Integrin-linked kinase mRNA expression in circulating mononuclear cells as a biomarker of kidney and vascular damage in experimental chronic kidney disease.

BACKGROUND: Traditional biomarkers of chronic kidney disease (CKD) detect the disease in its late stages and hardly predict associated vascular damage. Integrin-linked kinase (ILK) is a scaffolding protein and a serine/threonine protein kinase that plays multiple roles in several pathophysiological processes during renal damage. However, the involvement of ILK as a biomarker of CKD and its associated vascular problems remains to be fully elucidated. METHODS: CKD was induced by an adenine-rich diet for 6 weeks in mice. We used an inducible ILK knockdown mice (cKD-ILK) model to decrease ILK expression. ILK content in mice's peripheral blood mononuclear cells (PBMCs) was determined and correlated with renal function parameters and with the expression of ILK and fibrosis and inflammation markers in renal and aortic tissues. Also, the expression of five miRNAs that target ILK was analyzed in whole blood of mice. RESULTS: The adenine diet increased ILK expression in PBMCs, renal cortex, and aortas, and creatinine and urea nitrogen concentrations in the plasma of WT mice, while these increases were not observed in cKD-ILK mice. Furthermore, ILK content in PBMCs directly correlated with renal function parameters and with the expression of renal and vascular ILK and fibrosis and inflammation markers. Finally, the expression of the five miRNAs increased in the whole blood of adenine-fed mice, although only four correlated with plasma urea nitrogen, and of those, three were downregulated in cKD-ILK mice. CONCLUSIONS: ILK, in circulating mononuclear cells, could be a potential biomarker of CKD and CKD-associated renal and vascular damage.

Two years with GIOIA 'Effects of gliflozins and gliptins on markers of cardiovascular damage in type 2 diabetes': A prospective, multicentre, quasi-experimental study on sodium-glucose cotransporter 2 and dipeptidyl peptidase-4 inhibitors in diabetes clinical practice.

AIM: To assess and compare the metabolic and vascular effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) in the clinical practice of patients with type 2 diabetes in Italy. MATERIALS AND METHODS: GIOIA is a 2-year prospective, multicentre, quasi-experimental study that enrolled patients with type 2 diabetes initiating SGLT-2i or DPP-4i for inadequate glycaemic control [glycated haemoglobin (HbA1c) >7%] between March 2018 and March 2021. The primary endpoints were changes in markers of organ damage [carotid intima-media thickness (CIMT), albuminuria, myocardial function] and HbA1c from baseline to year 2. RESULTS: In total, 1150 patients were enrolled in the study (SGLT-2i n = 580, DPP-4i n = 570). Patients initiated on SGLT-2i were younger (about 6 years) and heavier (about 11 kg), had higher HbA1c level (1% more), more albuminuria and cardiovascular events (16% more) than patients initiated on DPP-4i. CIMT and echocardiographic parameters were not significantly different. Propensity score matching yielded two groups, each consisting of 155 patients with diabetes with similar baseline characteristics. Despite a significant similar reduction in HbA1c levels in both groups (-0.8%), more patients on SGLT-2i had regression of CIMT and albuminuria (22% and 10%, respectively, p < .001 vs. DPP-4i); more patients on DPP-4i had progression of CIMT and albuminuria (23% and 28%, respectively, p < .001 vs. SGLT-2i). Left ventricular ejection fraction improved slightly (3%, p = .043) on SGLT-2i only. CONCLUSIONS: In a real-world setting, both SGLT-2i and DPP-4i improve glycaemic control persisting after 2 years of treatment, with a robust effect on both CIMT and albuminuria regression for SGLT-2i as compared with DPP-4i in the propensity score matching.

Renal damage and old age: risk factors for thrombosis in patients with ANCA-associated vasculitis.

INTRODUCTION: Thrombosis in ANCA-associated vasculitis (AAV) was prevalent and has been neglected in Chinese patients. This study tried to describe the clinical characteristics, identify the risk factors, and investigate the causal relationship between AAV and venous thromboembolism (VTE) by two-sample Mendelian randomization (MR) analysis. METHODS: In this retrospective, observational study, we included all hospitalized AAV patients from Jan 2013 to Apr 2022 in Peking Union Medical College Hospital. We collected their clinical data for multivariate regression analysis to determine the risk factors for thrombosis. The nomogram was constructed by applying these risk factors to predict thrombosis in AAV patients. As for MR analysis, we selected single nucleotide polymorphisms (SNPs) related to AAV from published genome-wide association studies and extracted the outcome data containing deep vein thrombosis (DVT) and pulmonary embolism (PE) from the UK biobank. RESULTS: 1203 primary AAV patients were enrolled, and thrombosis occurred in 11.3%. Multivariate regression suggested that older than 65 years, EGPA, neurological involvement, lung involvement, significantly elevated serum creatinine (> 500µmol/L), and elevated D-dimer were associated with thrombosis in AAV patients. The model demonstrated satisfied discrimination with an AUC of 0.769 (95% CI, 0.726-0.812). MR analysis showed that EGPA could increase the risk of developing DVT and PE (OR = 1.0038, 95%CI = 1.0035-1.0041, P = 0.009). CONCLUSION: Thrombosis was not rare in Chinese patients with AAV. Renal damage and old age emerged as critical risk factors for thrombosis. EGPA might have a potential causal relationship with DVT and PE.

Systematic review and meta-analysis of the clinical features of MGRS.

BACKGROUND: It is crucial to identify patients with monoclonal gammopathy of renal significance (MGRS) from those without MGRS but with monoclonal gammopathy and concomitant kidney diseases. However, there have been few studies with large sample sizes, and their findings were inconsistent. This study aimed to conduct a meta-analysis of MGRS to describe the general characteristics of MGRS and its predictive factors. METHODS: Cohort or case-control studies published through December 2022 and related to clinicopathological features of MGRS were retrieved from the PubMed, Cochrane Library, Web of Science, Scopus, and Embase databases. Two researchers searched for studies that met the inclusion criteria. In the univariate analysis, fixed- or random- effects models were used to obtain pooled estimates of the weighted mean difference (WMD) and odds ratio (OR) for risk factors. In the multivariate analysis, the ORs of the independent risk factors from each study were pooled after transforming the original estimates. RESULTS: The meta-analysis included six studies. Univariate analysis showed that the following variables were statistically significant in MGRS: age (WMD = 1.78, 95%CI 0.21-3.35), hypertension (OR = 0.54, 95%CI 0.4-0.73), diabetes (OR = 0.42, 95%CI 0.29-0.59), albumin (WMD = - 0.26, 95%CI - 0.38--0.14), urinary protein level (WMD = 0.76, 95%CI 0.31-1.2), urinary protein ≥ 1.5 g/d (OR = 1.98, 95%CI 1.46-2.68), lambda-chain value (WMD = 29.02, 95%CI 16.55-41.49), abnormal free light-chain ratio (OR = 4.16, 95%CI 1.65-10.47), bone marrow puncture rate (OR = 5.11, 95% CI 1.31-19.95), and abnormal bone marrow outcome rate (OR = 9.63, 95%CI 1.98-46.88). Multivariate analysis showed urinary protein ≥ 1.5 g/d (OR = 2.80, 95%CI 1.53-5.15) and an abnormal free light-chain ratio (OR = 6.98, 95%CI 4.10-11.91) were associated with predictors of MGRS. CONCLUSIONS: Compared with non-MGRS patients with monoclonal gammopathy and concomitant kidney diseases, patients with MGRS were older, had fewer underlying diseases, more urinary protein, more abnormal free light-chain ratio, and more abnormal bone marrow results. Urinary protein ≥ 1.5 g/d and an abnormal free light-chain ratio were independent risk factors for MGRS.

Association between circulatory complement activation and hypertensive renal damage: a case-control study.

OBJECTIVE: The aim of this study was to investigate the potential importance of complement system activation, with particular emphasis on the complement alternative pathway (AP), in the pathogenesis of hypertensive renal damage. METHODS: Serum complement C3, complement Factor H (CFH) and AP activation were assessed in 66 participants with established essential hypertension with renal damage (RD). Fifty-nine patients with age- and sex-matched essential hypertension without renal damage (NRD) and 58 healthy participants (normal) were selected. RESULTS: Our study revealed that C3 and AP50 continuously increased from normal to NRD to RD (p < 0.05, respectively), while CFH was significantly lower than that in NRD and healthy participants (p < 0.05, respectively). After multifactorial logistic regression analysis corrected for confounders, elevated serum C3 (p = 0.001) and decreased CFH (p < 0.001) were found to be independent risk factors for hypertension in healthy participants; elevated serum C3 (p = 0.034), elevated AP50 (p < 0.001), decreased CFH (p < 0.001), increased age (p = 0.011) and increased BMI (p = 0.013) were found to be independent risk factors for the progression of hypertension to hypertensive renal damage; elevated serum C3 (p = 0.017), elevated AP50 (p = 0.023), decreased CFH (p = 0.005) and increased age (p = 0.041) were found to be independent risk factors for the development of hypertensive renal damage in healthy participants. CONCLUSION: Abnormal activation of complement, particularly complement AP, may be a risk factor for the development and progression of hypertensive renal damage.

Deletion of Sphingosine Kinase 2 Attenuates Acute Kidney Injury in Mice with Hemolytic-Uremic Syndrome.

Typical hemolytic uremic syndrome (HUS) can occur as a severe systemic complication of infections with Shiga toxin (Stx)-producing Escherichia coli. Its pathology can be induced by Stx types, resulting in toxin-mediated damage to renal barriers, inflammation, and the development of acute kidney injury (AKI). Two sphingosine kinase (SphK) isozymes, SphK1 and SphK2, have been shown to be involved in barrier maintenance and renal inflammatory diseases. Therefore, we sought to determine their role in the pathogenesis of HUS. Experimental HUS was induced by the repeated administration of Stx2 in wild-type (WT) and SphK1 (SphK1-/-) or SphK2 (SphK2-/-) null mutant mice. Disease severity was evaluated by assessing clinical symptoms, renal injury and dysfunction, inflammatory status and sphingolipid levels on day 5 of HUS development. Renal inflammation and injury were found to be attenuated in the SphK2-/- mice, but exacerbated in the SphK1-/- mice compared to the WT mice. The divergent outcome appeared to be associated with oppositely altered sphingolipid levels. This study represents the first description of the distinct roles of SphK1-/- and SphK2-/- in the pathogenesis of HUS. The identification of sphingolipid metabolism as a potential target for HUS therapy represents a significant advance in the field of HUS research.

Renoprotective effect of hyperin against CdCl2 prompted renal damage by activation of Nrf-2/Keap-1 ARE pathway in male mice.

OBJECTIVES: This study explored the mitigating properties of hyperin (HYP) on renotoxicity induced by cadmium chloride (CdCl2). METHODS: Four groups of seven male albino mice each were used in this experiment. Group 1 served as the control, receiving no treatment. Group 2 received daily oral gavage of CdCl2 at 0.3 mg/kg body weight for 28 d. Group 3 received both CdCl2 (0.3 mg/kg) and HYP (100 mg/kg) daily using the same administration method. Finally, Group 4 received only HYP (100 mg/kg) daily. RESULTS: Cd exposure significantly increased kidney dysfunction markers (blood urea nitrogen and creatinine) and oxidative stress (reactive oxygen species [ROS] and malondialdehyde [MDA]). Conversely, it decreased antioxidant enzyme activities (glutathione peroxidase (GPx] and catalase [CAT]) and glutathione (GSH) levels. Nuclear factor erythroid 2-related factor 2 (Nrf-2) and antioxidant gene expression decreased, while Kelch-like ECH-associated protein 1 expression increased. Additionally, Cd exposure increased inflammatory mediators (nuclear factor kappa B, tumor necrosis factor alpha [TNF-α], interleukin-1ß [IL-1ß], and cyclooxygenase-2) and apoptotic markers (Bax and caspase-3), alongside decreased Bcl-2 expression and renal tissue abnormalities. Mitochondrial dysfunction manifested with diminished activities of Krebs cycle and respiratory chain enzymes, and reduced mitochondrial membrane potential. Co-treatment with HYP significantly attenuated these detrimental effects through its anti-apoptotic, antioxidant, and anti-inflammatory properties. CONCLUSION: HYP co-treatment significantly attenuated CdCl2-induced renal damage in mice, suggesting its potential as a protective agent against Cd-induced kidney toxicity.

Levilactobacillus brevis MZ384011 and Levilactobacillus brevis MW362779 can mitigate lead induced hepato-renal damage by regulating visceral dispersion and fecal excretion.

Heavy metal pollution is a global issue. Current study provides evidence on Pb toxicity ameliorative potential and safe nature of Levilactobacillus brevis MZ384011 (S1) and Levilactobacillus brevis MW362779 (S2), isolated from carnivore gut and human milk, respectively. In a 60-days experiment, the rats were distributed into six groups. G-I, G-V and G-VI were kept on normal diet, while GII-IV were fed on lead nitrate (500 mg/kg) supplemented food, throughout experiment. After confirmation of Pb toxicity in GII-IV at 15th day, S1 was orally administered to G-III and G-V while S2 was given to G-IV and G-VI at a dose of 1 × 109 CFU/animal/day. On day 60 of experiment, positive control (G-II) displayed significant reduction in body weight, total protein, albumin, globulin, mineral profile, erythrocyte count, hemoglobin, hematocrit and hematological indices and elevation in leukocyte count, alanine aminotransferase, aspartate aminotransferase, bilirubin, uric acid and creatinine along with alterations in hepato-renal architecture. With reference to G-II, the G-III and G-IV displayed significant improvement in all aforementioned parameters, 40-60% reduction in tissue Pb levels (blood, liver, kidney and adipose tissue) and elevation in fecal Pb contents (p = 0.000). The groups V and VI did not show any sign of toxicity. The findings confirm that strains are safe for biological application and can reverse Pb toxicity by facilitating fecal Pb excretion and reducing its systemic dispersal. To best of our information this is the first report on Pb toxicity ameliorative role of Levilactobacillus brevis from human milk, the safest source.

Role of Alström syndrome 1 in the regulation of glomerular hemodynamics.

Inactivating mutations in the ALMS1 gene in humans cause Alström syndrome, characterized by the early onset of obesity, insulin resistance, and renal dysfunction. However, the role of ALMS1 in renal function and hemodynamics is unclear. We previously found that ALMS1 is expressed in thick ascending limbs, where it binds and decreases Na+-K+-2Cl- cotransporter activity. We hypothesized that ALMS1 is expressed in macula densa cells and that its deletion enhances tubuloglomerular feedback (TGF) and reduces glomerular filtration rate (GFR) in rats. To test this, homozygous ALMS1 knockout (KO) and littermate wild-type Dahl salt-sensitive rats were studied. TGF sensitivity was higher in ALMS1 KO rats as measured by in vivo renal micropuncture. Using confocal microscopy, we confirmed immunolabeling of ALMS1 in macula densa cells (nitric oxide synthase 1 positive), supporting a role for ALMS1 in TGF regulation. Baseline glomerular capillary pressure was higher in ALMS1 KO rats, as was mean arterial pressure. Renal interstitial hydrostatic pressure was lower in ALMS1 KO rats, which is linked to increased Na+ reabsorption and hypertension. GFR was reduced in ALMS1 KO rats. Seven-week-old ALMS1 KO rats were not proteinuric, but proteinuria was present in 18- to 22-wk-old ALMS1 KO rats. The glomerulosclerosis index was higher in 18-wk-old ALMS1 KO rats. In conclusion, ALMS1 is involved in the control of glomerular hemodynamics in part by enhancing TGF sensitivity, and this may contribute to decreased GFR. Increased TGF sensitivity, enhanced glomerular capillary pressure, and hypertension may lead to glomerular damage in ALMS1 KO rats. These are the first data supporting the role of ALMS1 in TGF and glomerular hemodynamics.NEW & NOTEWORTHY ALMS1 is a novel protein involved in regulating tubuloglomerular feedback (TGF) sensitivity, glomerular capillary pressure, and blood pressure, and its dysfunction may reduce renal function and cause glomerular damage.

Functional NADPH oxidase 2 in T cells amplifies salt-sensitive hypertension and associated renal damage.

Infiltrating T cells in the kidney amplify salt-sensitive (SS) hypertension and renal damage, but the mechanisms are not known. Genetic deletion of T cells (SSCD247-/-) or of the p67phox subunit of NADPH oxidase 2 (NOX2; SSp67phox-/-) attenuates SS hypertension in the Dahl SS rat. We hypothesized that reactive oxygen species produced by NOX2 in T cells drive the SS phenotype and renal damage. T cells were reconstituted by adoptively transferring splenocytes (∼10 million) from the Dahl SS (SS→CD247) rat, the SSp67phox-/- rat (p67phox→CD247), or only PBS (PBS→CD247) into the SSCD247-/- rat on postnatal day 5. Animals were instrumented with radiotelemeters and studied at 8 wk of age. There were no detectable differences in mean arterial pressure (MAP) or albuminuria between groups when rats were maintained on a low-salt (0.4% NaCl) diet. After 21 days of high-salt diet (4.0% NaCl), MAP and albuminuria were significantly greater in SS→CD247 rats compared with p67phox→CD247 and PBS→CD247 rats. Interestingly, there was no difference between p67phox→CD247 and PBS→CD247 rats in albuminuria or MAP after 21 days. The lack of CD3+ cells in PBS→CD247 rats and the presence of CD3+ cells in rats that received the T cell transfer demonstrated the effectiveness of the adoptive transfer. No differences in the number of CD3+, CD4+, or CD8+ cells were observed in the kidneys of SS→CD247 and p67phox→CD247 rats. These results indicate that reactive oxygen species produced by NOX2 in T cells participates in the amplification of SS hypertension and renal damage.NEW & NOTEWORTHY Our current work used the adoptive transfer of T cells that lack functional NADPH oxidase 2 into a genetically T cell-deficient Dahl salt-sensitive (SS) rat model. The results demonstrated that reactive oxygen species produced by NADPH oxidase 2 in T cells participate in the amplification of SS hypertension and associated renal damage and identifies a potential mechanism that exacerbates the salt-sensitive phenotype.

Association of Carotid-Femoral Pulse Wave Velocity and Ejection Duration with Target Organ Damage.

Background: Carotid-femoral pulse wave velocity (cfPWV) and ejection duration (ED) have different impacts on target organ damage (TOD). The aim of this study was to determine the relationship of cfPWV and ED with TOD. Methods: A total of 1254 patients (64.27% males) from Ruijin Hospital were enrolled in this study from December 2018 to August 2022. Medical records, blood samples and urine samples were collected. The cfPWV was measured and ED was generated using SphygmoCor software (version 8.0, AtCor Medical, Sydney, Australia). TOD including left ventricular hypertrophy (LVH), microalbuminuria, chronic kidney disease (CKD), and abnormality of carotid intima-media thickness (CIMT) were evaluated. Results: Multiple stepwise linear regression models of cfPWV and ED (individually or together) showed that cfPWV was positively correlated with left ventricular mass index (LVMI) ( ß = 0.131, p = 0.002) and Log (albumin-creatinine ratio, ACR) ( ß = 0.123, p = 0.004), while ED was negatively correlated with LVMI ( ß = -0.244, p < 0.001) and positively correlated with the estimated glomerular filtration rate (eGFR) ( ß = 0.115, p = 0.003). When cfPWV and ED were added separately or together in multiple stepwise logistic regression models, cfPWV was associated with CKD [odds ratio (OR) = 1.240, 95% confidence interval (CI) 1.055-1.458, p = 0.009], while ED was associated with LVH (OR = 0.983, 95% CI 0.975-0.992, p < 0.001). In the control group with normal cfPWV and normal ED, LVH was significantly lower in patients with high ED (OR = 0.574, 95% CI 0.374-0.882, p = 0.011), but significantly elevated in those with high cfPWV and low ED (OR = 6.799, 95% CI 1.305-35.427, p = 0.023). Conclusions: cfPWV was more strongly associated with renal damage, while ED was more strongly associated with cardiac dysfunction. cfPWV and ED affect each other, and together have an effect on LVH.

Normotensive placental extracellular vesicles provide long-term protection against hypertension and cardiovascular disease.

BACKGROUND: Women with normotensive pregnancy are at a reduced risk of developing cardiovascular disease postpartum compared with those who experience hypertensive conditions during pregnancy. However, the underlying mechanisms remain poorly understood. During normotensive pregnancy, vast numbers of placental extracellular vesicles are released into the maternal circulation, which protect endothelial cells from activation and alter maternal vascular tone. We hypothesized that placental extracellular vesicles play a mechanistic role in lowering the risk of cardiovascular disease following normotensive pregnancy. OBJECTIVE: This study aimed to investigate the long-term effects of placental extracellular vesicles derived from normotensive term placentae on the cardiovascular system and explore the mechanisms underlying their biological effects. STUDY DESIGN: Spontaneously hypertensive rats were injected with placental extracellular vesicles from normotensive term pregnancies (2 mg/kg each time, n=8) or vehicle control (n=9) at 3 months of age. Blood pressure and cardiac function were regularly monitored from 3 months to 15 months of age. The response of mesenteric resistance arteries to vasoactive substances was investigated to evaluate vascular function. Cardiac remodeling, small artery remodeling, and renal function were investigated to comprehensively assess the impact of placental extracellular vesicles on cardiovascular and renal health. RESULTS: Compared with vehicle-treated control animals, rats treated with normotensive placental extracellular vesicles exhibited a significantly lower increase in blood pressure and improved cardiac function. Furthermore, the vasodilator response to the endothelium-dependent agonist acetylcholine was significantly enhanced in the normotensive placental extracellular vesicle-treated spontaneously hypertensive rats compared with the control. Moreover, treatment with placental extracellular vesicles reduced wall thickening of small renal vessels and attenuated renal fibrosis. CONCLUSION: Placental extracellular vesicles from normotensive term pregnancies have long-lasting protective effects reducing hypertension and mitigating cardiovascular damage in vivo.

The new visceral adiposity index outperforms traditional obesity indices as a predictor of subclinical renal damage in Chinese individuals: a cross-sectional study.

BACKGROUND: The new visceral adiposity index (NVAI) was superior to previous obesity indices in predicting cardiovascular diseases among Asians. Nevertheless, the utility of the NVAI for predicting chronic kidney disease is still unclear. The objective of this research was to explore the relationship between the NVAI and subclinical renal damage (SRD) and to investigate whether the NVAI outperforms other common obesity indices in predicting SRD in the Chinese population. METHODS: Participants in this cross-sectional study were from the Hanzhong Adolescent Hypertension Cohort. The NVAI and seven other common obesity indices were calculated, including body mass index, waist circumference, lipid accumulation product, visceral adiposity index, Chinese visceral adiposity index, a body shape index and metabolic score for visceral fat. Logistic regression models revealed the association between NVAI and SRD. The odds ratio (OR) and the 95% confidence interval (CI) were calculated to show the association between the two variables. The predictive power of eight obesity indices for SRD was evaluated through the receiver operating characteristic curve and area under the curve (AUC). In addition, the net reclassification index (NRI) and integrated discrimination improvement (IDI) were also applied to compare the incremental predictive value for SRD of different obesity indices. RESULTS: The median age of the 2358 subjects was 42.00 years. Across NVAI tertiles, the prevalence of SRD was 7.25%, 11.21%, and 21.60%, respectively. After adjusting for confounders, a high level of NVAI remained a risk factor for SRD. The ORs of the middle and top NVAI tertiles for SRD were 1.920 (95% CI: 1.322, 2.787) and 4.129 (95% CI: 2.750, 6.202), respectively. The AUC of the NVAI was 0.666 (95% CI: 0.647, 0.685), which was significantly larger than the AUC of any of the other obesity indicators. Moreover, the NRI and IDI were significantly improved when NVAI was added to the basic model for predicting SRD. Among eight obesity indices, NVAI had the highest NRI (0.392; 95% CI: 0.280, 0.503), and its IDI (0.021; 95% CI: 0.014, 0.027) was second only to that of the body mass index (0.023; 95% CI: 0.014, 0.032). CONCLUSIONS: NVAI is independently and positively associated with SRD. Among the eight obesity indices, the NVAI shows the strongest predictive power for SRD in the Chinese population. The NVAI may be useful as an effective warning indicator of chronic kidney disease in Chinese adults.

Far-red light-activated human islet-like designer cells enable sustained fine-tuned secretion of insulin for glucose control.

Diabetes affects almost half a billion people, and all individuals with type 1 diabetes (T1D) and a large portion of individuals with type 2 diabetes rely on self-administration of the peptide hormone insulin to achieve glucose control. However, this treatment modality has cumbersome storage and equipment requirements and is susceptible to fatal user error. Here, reasoning that a cell-based therapy could be coupled to an external induction circuit for blood glucose control, as a proof of concept we developed far-red light (FRL)-activated human islet-like designer (FAID) cells and demonstrated how FAID cell implants achieved safe and sustained glucose control in diabetic model mice. Specifically, by introducing a FRL-triggered optogenetic device into human mesenchymal stem cells (hMSCs), which we encapsulated in poly-(l-lysine)-alginate and implanted subcutaneously under the dorsum of T1D model mice, we achieved FRL illumination-inducible secretion of insulin that yielded improvements in glucose tolerance and sustained blood glucose control over traditional insulin glargine treatment. Moreover, the FAID cell implants attenuated both oxidative stress and development of multiple diabetes-related complications in kidneys. This optogenetics-controlled "living cell factory" platform could be harnessed to develop multiple synthetic designer therapeutic cells to achieve long-term yet precisely controllable drug delivery.

Clinical features and prognosis of pregnancy-related renal damage and pregnancy after chronic kidney disease.

OBJECTIVE: To explore the clinical features of renal damage related to pregnancy and pregnancy after chronic kidney disease (CKD), providing clinical evidence for the relationship between renal damage and pregnancy. METHODS: A retrospective analysis was performed on patients admitted to our hospital between March 2013 and February 2021 who had both pregnancy and kidney damage. The study collected pathology results from renal biopsies, 24-hour urinary protein quantity, albumin (Alb), serum creatinine (Scr), blood lipids, coagulation function, blood routine, and other indicators during and after pregnancy. RESULTS: This study included 82 cases, with 48 cases in the pregnancy-related renal damage group. Thirty-four cases were in the post-CKD pregnancy group. Of the patients, 30 cases (88.24%) had CKD stage 1-2. Results showed better pregnancy and fetal outcomes in the post-CKD pregnancy group compared to the pregnancy-related renal damage group (Ρ was 0.029 and 0.036, respectively). Renal biopsy pathology revealed that 16 cases (33.33%) in the pregnancy-related renal damage group mainly had focal segmental glomerulosclerosis (FSGS), while the post-CKD pregnancy group was dominated by 14 cases (43.75%) of IgA nephropathy. The first blood test indicators revealed that the pregnancy-related renal damage group had lower estimated glomerular filtration (eGFR) and Alb levels compared to the post-CKD pregnancy group (Ρ was 0.003 and 0.000, respectively). Additionally, 24-hour urinary protein quantity, total cholesterol (Tch), triglyceride (TG), and platelet (PLT) counts were higher in the pregnancy-related renal damage group compared to the post-CKD pregnancy group (Ρ was 0.005, 0.001, 0.008, and 0.031, respectively). The abnormal rate of Scr during pregnancy was 41.67% (20/48) in the pregnancy-related renal damage group and 17.39% (4/23) in the post-CKD pregnancy group, with a statistically significant difference (Ρ was 0.043). CONCLUSION: The pregnancy-related renal damage group is mainly associated with FSGS, while the post-CKD pregnancy group is characterized by IgA nephropathy. Patients with CKD1-2 can have a successful pregnancy after achieving good control of eGFR, albumin, 24-hour urinary protein quantity and other indicators, resulting in better pregnancy and fetal outcomes. Abnormal Scr levels during pregnancy of pregnancy-related renal damage can be improved within 3 months after delivery.

The effect of arteriosclerosis on new-onset renal damage in diabetic patients.

The aim of this study was to investigate the effect of arteriosclerosis on new-onset renal damage in a Chinese community population with diabetes. Patients with diabetes who had attended at least one physical examination after the Brachial-ankle pulse wave velocity (BaPWV) test from 2010 to 2018 were selected as subjects. A total of 4,462 patients were included in the study cohort. BaPWV levels <1,400 cm/s, 1,400-1,799 cm/s, and ≥1,800 cm/s were applied to divide the subjects into a normal arterial stiffness group, borderline atherosclerosis group and atherosclerosis group. Renal damage was defined by isolated proteinuria, isolated eGFR <60 mL/min/1.73 m2, proteinuria and eGFR <60 mL/min/1.73 m2. A Cox proportional risk model was used to analyze the effect of different groups on new-onset renal damage. After a median follow-up of 2.85 (1.88-4.90) years, Cox proportional risk models showed that after adjusting for risk factors, compared with the normal group, the HR and 95% CI of the risk of new-onset renal damage were 1.29 (95% CI: 0.95-1.76) and 1.59 (95% CI: 1.14-2.22) in the borderline atherosclerosis group and the atherosclerosis group, respectively. Atherosclerosis is a risk factor for new-onset renal damage, especially new-onset proteinuria, in diabetic patients.

Association between renal surface nodularity and increased adverse vascular event risk in patients with arterial hypertension.

OBJECTIVE: To explore the association of renal surface nodularity (RSN) with the increased adverse vascular event (AVE) risk in patients with arterial hypertension. METHODS: This cross-sectional study included patients with arterial hypertension aged 18-60 years who underwent contrasted computed tomography (CT) of kidney from January 2012 to December 2020. The subjects were classified into AVE or not (non-AVE) matched with age (≤5 years) and sex. Their CT images were analyzed using both qualitative (semiRSN) and quantitative RSN (qRSN) methods, respectively. Their clinical characteristics included age, sex, systolic blood pressure (SBP), diastolic blood pressure, hypertension course, diabetes history, hyperlipidemia, and estimated glomerular filtration rate (eGFR). RESULTS: Compared with non-AVE group (n = 91), AVE (n = 91) was at lower age, higher SBP, and fewer rate of diabetes and hyperlipidemia history (all P < .01). Rate of positive semiRSN was higher in AVE than non-AVE (49.45% vs 14.29%, P < .001). qRSN was larger in AVE than non-AVE [1.03 (0.85, 1.33) vs 0.86 (0.75,1.03), P < .001]. The increased AVE was associated with semiRSN (odds ratio = 7.04, P < .001) and qRSN (odds ratio = 5.09, P = .003), respectively. For distinguishing AVE from non-AVE, the area under receiver operating characteristic was bigger in the models combining the clinical characteristics with either semiRSN or qRSN than that of semiRSN or qRSN alone (P ≤.01). CONCLUSION: Among the patients with arterial hypertension aged 18-60 years, CT imaging-based RSN was associated with increased AVE risk.

Visceral fat and its dynamic change are associated with renal damage: Evidence from two cohorts.

BACKGROUND AND AIMS: To evaluate the association of Chinese visceral adiposity index (CVAI) and its dynamic trends with risk of renal damage, and to compare its prediction performance with that of other obesity indices. METHODS AND RESULTS: A community-based population with 23 905 participants from Shantou city was included in the cross-sectional analysis. A total of 9,778 individuals from two separated cohort were included in the longitudinal portion. Five patterns of CVAI change were predefined (low-stable, decreasing, moderate, increasing, and persistent-high). Logistic and Cox regressions were used to evaluate the association between CVAI and renal damage. We explored potential mechanisms using the mediating effect method, and the prediction performance was determined by receiver operating characteristic curve analysis. Results from both cross-sectional and longitudinal data revealed a positive and linear association between CVAI and risk of renal damage. Pooled analysis of the two cohorts showed that per unit increase in Z score of CVAI induced 18% increased risk of renal damage (P = .008). Longitudinal trends of CVAI were also associated with renal damage, and the moderate, increasing, and persistent-high patterns showing a higher risk. Blood pressure and glucose had a mediating effect on renal damage induced by CVAI. Among several obesity indices, CVAI was the optimal for predicting renal damage. CONCLUSION: A higher level of immediate CVAI and longitudinal increasing and persistent-high patterns of CVAI were independently associated with increased risk of renal damage. Monitoring immediate level and long-term trend of CVAI may contribute to the prevention of renal damage.

Cadmium exposure exacerbates kidney damage by inhibiting autophagy in diabetic rats.

The incidence of diabetes mellitus (DM) is gradually increasing, making it a widespread global health concern. Cadmium (Cd) is a common toxic heavy metal in the environment, and cadmium exposure may be associated with diabetic nephropathy (DN). However, the mechanism of Cd-induced DN remains unclear. In this study, we aimed to determine the effect of cadmium on diabetic kidney injury and the underlying mechanism in diabetic rats and a renal tubular epithelial cell line (NRK-52E cells). Our results could provide novel insights on the nephrotoxic mechanism of cadmium. HE, PAS, and Masson staining were used to observe pathological renal injury. COL-I, COL-IV, CTSB, and CTSD protein levels were detected by immunohistochemistry and western blotting. Immunofluorescence was used to detect the fluorescence intensity of p62 and LC3 proteins in kidney tissue. TEM was used to observe the ultrastructure of mitochondria and number of autophagosomes. After cadmium exposure, DM rats showed a dramatic decrease in body weight compared to the unexposed DM group. Relative kidney weight showed a contrasting trend after cadmium exposure. Urinary microalbumin/creatinine significantly increased in normal and DM rats after cadmium exposure. However, the trend was clearer in the DM groups than in the control groups. Endogenous creatinine clearance exhibited a contrasting trend. After cadmium exposure in DM rats, MDA content significantly increased and GSH, CAT, SOD, and GSH-PX activation reduced compared to normal controls. Pathological damage was more pronounced, and the expression of autophagy related proteins and apoptosis and fibrosis proteins was significantly higher in vivo and vitro in the cadmium-exposed groups than in unexposed controls. Further, lysosomal protein levels were lower, and ROS content and autophagosome count significantly higher in the cadmium exposed groups compared to the unexposed controls. Therefore, Cadmium exposure aggravates diabetic kidney injury via autophagy inhibition.

Total Outflow of High-Density Lipoprotein-Cholesteryl Esters from Plasma Is Decreased in a Model of 3/4 Renal Mass Reduction.

(1) Background: Previous studies have enriched high-density lipoproteins (HDL) using cholesteryl esters in rabbits with a three-quarter reduction in functional renal mass, suggesting that the kidneys participate in the cholesterol homeostasis of these lipoproteins. However, the possible role of the kidneys in lipoprotein metabolism is still controversial. To understand the role of the kidneys in regulating the HDL lipid content, we determined the turnover of HDL-cholesteryl esters in rabbits with a three-quarter renal mass reduction. (2) Methods: HDL subclass characterization was conducted, and the kinetics of plasma HDL-cholesteryl esters, labeled with tritium, were studied in rabbits with a 75% reduction in functional renal mass (Ntx). (3) Results: The reduced renal mass triggered the enrichment of cholesterol, specifically cholesteryl esters, in HDL subclasses. The exchange of cholesteryl esters between HDL and apo B-containing lipoproteins (VLDL/LDL) was not significantly modified in Ntx rabbits. Moreover, the cholesteryl esters of HDL and VLDL/LDL fluxes from the plasmatic compartment tended to decrease, but they only reached statistical significance when both fluxes were added to the Nxt group. Accordingly, the fractional catabolic rate (FCR) of the HDL-cholesteryl esters was lower in Ntx rabbits, concomitantly with its accumulation in HDL subclasses, probably because of the reduced mass of renal cells requiring this lipid from lipoproteins.