[Mechanism of Notoginseng Radix et Rhizoma in regulating PI3K/Akt/mTORC1-mitochondrial energy metabolism to treat chronic renal failure in rats with blood stasis syndrome].

This study observed the effects of Notoginseng Radix et Rhizoma on the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin complex 1(mTORC1) signaling pathway and mitochondrial energy metabolism in the rat model of adriamycin-induced renal fibrosis with blood stasis syndrome to explore the mechanism of Notoginseng Radix et Rhizoma in protecting the kidney. Thirty male rats with adriamycin-induced renal fibrosis were randomized into model, low-, medium-, and high-dose Notoginseng Radix et Rhizoma, and positive control groups(n=6). Six clean SD male rats were selected into the normal group. The normal group and model group were administrated with normal saline, and other groups with corresponding drugs. After 8 weeks of treatment, the renal function, renal pathology, adenosine triphosphate(ATP) levels, Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase activities, and the protein levels of ATP5B, mTORC1, 70 kDa ribosomal protein S6 kinase(P70S6K), P85, Akt, p-Akt, and SH2-containing inositol phosphatase(SHIP2) in the renal tissue were determined. Compared with the normal group, the model group showed elevated levels of blood urea nitrogen(BUN) and serum creatinine(SCr)(P<0.01). Compared with the model group, Notoginseng Radix et Rhizoma and the positive control lowered the levels of BUN and SCr, which were significant in the medium-and high-dose Noto-ginseng Radix et Rhizoma groups and the positive control group(P<0.05). Compared with the model group, Notoginseng Radix et Rhizoma and the positive control alleviated the pathological changes in the renal tissue, such as vacuolar and fibroid changes, glomerulus atrophy, cystic expansion of renal tubules, and massive infiltration of inflammatory cells. Compared with the normal group, the model group showed decreased mitochondrial ATP content and Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase activities in the renal tissue(P<0.05), and medium-and high-dose Notoginseng Radix et Rhizoma and positive control mitigated such decreases(P<0.05). Compared with the model group, medium-and high-dose Notoginseng Radix et Rhizoma and the positive control up-regulated the protein levels of ATP5B and SHIP2 and down-regulated the protein levels of mTORC1, P70S6K, P85, Akt, and p-Akt(P<0.05 or P<0.01 or P<0.001). Notoginseng Radix et Rhizoma may exert an anti-fibrosis effect by inhibiting the activation of the PI3K/Akt/mTORC1 pathway to restore mitochondrial energy metabolism, thus protecting the kidney.

Studying the impact of marital status on diagnosis and survival prediction in pancreatic ductal carcinoma using machine learning methods.

Pancreatic cancer is a commonly occurring malignant tumor, with pancreatic ductal carcinoma (PDAC) accounting for approximately 95% of cases. According of its poor prognosis, identifying prognostic factors of pancreatic ductal carcinoma can provide physicians with a reliable theoretical foundation when predicting patient survival. This study aimed to analyze the impact of marital status on survival outcomes of PDAC patients using propensity score matching and machine learning. The goal was to develop a prognosis prediction model specific to married patients with PDAC. We extracted a total of 206,968 patient records of pancreatic cancer from the SEER database. To ensure the baseline characteristics of married and unmarried individuals were balanced, we used a 1:1 propensity matching score. We then conducted Kaplan-Meier analysis and Cox proportional-hazards regression to examine the impact of marital status on PDAC survival before and after matching. Additionally, we developed machine learning models to predict 5-year CSS and OS for married patients with PDAC specifically. In total, 24,044 PDAC patients were included in this study. After 1:1 propensity matching, 8043 married patients and 8,043 unmarried patients were successfully enrolled. Multivariate analysis and the Kaplan-Meier curves demonstrated that unmarried individuals had a poorer survival rate than their married counterparts. Among the algorithms tested, the random forest performed the best, with 0.734 5-year CSS and 0.795 5-year OS AUC. This study found a significant association between marital status and survival in PDAC patients. Married patients had the best prognosis, while widowed patients had the worst. The random forest is a reliable model for predicting survival in married patients with PDAC.

Utilization of the corticomedullary difference in magnetic resonance imaging-derived apparent diffusion coefficient for noninvasive assessment of chronic kidney disease in type 2 diabetes.

BACKGROUNDS: Accumulating data demonstrated that the cortico-medullary difference in apparent diffusion coefficient (ΔADC) of diffusion-weighted magnetic resonance imaging (DWI) was a better correlation with kidney fibrosis, tubular atrophy progression, and a predictor of kidney function evolution in chronic kidney disease (CKD). OBJECTIVES: We aimed to assess the value of ΔADC in evaluating disease severity, differential diagnosis, and the prognostic risk stratification for patients with type 2 diabetes (T2D) and CKD. METHODS: Total 119 patients with T2D and CKD who underwent renal MRI were prospectively enrolled. Of them, 89 patients had performed kidney biopsy for pathological examination, including 38 patients with biopsy-proven diabetic kidney disease (DKD) and 51 patients with biopsy-proven non-diabetic kidney disease (NDKD) and Mix (DKD + NDKD). Clinicopathological characteristics were compared according to different ΔADC levels. Moreover, univariate and multivariate-linear regression analyses were performed to explore whether ΔADC was independently associated with estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR). The diagnostic performance of ΔADC for discriminating DKD from NDKD + Mix was evaluated by receiver operating characteristic (ROC) analysis. In addition, an individual's 2- or 5-year risk probability of progressing to end-stage kidney disease (ESKD) was calculated by the kidney failure risk equation (KFRE). The effect of ΔADC on prognostic risk stratification was assessed. Additionally, net reclassification improvement (NRI) was used to evaluate the model performance. RESULTS: All enrolled patients had a median ΔADC level of 86 (IQR 28, 155) × 10-6 mm2/s. ΔADC significantly decreased across the increasing staging of CKD (P < 0.001). Moreover, those with pathological-confirmed DKD has a significantly lower level of ΔADC than those with NDKD and Mix (P < 0.001). It showed that ΔADC was independently associated with eGFR (ß = 1.058, 95% CI = [1.002,1.118], P = 0.042) and UACR (ß = -3.862, 95% CI = [-7.360, -0.365], P = 0.031) at multivariate linear regression analyses. Besides, ΔADC achieved an AUC of 0.707 (71% sensitivity and 75% specificity) and AUC of 0.823 (94% sensitivity and 67% specificity) for discriminating DKD from NDKD + Mix and higher ESKD risk categories (≥50% at 5 years; ≥10% at 2 years) from lower risk categories (<50% at 5 years; <10% at 2 years). Accordingly, the optimal cutoff value of ΔADC for higher ESKD risk categories was 66 × 10-6 mm2/s, and the group with the low-cutoff level of ΔADC group was associated with 1.232 -fold (95% CI 1.086, 1.398) likelihood of higher ESKD risk categories as compared to the high-cutoff level of ΔADC group in the fully-adjusted model. Reclassification analyses confirmed that the final adjusted model improved NRI. CONCLUSIONS: ΔADC was strongly associated with eGFR and UACR in patients with T2D and CKD. More importantly, baseline ΔADC was predictive of higher ESKD risk, independently of significant clinical confounding. Specifically, ΔADC <78 × 10-6 mm2/s and <66 × 10-6 mm2/s would help to identify T2D patients with the diagnosis of DKD and higher ESKD risk categories, respectively.

Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis.

BACKGROUND: Upregulation of an RNA-binding protein HuR has been implicated in glomerular diseases. Herein, we evaluated whether it is involved in renal tubular fibrosis. METHODS: HuR was firstly examined in human kidney biopsy tissue with tubular disease. Second, its expression and the effect of HuR inhibition with KH3 on tubular injury were further assessed in a mouse model induced by a unilateral renal ischemia/reperfusion (IR). KH3 (50 mg kg-1) was given daily via intraperitoneal injection from day 3 to 14 after IR. Last, one of HuR-targeted pathways was examined in cultured proximal tubular cells. RESULTS: HuR significantly increases at the site of tubular injury both in progressive CKD in patients and in IR-injured kidneys in mice, accompanied by upregulation of HuR targets that are involved in inflammation, profibrotic cytokines, oxidative stress, proliferation, apoptosis, tubular EMT process, matrix remodeling and fibrosis in renal tubulointerstitial fibrosis. KH3 treatment reduces the IR-induced tubular injury and fibrosis, accompanied by the remarkable amelioration in those involved pathways. A panel of mRNA array further revealed that 519 molecules in mouse kidney following IR injury changed their expression and 71.3% of them that are involved in 50 profibrotic pathways, were ameliorated when treated with KH3. In vitro, TGFß1 induced tubular HuR cytoplasmic translocation and subsequent tubular EMT, which were abrogated by KH3 administration in cultured HK-2 cells. CONCLUSIONS: These results suggest that excessive upregulation of HuR contributes to renal tubulointerstitial fibrosis by dysregulating genes involved in multiple profibrotic pathways and activating the TGFß1/HuR feedback circuit in tubular cells. Inhibition of HuR may have therapeutic potential for renal tubular fibrosis.

Serum 25-hydroxyvitamin D as a predictive biomarker of clinical outcomes in patients with primary membranous nephropathy.

Background: Primary membranous nephropathy (PMN) is an immune-related disease with increased morbidity and the most common cause of adult nephrotic syndrome (NS). The serum 25-hydroxyvitamin D [25(OH)D)], a biomarker of vitamin D (VD) status, tends to decline in patients with kidney disease. However, the relationship between 25(OH)D and PMN is still unclear. Therefore, this study aims to clarify the association between 25(OH)D and disease severity and therapy response of PMN. Methods: A total of 490 participants diagnosed with PMN by biopsy from January 2017 to April 2022 were recruited at the First Affiliated Hospital of Nanjing Medical University. The correlations between baseline 25(OH)D and manifestations of nephrotic syndrome (NS) or seropositivity of anti-PLA2R Ab were confirmed by univariate and multivariate logistic analyses. Spearman's correlations were used to examine the associations between baseline 25(OH)D and other clinical parameters. In the follow-up cohort, Kaplan-Meier analysis was used to assess remission outcomes among groups with low, medium, and high levels of 25(OH)D. Furthermore, the independent risk factors for non-remission (NR) were explored by COX regression analysis. Results: At baseline, 25(OH)D was negatively related to 24-h urinary protein and serum anti-PLA2R Ab. The lower level of baseline 25(OH)D was associated with an increased risk for the incidence of NS in PMN (model 2, OR 6.8, 95% CI 4.4, 10.7, P < 0.001) and seropositivity of anti-PLA2R Ab (model 2, OR 2.4, 95% CI 1.6, 3.7, P < 0.001). Furthermore, the lower level of 25(OH)D during follow-up was demonstrated as an independent risk factor for NR even after adjusting age, gender, MBP, 24 h UP, serum anti-PLA2R Ab, serum albumin, and serum C3 [25(OH)D (39.2-62.3 nmol/L): HR 4.90, 95% CI 1.02, 23.53 P = 0.047; 25(OH)D < 39.2 nmol/L: HR 17.52, 95% CI 4.04, 76.03 P < 0.001); vs. 25(OH)D ≥ 62.3 nmol/L]. The Kaplan-Meier survival analysis also demonstrated that the higher level of follow-up 25(OH)D had a higher possibility of remission than the lower one (log-rank test, P < 0.001). Conclusion: Baseline 25(OH)D was significantly correlated with nephrotic proteinuria and seropositivity of anti-PLA2R Ab in PMN. As an independent risk factor for NR, a low level of 25(OH)D during follow-up might serve as a prognostic tool for sensitively identifying cases with a high probability of poor treatment response.

Metabolic Glycan Labeling in Primary Neurons Enabled by Unnatural Sugars with No S-Glyco-Modification.

It is of great interest to probe glycosylation in primary neuron cultures. However, per-O-acetylated clickable unnatural sugars, which have been routinely utilized in metabolic glycan labeling (MGL) for analyzing glycans, showed cytotoxicity to cultured primary neurons and thus led to the speculation that MGL was not compatible with primary neuron cell cultures. Here, we uncovered that neuron cytotoxicity of per-O-acetylated unnatural sugars was related to their reactions with protein cysteines via non-enzymatic S-glyco-modification. The modified proteins were enriched in biological functions related to microtubule cytoskeleton organization, positive regulation of axon extension, neuron projection development, and axonogenesis. We thus established MGL in cultured primary neurons without cytotoxicity using S-glyco-modification-free unnatural sugars including ManNAz, 1,3-Pr2ManNAz, and 1,6-Pr2ManNAz, which allowed for visualization of cell-surface sialylated glycans, probing the dynamics of sialylation, and large-scale identification of sialylated N-linked glycoproteins and the modification sites in primary neurons. Particularly, a total of 505 sialylated N-glycosylation sites distributed on 345 glycoproteins were identified by 1,6-Pr2ManNAz.

The association of RNA-binding protein Human antigen R with kidney clinicopathologic features and renal outcomes in patients with diabetic nephropathy.

AIMS: RNA-binding protein Human antigen R (HuR) is closely related to diabetic nephropathy (DN) pathogenesis. However, the capacity of histological HuR level as a biomarker for DN progression remains unclear. METHODS: A total of 147 patients with type 2 diabetes mellitus who had biopsy-proven DN were enrolled. Renal outcomes were defined by doubling serum creatinine level or progression to end-stage renal disease (ESRD). A nomogram was built to predict renal outcomes based on Cox proportional hazards regression. RESULTS: The median follow-up period was 31 months, during which 71 (48.30 %) patients confronted DN progression. Pearson's correlation indicated that histological HuR increased along with DN pathological class rising (r = 0.776, p < 0.001). Notably, multivariate Cox regression analysis showed that elevated HuR was associated with a greater risk of DN progression (HR 2.431, 95 %CI: 1.275-4.634, p = 0.007) beyond 6 months after renal biopsy. Patients in the higher HuR expression group had lower cumulative renal survival rates beyond the first 6 months. Simultaneously, a well-performed nomogram including HuR classification, was developed to predict the individual progression risk (C-index 0.828). CONCLUSIONS: Our findings demonstrated that the histologic HuR expression was an independent risk factor for kidney progression beyond 6 months after renal biopsy in DN.

Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells.

SIRT6 belongs to the conserved NAD+-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD+. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC50 of 2.33 µmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

A Novel Metabolic Reprogramming Strategy for the Treatment of Diabetes-Associated Breast Cancer.

Diabetes is directly related to the risk of breast cancer (BC) occurrence and worsened BC prognosis. Currently, there are no specific treatments for diabetes-associated BC. This paper aims to understand the fundamental mechanisms of diabetes-induced BC progression and to develop personalized treatments. It reports a metabolic reprogramming strategy (MRS) that pharmaceutical induction of glucose import and glycolysis with metformin and NF-κB inhibitor (NF-κBi) while blocking the export of excessive lactate via inhibiting monocarboxylate transporter 4 (MCT4) leads to a metabolic crisis within the cancer cells. It demonstrates that the MRS shifts the metabolism of BC cells toward higher production of lactate, blocks lactate secretion, prompts intracellular acidification and induces significant cytotoxicity. Moreover, a novel MCT4 inhibitor CB-2 has been identified by structure-based virtual screening. A triple combination of metformin, CB-2, and trabectedin, a drug that impedes NF-κB signaling, strongly inhibits BC cells. Compared to normal glucose condition, MRS elicits more potent cancer cell-killing effects under high glucose condition. Animal model studies show that diabetic conditions promote the proliferation and progression of BC xenografts in nude mice and that MRS treatment significantly inhibits HG-induced BC progression. Therefore, inhibition of MCT4 combined with metformin/NF-κBi is a promising cancer therapy, especially for diabetes-associated BC.

Value of urine/serum Neutrophil gelatinase-associated lipocalin ratio in distinguishing acute kidney injury from chronic kidney disease.

OBJECTIVE: This study was performed to test the hypothesis that neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker would be helpful for differentiation acute kidney injury (AKI) from chronic kidney disease (CKD) in kidney malfunction patients from the nephrology department. METHODS: This retrospective study included 355 patients admitted from the nephrology department with modification of diet in renal disease estimated glomerular filtration rate (MDRD eGFR) < 60 ml/min/1.73 m2. The subjects were categorized into AKI group (n = 204) and CKD group (n = 151). A propensity-matched analysis, incorporating 17 variables, was performed to control potential selection bias. RESULTS: Urinary NGAL (uNGAL) level in the AKI group was higher than in the CKD group (372.10 (170.10-690.63) vs 88.10 (52.00-238.80), P < 0.001), but there was no significant difference in serum NGAL (sNGAL). Both sNGAL and uNGAL had a correlation with MDRD eGFR in total patients, AKI patients, and CKD patients. The propensity-matched analysis enrolled 75 patients in each group. In matched AKI group, sNGAL was lower (401.20 (239.10-616.00) vs 468.50 (305.00-709.40), P = 0.049) and uNGAL was elevated (284.00 (136.90-690.90) vs 203.70 (69.20-596.00), P = 0.032), compared with the matched CKD group. In all patients (n = 355), the ratio of uNGAL and sNGAL (u/s NGAL), fractional excretion of NGAL (Fe NGAL) discriminated AKI from CKD (area under the curve, 0.803 and 0.790, respectively). After stratified kidney function, the sub-analyses found that u/s NGAL and Fe NGAL were shown to differ substantially between the AKI group and CKD group (all P < 0.01). The u/s NGAL ratio always had the highest AUC area in the sub-analyses. CONCLUSIONS: u/s NGAL might be helpful to discriminate AKI from CKD in kidney malfunction patients admitted to the nephrology department. Further confirmatory studies might be warranted.

Genetic Variations and Clinical Features of NPHS1-Related Nephrotic Syndrome in Chinese Children: A Multicenter, Retrospective Study.

Introduction: Few studies have addressed the genetic spectrum of NPHS1 variants in Chinese children with nephrotic syndrome. In this multicenter study, the clinical manifestations and features of NPHS1 variants in Chinese children with nephrotic syndrome were researched. Method: Genotypical and phenotypical data from 30 children affected by NPHS1 variants were collected from a multicenter registration system in China and analyzed retrospectively. Results: The patients were divided into two groups: congenital nephrotic syndrome (CNS [n = 24]) and non-CNS (early onset nephrotic syndrome [n = 6]). Renal biopsy was performed on four patients in the non-CNS group, revealing minimal change disease in three and focal segmental glomerulosclerosis in one. A total of 61 NPHS1 variants were detected, involving 25 novel variants. The "recurrent variants" included c.928G>A(p.Asp310Asn) in eight patients with CNS, followed by c.616C>A(p.Pro206Thr) in four, and c.2207T>C (p.Val736Ala) in three. Steroid treatment was applied in 29.2% (7/24)of the patients in the CNS group and 50% (3/6) of the patients in the non-CNS group. One patient in each group experienced complete remission but relapsed subsequently. Immunosuppressants were administered to three patients in the non-CNS group, eliciting an effective response. In the CNS group, three patients underwent renal transplantation and six died mainly from infection. Conclusion: Variants of NPHS1 cause CNS and early childhood-onset nephrotic syndrome. NPHS1 variants in Chinese individuals with nephrotic syndrome (NS) were mainly compound heterozygous variants, and c.928G>A(p.Asp310Asn) in exon 8 may act as a recurrent variant in the Chinese population, followed by c.616C>A(p.Pro206Thr) in exon 6. Steroids and immunosuppressants may be effective in selected patients.

Effects of Persimmon Tannin-Aloe vera Composite on Cytotoxic Activities, and Radioprotection Against X-rays Irradiated in Human Hepatoma and Hepatic Cells.

A persimmon tannin-Aloe vera composite powder (PT-A) was investigated for its capacity to protect against ionizing radiation. Human hepatic cells (L02 cells) and human hepatoma cells (HepG2 cells) were pretreated with different concentrations of PT-A or the single compounds (PT or Aloe vera) and radiated with X-rays. After radiation and post-incubation for 12 h or 24 h, the cell viability, apoptosis, and reactive oxygen species (ROS) production were analyzed by Cell Counting Kit 8 (CCK-8), 2',7'-dichlorfluorescein diacetate (DCFH-DA) staining, and Hoechst 33258 staining/flow cytometry, respectively. CCK-8 results illustrated that the optimal radiation dose L02 cells was 8 Gy for L02 cells, and the cell activity was 71.72% (IC50 = 412.1 µg/mL) after post-radiation incubation of 12 h. For HepG2 cells, the optimal radiation dose was 8 Gy, and the cell activity was 62.37% (IC50 = 213.0 µg/mL). The cell apoptotic rate was the lowest at a PT-A concentration of 200 µg/mL in L02 cells (4.32%, P < 0.05), and at 100 µg/mL in HepG2 cells (9.80%, P < 0.05). ROS production induced by radiation could be effectively inhibited by 200 µg/mL of PT-A in L02 cells, and by 100 µg/mL of PT-A in HepG2 cells. The PT-A composite has good radioprotective effects on cell vitality and apoptosis of X-rays radiation exposure towards L02 cells and HepG2 cells compared to the persimmon tannin or Aloe vera. Therefore, PT-A composite might be useful as a natural, harmless anti-ionizing radiation agent, and has various clinical application prospects in future.

Association of platelet-to-lymphocyte ratio with kidney clinicopathologic features and renal outcomes in patients with diabetic kidney disease.

BACKGROUND: Growing evidence points to the pivotal role of inflammation in the pathogenesis of diabetic kidney disease (DKD). However, as an inflammation-based prognostic score, the significance of platelet-to-lymphocyte ratio (PLR) in biopsy-proven DKD remains uncertain. Therefore, the current study aimed to evaluate the association of PLR with the clinicopathological features and the progression of DKD. METHODS: In total, 167 patients with biopsy-proven T2DKD were retrospectively recruited. Clinicopathological characteristics were compared according to the tertiles of baseline PLR. Pearson's or Spearman correlations were used to examine the associations between PLR and baseline characteristics. Assessment of the prospective relationship of PLR with the kidney outcomes defined as a doubling of baseline serum creatinine or onset of end stage renal disease (ESRD), were investigated by Kaplan-Meier survival analysis. Moreover, a cubic spline curve was further calculated to explore the significance of PLR in DKD prognosis. On top of that, identification of the risk factors associated with DKD progression was executed by a model of Cox proportional hazards. RESULTS: Median follow-up period was 23.77 months, during which 92 (55.1%) patients confronted DKD progression. Pearson's correlation indicated that urinary protein increased along with PLR rising (r = 0.193, P = 0.012). Kaplan-Meier survival curves revealed a significantly increased probability of event-free survival in the lowest tertile of PLR compared to those in the highest tertile (P = 0.018). A statistical linear correlation between PLR and DKD development was demonstrated by a restricted cubic spline analysis (P for nonlinear = 0.784). In addition, the analyses of multivariate Cox regression indicated that elevated PLR had an association with a greater risk of DKD progression (HR 1.004, 95%CI [1.000-1.008], P = 0.035), which was verified to be an independent risk factor for renal outcomes. CONCLUSIONS: Our findings demonstrated that the PLR was associated with proteinuria and prognosis in DKD patients. It was an independent risk factor for kidney progression in biopsy-proven DKD.

Association of Glomerular Complement C4c Deposition With the Progression of Diabetic Kidney Disease in Patients With Type 2 Diabetes.

Objectives: As accumulating data supporting the potential role of the complement system in the pathogenesis of diabetic kidney disease (DKD), the present study aimed to explore the association of glomerular complement C4c deposition with the baseline clinicopathological characteristics and the prognosis of DKD in type 2 diabetes (T2DM) patients. Methods: A total of 79 T2DM patients with biopsy-proven DKD were enrolled. Clinicopathological features and renal outcomes were compared between groups divided by the glomerular C4c deposition patterns and median values of serum C4. Renal outcomes were defined by doubling of serum creatinine level or progression to end-stage renal disease (ESRD). A Cox proportional hazards model was employed to identify the risk factors associated with renal events. Results: Patients with glomerular C4c deposition had worse renal insufficiency than those without C4c deposits, along with higher 24-h urinary protein, triglyceride, but lower serum albumin and higher interstitial inflammation score. Besides, serum C4 levels positively correlated with urinary protein and serum C3 levels. During 21.85 ± 16.32 months of follow-up, Kaplan-Meier curve analysis showed significantly faster deterioration of renal function for patients with positive glomerular C4c deposition as well as higher levels of serum C4. More specifically, more than 50% of the patients with glomerular C4c had co-deposition of C3c or C1q, and patients with glomerular complement complex of C4c and one or two of C3/C1q deposition had more severe proteinuria and a higher rate of DKD progression than those with negative C4c deposits. The univariate Cox regression indicated that factors of combined serum and glomerular C4, urinary protein, serum creatinine, serum C3, combined glomerular C4c and IgM and interstitial inflammation were associated with an increased risk of DKD, but only glomerular C4c intensity (HR 1.584, 95% CI [1.001, 2.508], p = 0.0497), as well as baseline age and diabetic neuropathy, were independent risk factors for renal survival by the multivariate Cox analysis. Conclusions: Glomerular C4c deposition was associated with deteriorated renal function and outcomes in patients with T2DKD. Glomerular C4c deposition was an independent risk factor for DKD progression.

Prior bariatric surgery and perioperative cardiovascular outcomes following noncardiac surgery in patients with type 2 diabetes mellitus: hint from National Inpatient Sample Database.

BACKGROUND: Both diabetes and obesity are risk factors for perioperative major adverse events. This study aims to evaluate the association between prior bariatric surgery (prior-BS) and perioperative cardiovascular outcomes following noncardiac surgery in patients with type 2 diabetes mellitus (T2DM). METHODS: We used the National Inpatient Sample Database to identify T2DM patients undergoing major noncardiac surgery from 2006 to 2014. The primary outcome was major perioperative adverse cardiovascular and cerebrovascular events (MACCEs), which include death, acute myocardial infarction and acute ischaemic stroke. In-hospital outcomes between patients with prior BS and morbid obesity were compared using unadjusted logistic, multivariable logistic and propensity score matching analyses. RESULTS: A weighted of 1,526,820 patients diagnosed with T2DM who underwent noncardiac surgery were included. The rates of both prior BS and morbid obesity significantly increased during the study period (P < 0.0001). Patients with prior BS were younger, were more likely to be female, and had lower rates of cardiovascular risk factors but had higher rates of smoking, alcohol abuse, anaemia, prior venous thromboembolism and prior percutaneous coronary intervention. The incidence of MACCEs was 1.01% and 3.25% in patients with prior BS and morbid obesity, respectively. After multivariable adjustment, we found that prior BS was associated with a reduced risk of MACCEs (odds ratio [OR] = 0.71; 95% confidence interval [CI] 0.62-0.81), death (OR = 0.64, 95% CI 0.52-0.78), acute kidney injury (OR = 0.66, 95% CI 0.62-0.70) and acute respiratory failure (OR: 0.46; 95% CI 0.42-0.50). CONCLUSIONS: Prior bariatric surgery in T2DM patients undergoing noncardiac surgery is associated with a lower risk of MACCEs. Prospective studies are needed to verify the benefits of bariatric surgery in patients undergoing noncardiac surgery.

Assessment of urinary NGAL for differential diagnosis and progression of diabetic kidney disease.

OBJECTIVE: Chronic kidney disease (CKD) related to diabetes has become more common than glomerulonephritis in recent years. Given the inefficient and difficult identification of diabetic kidney disease (DKD) from non-diabetic kidney disease (NDKD) as well as a result of emerging evidence supporting a role for tubular involvement in DKD, we aimed to investigate the utility of urinary neutrophil gelatinase-associated lipocalin (uNGAL) in the differential diagnosis and predictive value of DKD from NDKD. METHODS: Data for 100 type 2 diabetic patients with CKD at our center from June 2016 to August 2019 were reviewed. All the patients were categorized into 2 groups by the renal biopsy results: DKD and NDKD. Urinary NGAL levels were normalized by urinary creatinine and calculated as uNGAL/creatinine ratios (uNCR). The independent factors of the occurrence of DKD and the diagnostic implications of uNCR were explored by logistic regression and receiver-operating characteristic (ROC) curve analysis. In addition, we analyzed the relationship between uNCR and proteinuria in patients with DKD by Pearson test and linear regression. Kaplan-Meier survival analysis was performed to assess the prospective association of uNCR with the renal outcome. RESULTS: Significantly higher levels of uNCR were observed in patients with DKD when compared to those with NDKD (28.65 ng/mg vs 27.47 ng/mg, p< .001). uNCR was identified as an independent risk factor for the occurrence of DKD in diabetic patients with CKD (odds ratio [OR] = 1.020; 95%CI = [1.001-1.399], p = .042). The optimal cutoff value of uNCR for predicting DKD was 60.685 ng/mg with high specificity (90.5%) but relatively low sensitivity (55.7%). In Pearson test, uNCR was positively correlated with proteinuria, serum creatine, blood urea nitrogen, duration of diabetes, interstitial inflammation score and global sclerosis, whereas it was inversely correlated with eGFR, hemoglobin, serum albumin and 25-hydroxy vitamin D. Furthermore, in a fully adjusted model including eGFR, serum albumin and total cholesterol, the group with uNCR>60.685 ng/mg was associated with 7.595 times higher likelihood of nephrotic-range proteinuria compared to the group with uNCR≤60.685 ng/mg. In the Kaplan-Meier survival analysis, the event-free survival probability in patients with uNCR>60.685 ng/mg was significantly lower than those with uNCR≤60.685 ng/mg (p = .048). CONCLUSIONS: uNCR might serve as a potential tool for identifying cases in which there was a high clinical suspicion of DKD and that in whom confirmatory biopsy could be considered, and the best predictive cutoff value of normalized uNCR for DKD diagnosis was 60.685 ng/mg. Type 2 diabetic patients with increased level of uNCR had higher risk to nephrotic-range proteinuria and worse renal outcome.

Inhibition of RNA-binding protein HuR reduces glomerulosclerosis in experimental nephritis.

Recent identification of an RNA-binding protein (HuR) that regulates mRNA turnover and translation of numerous transcripts via binding to an ARE in their 3'-UTR involved in inflammation and is abnormally elevated in varied kidney diseases offers a novel target for the treatment of renal inflammation and subsequent fibrosis. Thus, we hypothesized that treatment with a selective inhibition of HuR function with a small molecule, KH-3, would down-regulate HuR-targeted proinflammatory transcripts thereby improving glomerulosclerosis in experimental nephritis, where glomerular cellular HuR is elevated. Three experimental groups included normal and diseased rats treated with or without KH-3. Disease was induced by the monoclonal anti-Thy 1.1 antibody. KH-3 was given via daily intraperitoneal injection from day 1 after disease induction to day 5 at the dose of 50 mg/kg BW/day. At day 6, diseased animals treated with KH-3 showed significant reduction in glomerular HuR levels, proteinuria, podocyte injury determined by ameliorated podocyte loss and podocin expression, glomerular staining for periodic acid-Schiff positive extracellular matrix proteins, fibronectin and collagen IV and mRNA and protein levels of profibrotic markers, compared with untreated disease rats. KH-3 treatment also reduced disease-induced increases in renal TGFß1 and PAI-1 transcripts. Additionally, a marked increase in renal NF-κB-p65, Nox4, and glomerular macrophage cell infiltration observed in disease control group was largely reversed by KH-3 treatment. These results strongly support our hypothesis that down-regulation of HuR function with KH-3 has therapeutic potential for reversing glomerulosclerosis by reducing abundance of pro-inflammatory transcripts and related inflammation.

Adenosine kinase inhibition attenuates ischemia reperfusion-induced acute kidney injury.

Acute kidney injury (AKI) has a high morbidity and mortality, and there is no targeted treatment yet. One of the main causes of AKI is ischemia-reperfusion (IR). Increased release of adenosine under stress and hypoxia exerts anti-inflammatory and antioxidant effects. Adenosine kinase (ADK) is an important enzyme that eliminates adenosine in cells, and can maintain low adenosine concentration in cells. Our previous studies have shown that pretreatment of adenosine kinase inhibitor ABT-702 could markedly attenuate cisplatin-induced nephrotoxicity both in vivo and in vitro. This study is designed to investigate the effect of ADK inhibition on IR-induced AKI. The results showed that ADK expression was positively correlated with the degree of renal tubular injury, which suggested that the degree of ADK inhibition reflected the severity of acute tubular necrosis. In vivo, ADK inhibitor could reduce IR-induced renal injury, which might play a protective role by increasing tissue adenosine level, inhibiting oxidative stress, and reducing cell apoptosis. In HK2 cells, cobaltous dichloride (CoCl2) increased the level of oxidative stress, up-regulated the production of pro-inflammatory factor, and induced apoptosis, ADK inhibition could alleviate the above damaging effects. Moreover, the anti-apoptotic effect exerted by ADK inhibition was independent of inosine. In summary, our results support the idea that ADK inhibition has protective effects on IR-induced AKI. Adenosine kinase inhibition might provide a new target for AKI prevention and treatment.

miR-133 inhibits proliferation and promotes apoptosis by targeting LASP1 in lupus nephritis.

Lupus nephritis (LN) is a chronic autoimmune disease. Recently, microRNA (miR)-133 has been demonstrated to play an important role in renal cell carcinoma. Our current study was designed to test the role of miR-133 and its potential target in LN. First, significant correlation of LASP1 and miR-133 levels was observed in the human LN tissue. Modification of miR-133 level in the human mesangial cells (HMCs) by either overexpression or knockdown demonstrated a suppressive role of miR-133 in cell proliferation and an inductive role in cell apoptosis. Modification of LASP1 level in the HMCs demonstrated the opposing effects of LASP1 to miR-133 on proliferation and apoptosis. In addition, luciferase assay showed miR-133 directly regulates LASP1 expression through its binding site in the 3'UTR of LASP1. At last, our data showed that the changes in properties, such as suppression in proliferation and induction in apoptosis, induced by overexpression of miR-133 were restored by additional expression of LASP1. In summary, our obtained data demonstrated that miR-133 suppresses proliferation and promotes apoptosis through its binding with LASP1 in human mesangial cells. This study revealed a new mechanism involving the interaction of miR-133 and LASP1 in the pathogenesis of LN.