To investigate the role and underlying mechanisms of oxoglutarate dehydrogenase-L (OGDHL) in renal fibrosis.

Twelve male wild-type C57BL/6J mice (8 weeks old, weighting about 25 g) were randomly divided into control group and model group (n=6). A mouse model of renal fibrosis was established by unilateral ureteral obstruction (UUO). HE staining, immunofluorescence assay, and immunohistochemical and Masson staining were applied to assess the extent of renal fibrosis. Human kidney-2 proximal tubule cell line (HK-2) were randomly divided into blank plasmid group (Vector), OGDHL overexpression group (OGDHL OE), blank plasmid + TGF-β1 treatment group (TGF-β1+Vector), TGF-β1 treatment and OGDHL overexpression group (TGF-β1+OGDHL OE). Transmission electron microscopy (TEM) was employed to observe mitochondrial morphology. RT-qPCR, Western blotting and immunofluorescence assay were used to detect the expression levels of OGDHL and mitochondrial metabolism-related genes. Adenosine triphosphate (ATP) level, oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and other mitochondrial metabolism-related indicators were detected with corresponding reagent kits and Agilent Seahorse.

UUO operation resulted in obvious thinning of the renal cortex, significant hydronephrosis. HE staining revealed that tubular atrophy accompanied by dilated tubular lumens in the kidneys. Immunofluorescence, immunohistochemical and Masson staining showed obvious renal fibrosis after UUO operation. In the mouse model of renal fibrosis, the expression of OGDHL was decreased by 82.9% at mRNA level (P<0.001) and 81.9% at protein level (P<0.001), the production of mitochondrial ATP was reduced by 0.970±0.151 µmol/L (P<0.01), and notable damaged mitochondrial structure was observed, with maximum breathing capacity decreased by 25.260±1.920 pmol/min (P<0.001), expression levels of fatty acid oxidation-related genes were declined by 50.2% (P<0.05), while glycolysis was enhanced, with the genes related to glycolysis increased by 2.5 times when compared with those in the control group (P<0.05). After OGDHL overexpression, mitochondrial morphological damage was significantly improved, ATP production was increased by 0.980±0.090 µmol/L (P<0.05), with significantly alleviated energy metabolism disorder and renal fibrosis (P<0.05).

OGDHL regulates mitochondrial metabolic reprogramming of renal tubular epithelial cells to alleviate fibrosis, suggesting that OGDHL may be a new therapeutic target for renal fibrosis.

To systematically investigate the bidirectional causal relationship between 10 uremia-related toxins and metabolites and CD8⁺ T cell senescence phenotypes using Mendelian randomization (MR).

A bidirectional MR analysis was performed using genome-wide association studies (GWAS) data to extract single nucleotide polymorphisms closely associated with 10 uremia-related toxins and metabolites and CD8⁺ T cell senescence phenotypes as instrumental variables. The primary analytical method was inverse variance weighting (IVW), supplemented by MR-Egger, weighted median, simple mode, and weighted mode. The robustness and potential pleiotropy of the results were verified by sensitivity analyses including Cochran's Q test, MR-Egger intercept test, MR-PRESSO and leave-one-out analysis.

MR analysis showed that carnitine level was positively associated with the proportion of terminally differentiated CD8⁺ T cells (IVW: β=1.71, 95%CI: 0.59 to 2.83, P=0.003), the proportion of CD45 RA⁺CD28^-CD8⁺T cells (IVW: β=2.23, 95%CI: 0.65 to 3.80, P=0.006), and the proportion of CD28^-CD8⁺T cells (IVW: β=1.13, 95%CI: 0.11 to 2.15, P=0.030). Kynurenine level also showed a significant positive association with the proportion of terminally differentiated CD8⁺T cells (IVW: β=1.69, 95%CI: 0.57 to 2.82, P=0.0003), while IL-6 level presented a positive correlation with the proportion of CD28^-CD8⁺T cells (IVW: β=0.28, 95%CI: 0.03 to 0.53, P=0.026) and the proportion of CD45 RA⁺CD28^-CD8⁺T cells (IVW: β=0.41, 95%CI: 0.02 to 0.79, P=0.04). N², N²-dimethylguanosine level was positively correlated with CD45 RA⁺CD28^-CD8⁺T cell absolute count (IVW: β=2.53, 95%CI: 0.51 to 4.55, P=0.014). Reverse MR analysis revealed an increase in the absolute count of CD45 RA⁺CD28^-CD8⁺T cells was causally associated with a reduction in carnitine levels (IVW: β=-0.00003, 95%CI: -0.000062 to 0.000004, P=0.024). All sensitivity analyses supported the robustness of the main findings.

There are bidirectional causal associations between uremiarelated toxins and metabolites and CD8⁺T cell senescence, providing novel causal insights and potential intervention targets for immune dysfunction in uremic patients.

To develop and validate a machine learning (ML) model based on serum Klotho protein that can accurately predict all-cause mortality in chronic kidney disease (CKD) patients.

A retrospective cohort trial was conducted on all the non-dialysis adult patients diagnosed with CKD stages 1~5 in our department from February 7, 2012 to October 18, 2019. They were assigned into a training set and an internal validation set in a ratio of 7∶3. A total of 47 clinical features, including serum Klotho protein level, were used as variables to inform these models. Based on the training set, univariate Cox regression model was employed to screen out the possible risk factors for all-cause mortality, and Lasso-Cox regression model was further applied for the screening. Then multivariate Cox stepwise regression analysis was conducted to develop a nomogram risk prediction model for all-cause mortality, and the model performance was evaluated through internal validation.

There were totally 400 patients enrolled in this trial, and 280 of them (including 52 dead and 228 survival) were assigned into the training set and other 120 (including 21 dead and 99 survival) into the validation set. For the constructed 5-year all-cause mortality risk prediction model, the area under the curve (AUC) value was 0.760 (95%CI: 0.676~0.844) in the training set and 0.788 (95%CI: 0.679~0.897) in the validation set, and the overall C-index was 0.755 (95%CI: 0.685~0.826) and 0.720 (95%CI: 0.614~0.826), respectively in the 2 sets. Univariate Cox regression analysis showed that age, history of cardiovascular disease(CVD), cystatin C(Cys-C), alkaline phosphatase (ALP), albumin, eosinophil (EOS) count, hemoglobin (Hb), complement C3, calcium, C-reactive protein (CRP), TNF-α and serum Klotho protein may be predictive factors for all-cause mortality (P<0.05). Multivariate Cox stepwise regression analysis finally screened age, albumin, complement C3 and serum Klotho protein as independent predictors (P<0.05). Based on these 4 predictors, a risk prediction model for all-cause mortality was constructed and validated.

A Klotho-based risk ML model for predicting all-cause mortality in CKD patients is successfully developed and validated. Advanced age is a risk factor, and higher albumin, complement C3 and serum Klotho protein levels are protective factors for all-cause mortality in CKD patients.

To explore the role and mechanism of glutamate-cysteine ligase modifier subunit（GCLM）in alleviation of hypoxia reoxygenation（HR）injury in renal tubular epithelial cells.

Human proximal tubular epithelial HK2 cells were cultured and divided into control group（Ctrl group）, HR group, and HR+GCLM overexpression group（HR+GCLM OE group）. Cell model of HR was established by hypoxia（94% N₂+1% O₂+5% CO₂, glucose and serum-free DMEM/F12 medium）for 24 h, and then followed by of reoxygenation（95% air +5% CO₂, DMEM/F12 medium with 10% FBS）for 6 h. The cells of the HR+GCLM OE group was transfected with REST overexpression plasmid for 24 h and then exposed to HR injury. The protein levels of GCLM and glutathione peroxidase 4（GPX4）were detected with Western blotting, the contents of glutathione（GSH）, malonaldehyde（MDA）and reactive oxygens（ROS）were measured, and mitochondrial morphology was observed with transmission electron microscopy（TEM）.

Under HR condition, the HK2 cells showed significantly accumulated MDA（P<0.01）and ROS（P<0.01）contents, obviously reduced GSH level（P<0.01）, typical ferroptosis changes under TEM, and decreased expression of GCLM and GPX4（P<0.01）. However, overexpression of GCLM inhibited MDA and ROS production（P<0.01）while increased GSH generation and GPX4 expression（P<0.01）, and alleviated HR injury.

Up-regulation of GCLM protects renal tubular epithelial cells against HR injury probably by suppressing ferroptosis, indicating a potential therapeutic effect of GCLM in acute kidney injury.

To investigate the efficacy and safety of hydroxychloroquine (HCQ) versus spironolactone in patients with IgA nephropathy based on sufficient renin-angiotensin-aldosterone system inhibitors (RAASi) treatment.

A prospective, non-randomized study was carried out on 172 patients with primary IgA nephropathy admitted in our department from April 2019 to March 2021. They were 56 males and 116 females, at an average age of 37.5±10.7 years. They were divided into HCQ group (n=104) and double RAASi group (n=68) and were followed up for 6 months. The decreasing rate of urine protein creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) were compared between the 2 groups during follow-up, and subgroup analysis was conducted to explore the effects of corticosteroids or immunosuppressants on the outcomes.

Compared with the dual RAASi group, the patients in the HCQ group had worse baseline renal function, lower eGFR and larger proportion of Lee's grades Ⅲ~Ⅳ (P<0.05). At the 6th month of follow-up, the decreasing rate of UPCR was comparable between the 2 groups (-54.7% vs -52.0%, P=0.551), but the decreasing rate of eGFR was significantly lower in the HCQ group than that in the dual RAASi group (-3.3% vs -11.5%, P<0.001). In addition, subgroup analysis found that there was no significant difference between HCQ and spironolactone in reducing urine protein, but for those who did not use corticosteroids or immunosuppressants before and after enrollment, those who did not use corticosteroids or immunosuppressants before enrollment but added them after enrollment, and those who used corticosteroids or immunosuppressants before and after enrollment, the HCQ group had a significantly lower eGFR decline rate at 6 months of follow-up than the dual RAAS group (P<0.05). Moreover, no serious adverse events (SAEs) were observed in either group during the course of the study.

On the basis of sufficient RAASi treatment, HCQ and spironolactone have similar effects in controlling urine protein level in patients with IgA nephropathy whose urine protein does not reach the target level, and there are no serious adverse events. But HCQ has a significantly better renal protective effect of eGFR than spironolactone.

To explore the differences in clinical indicators and clinicopathological characteristics immunoglobulin A nephropathy (IgAN) patients with hypertension accompanied with arteriolar hyalinosis and those without.

A total of 246 patients who was diagnosed with biopsy-proven primary IgAN and hypertension in our hospital from 2012 to 2018 were enrolled in our study. According to the severity of arteriolar hyalinosis, they were divided into 3 groups, without (n=73) and with mild (n=136, severity: 1%~25%) and moderate arteriolar hyalinosis (n=37, severity: 26%~50%), respectively. The correlations of clinicopathological parameters with arteriolar hyalinosis were analyzed in the groups.

The incidence (55.3%) of mild arteriolar hyalinosis was the highest in the patients. There were significant differences in tumor necrosis factor-α (TNF-α), urea, serum creatinine (Scr), uric acid, and estimated glomerular filtration rate (eGFR) among the 3 groups (P<0.05). In clinicopathological parameters, glomerulosclerosis, mesangial hypercellularity (M), segmental sclerosis (S), and interstitial fibrosis/tubular atrophy (T) lesions and grades of Lee classification differed statistically among the 3 groups (P<0.05). Moreover, correlation analysis showed that arteriolar hyalinosis had a strong positive correlation with grade of Lee classification (r_s=0.433, P<0.001), Scr (r_s=0.319, P<0.001) and T (V=0.317, P<0.001), respectively, while a strong negative correlation with eGFR (r_s=-0.367, P<0.001).

Significant differences are observed in clinical and pathological indicators in patients with IgAN and hypertension accompanied with arteriolar hyalinosis or not. Its severity is closely associated with renal function, so arteriolar hyalinosis can be used as an indicator to evaluate the function.