compared to the model group with a more protracted intervention of 18 weeks and 22 weeks. Furthermore, the decrease of Lactobacillus and the increase of norank_f:Muribaculaceae could account for the differences at the phylum level observed between the treat group and the model group at 18 weeks and 22 weeks. Conclusion: We firstly found that the protective effect of DAPA on DKD may be related to the dynamic improvement of the gut microbiota over time, possibly associated with the impact of DAPA on the bile acid pool and its antioxidation effect.

Dapagliflozin alleviates renal inflammation and protects against diabetic kidney diseases, both dependent and independent of blood glucose levels.

Introduction: Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide. Therefore, efforts to understand DKD pathophysiology and prevent its development at the early phase are highly warranted. Methods: Here, we analyzed kidneys from healthy mice, diabetic mice, and diabetic mice treated with the sodium-glucose cotransporter 2 inhibitor dapagliflozin using ATAC and RNA sequencing. The findings were verified at the protein levels and in cultured cells. Results: Our combined method of ATAC and RNA sequencing revealed Csf2rb, Btla, and Isg15 as the key candidate genes associated with hyperglycemia, azotemia, and albuminuria. Their protein levels were altered together with multiple other inflammatory cytokines in the diabetic kidney, which was alleviated by dapagliflozin treatment. Cell culture of immortalized renal tubular cells and macrophages unraveled that dapagliflozin could directly effect on these cells in vitro as an anti-inflammatory agent independent of glucose concentrations. We further proved that dapagliflozin attenuated ischemia/reperfusion-induced chronic kidney injury and renal inflammation in mice. Discussion: Overall, our data emphasize the importance of inflammatory factors to the pathogenesis of DKD, and provide valuable mechanistic insights into the renoprotective role of dapagliflozin.

P2X7R/AKT/mTOR signaling mediates high glucose-induced decrease in podocyte autophagy.

Diabetic nephropathy is one of the leading causes of end-stage renal disease worldwide. In our study we found that Adenosine triphosphate (ATP) content was significantly increased in the urine of diabetic mice. We examined the expression of all purinergic receptors in the renal cortex and found that only purinergic P2X7 receptor (P2X7R) expression was significantly increased in the renal cortex of wild-type diabetic mice and that the P2X7R protein partially co-localized with podocytes. Compared with P2X7R(-/-) non-diabetic mice, P2X7R(-/-) diabetic mice showed stable expression of the podocyte marker protein podocin in the renal cortex. The renal expression of microtubule associated protein light chain 3 (LC-3II) in wild-type diabetic mice was significantly lower than in wild-type controls, whereas the expression of LC-3II in the kidneys of P2X7R(-/-) diabetic mice was not significantly different from that of P2X7R(-/-) non-diabetic mice. In vitro, high glucose induced an increase in p-Akt/Akt, p-mTOR/mTOR and p62 protein expression along with a decrease in LC-3II levels in podocytes, whereas after transfection with P2X7R siRNA, Phosphorylated protein kinase B (p-Akt)/Akt, Phosphorylated mammalian target of rapamycin (p-mTOR)/mTOR, and p62 expression were restored and LC-3II expression was increased. In addition, LC-3II expression was also restored after inhibition of Akt and mTOR signaling with MK2206 and rapamycin, respectively. Our results suggest that P2X7R expression is increased in podocytes in diabetes, and that P2X7R is involved in the inhibition of podocyte autophagy by high glucose, at least in part through the Akt-mTOR pathway, thereby exacerbating podocyte damage and promoting the onset of diabetic nephropathy. Targeting P2X7R may be a potential treatment for diabetic nephropathy.

Nirmatrelvir/ritonavir for patients with SARS-CoV-2 infection and impaired kidney function during the Omicron surge.

Background: Nirmatrelvir/ritonavir has demonstrated effectiveness in high-risk patients with coronavirus disease 2019 (COVID-19). However, investigations on the efficacy and safety of nirmatrelvir/ritonavir in patients with kidney dysfunction are limited. Methods: Data were collected from the patients admitted to a COVID-19 referral center in Shanghai, China. Patients were at least 18 years of age and had a baseline estimated glomerular filtration rate (eGFR) of <60 ml/min/1·73 m2. The primary endpoint was a composite of all-cause mortality, intensive care unit admission, or cardiovascular events. The secondary endpoint was viral shedding. Results: Among the 195 participants, 73 received nirmatrelvir/ritonavir. A lower risk of the primary endpoint was observed in nirmatrelvir/ritonavir recipients compared with non-recipients [adjusted HR 0.56 (95% CI: 0.32-0.96); p = 0.035]. Nirmatrelvir/ritonavir recipients experienced a shorter duration of viral shedding [adjusted HR 3·70 (95%CI: 2.60-5.28); p < 0.001) and faster viral load clearance versus non-recipients. Among the nirmatrelvir/ritonavir users, earlier initiation of nirmatrelvir/ritonavir within 5 days since COVID-19 diagnosis was related with shorter viral shedding time (adjusted HR 7.84 [95% CI: 3.28-18.76]; p < 0.001) compared to late initiation. No patients reported serious adverse events during treatment. Conclusion: Our findings support the early initiation of nirmatrelvir/ritonavir for high-risk patients with impaired kidney function. This could improve patient outcomes and shorten the viral shedding period.