#2458 Renal multiparametric MRI detects changes in renal blood flow and microstructure related to macroalbuminuria in Stage 3 Diabetic Kidney Disease patients

Rationale and Strategies for Early Detection and Management of Diabetic Kidney Disease

Objective To analyze the predictive value of apolipoprotein B (ApoB) in the risk of progression to renal replacement therapy (RRT) in diabetic kidney disease (DKD) patients with chronic kidney disease (CKD) stage 3-5. Methods The data of DKD patients with CKD stage 3-5 who were hospitalized and followed up with detailed clinical data from January 2011 to November 2014 in the Third Affiliated Hospital of Sun Yat-sen University were retrospectively collected. Estimated glomerular filtration rate (eGFR) was calculated according to the CKD-EPI formula. After 2 years of follow-up, the patients were divided into RRT group and non-RRT group according to whether they had entered renal replacement therapy. Cox regression analysis was used to analyze the influencing factors of DKD progression to RRT. The predicted value of ApoB in the risk of progression to renal replacement therapy (RRT) of DKD patients within 2 years of follow-up was analyzed by plotting the receiver operating characteristic curve (ROC). By establishing multiple Cox models, the effect of ApoB elevation on the progression of DKD patients to RRT was analyzed after adjusting for the influencing factors gradually. Results A total of 258 cases were included in this study, including 156 males and 102 females. They were (66.13±11.88) years old (27-91 years old). CKD 3-5 patients were 181 cases, 50 cases and 27 cases respectively. There were 165 cases in the non-RRT group and 93 cases in the RRT group. There were statistically significant difference in hemoglobin, hematocrit, blood phosphorus, ApoB, serum creatinine, urea nitrogen, serum cystatin C, eGFR and in the proportion of using angiotensin converting enzyme inhibitor, diuretic, β blockers between the two groups (all P<0.05). Multivariate Cox regression analysis showed that ApoB was an independent predictor of progression to RRT in patients with DKD within 2 years (HR=2.203, 95% CI 1.352-3.589, P=0.002). The area under the ROC curve of ApoB for DKD progression to RRT within 2 years of follow-up was 0.641 (C-index=0.749, P<0.01). After adjusting for confounding factors, Cox regression analysis showed that for every 1 mmol/L increase in ApoB, the risk of RRT increased by 1.038 times in DKD patients with CKD stage 3-5 (HR=2.038, 95% CI 1.312-3.168, P=0.002). Conclusions ApoB is an independent predictor of progression to RRT with CKD stage 3-5 diabetic kidney disease (DKD). For every 1 mmol/L increase in ApoB, the risk of progression to RRT in patients with CKD 3-5 DKD increases by 1.038 times. Key words: Apolipoproteins B; Diabetic nephropathies; Risk factors; Predictive value

Background and objectiveSodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to prevent the progression of diabetic kidney disease (DKD). However, their impact on renal fibrosis remains largely uninvestigated. This study aimed to explore the effect of SGLT2 inhibitor empagliflozin on renal fibrosis in DKD patients and DKD models, and the molecular mechanisms involved.MethodsKidney samples of DKD patients and DKD models were used in this study. DKD mouse models included STZ-treated CD-1 mice and HFD-fed C57BL/6 mice were all treated with empagliflozin for 6 to 12 weeks. Kidney pathological changes were analysed and fibrotic factors were detected. HK-2 cells were treated with normal glucose (NG), high glucose (HG), or HG with empagliflozin. RNA sequencing was employed to identify the differentially expressed genes. Epithelial–mesenchymal transition (EMT) markers were detected. Binding of transcription factor and target gene was determined using a dual-luciferase reporter assay.ResultsEmpagliflozin significantly ameliorated kidney fibrosis in DKD patients and DKD models. This was evidenced by tubulointerstitial fibrosis reduction observed through PAS and Masson staining, along with fibrotic factors downregulation. RNA sequencing and the subsequent in vitro and in vivo validation identified PKM2 as the most significantly upregulated glycolytic enzyme in DKD patients and models. Empagliflozin downregulated PKM2 and alleviated EMT and renal fibrosis. Importantly, empagliflozin improves fibrosis by downregulating PKM2. The downregulation of PKM2 by empagliflozin was achieved by inhibiting the binding of estrogen-related receptor α at the promoter.ConclusionsEmpagliflozin ameliorates kidney fibrosis via downregulating PKM2 in DKD.

Background: Diabetes mellitus (DM) is a major cause of chronic kidney disease (CKD) leading to diabetic kidney disease (DKD). Several studies have observed lipid profile abnormalities in non-diabetic CKD patients with and without haemodialysis. Our study aims to reveal lipid profile abnormalities both in DKD and non-diabetic CKD patients on haemodialysis.Methods: A prospective comparative study included 50 DKD and 50 non-diabetic CKD patients on haemodialysis and 50 controls after fulfilling the inclusion and exclusion criteria. The demographic and biochemical, including lipid profile parameters data of all subjects was collected and statistically analysed. p&lt;0.05 was considered as statically significant.Results: A total of 100 study patients, 50 DKD and 50 non-diabetic CKD patients, both on haemodialysis revealed significant dyslipidaemia when compared to controls. Total cholesterol in DKD patients on haemodialysis when compared to controls (177.5±80.5 versus 146.5±31.8 mg/dl) was significantly elevated (p=0.01). Low density lipoprotein (LDL) in DKD patients when compared to controls (94.1±43.3 versus 76.3±26.3 mg/dl) was also significantly elevated (p=0.01). Triglyceride levels in both DKD and non-diabetic CKD patients on haemodialysis in comparison to controls (213.8±182.1 and 169.2±132.3 versus 109.2±28.9 mg/dl respectively) were significantly elevated (p=0.0002 and p=0.003 respectively). Similarly, very low-density lipoprotein (VLDL) levels in both DKD and non-diabetic CKD patients were also significantly elevated when compared to controls (p=0.002 and p=0.003 respectively) whereas high density lipoprotein (HDL) was significantly reduced.Conclusion: Both DKD and non-diabetic CKD patients on haemodialysis revealed significant dyslipidaemia, a major cause of increased risk for cardiovascular diseases necessitating early treatment with statins.

The pathogenesis of Diabetic kidney disease(DKD) involves pathological changes in both tubulo‐interstitium and the glomerulus. Surprisingly, tubulo‐interstitial fibrosis (TIF), does not develop significantly until the late stage of DKD. Here, it is demonstrated that PR domain‐containing 16 (PRDM16) is a key to the low level of TIF in DKD. In the experiments, PRDM16 is upregulated in high glucose‐treated renal tubular cells, DKD mouse kidneys, and renal biopsy of human DKD patients via activation of NF‐κB signal pathway. High glucose‐induced expression of fibrotic proteins in renal tubular cells is suppressed by PRDM16. Mechanistically, PRDM16 bound to the promotor region of Transient receptor potential ankyrin 1 (TRPA1) to transactivate its expression and then suppressed MAPK (P38, ERK1/2) activation and downstream expression of TGF‐β1. Knockout of PRDM16 from kidney proximal tubules in mice blocked TRPA1 expression and enhanced MAPK activation, TGF‐β1 production, TIF development, and DKD progression, whereas knock‐in of PRDM16 has opposite effects. In addition, overexpression of PRDM16 or its induction by formononetin ameliorated renal dysfunction and fibrosis in db/db diabetic mice. Finally, the above finding are detected in renal biopsies of DKD patients. Together, these results unveil PRDM16/TRPA1 as the mechanism responsible for the low level of TIF in the early stage of DKD by suppressing and TGF‐β1 expression.

Clinical Challenges in Diagnosis and Management of Diabetic Kidney Disease

Introduction: Diabetic kidney disease (DKD) is a major source of chronic kidney disease and end-stage renal disease. The injury of glomerulus in DKD is the primary focus; however, proximal tubulopathy also is an indispensable factor in the progression of DKD. Interleukin-37 (IL-37), an anti-inflammatory cytokine of IL-1 family member, has been demonstrated to be associated with diabetes and its relative complications in recent years, but the effect of IL-37 on renal fibrosis in DKD is unclear. Methods: We established streptozotocin plus high fat diet-induced DKD mice model with wild type or IL-37 transgenic mice. Masson and HE staining, immunostaining, and Western blot were used to observe renal fibrosis. In addition, RNA-sequencing was applied to explore the potential mechanisms of IL-37. In vitro, treatment of human proximal tubular (HK-2) cells with 30 mmol/L high glucose or 300 ng/mL recombinant IL-37 further elucidated the possible mechanism of IL-37 inhibition of DKD renal fibrosis. Results: In this work, we first verified the decreased expression of IL-37 in kidney of DKD patient and its correlation with clinical features of renal impairment. Moreover, IL-37 expression markedly attenuated proteinuria and renal fibrosis in DKD mice. Using RNA-sequencing, we found and confirmed a novel role of IL-37 in ameliorating fatty acid oxidation (FAO) reduction of renal tubular epithelial cells both in vivo and in intro. In addition, further mechanistic studies showed that IL-37 alleviated the FAO reduction in HK-2 cells and renal fibrosis in DKD mice through upregulating carnitine palmitoyl-transferase 1A (CPT1A), an important catalyzer for FAO pathway. Conclusion: These data suggest that IL-37 attenuates renal fibrosis via regulating FAO in renal epithelial cells. Upregulation of IL-37 levels might be an effective therapeutic avenue for DKD.

BackgroundRenal fibrosis is crucial to be detected early in diabetic kidney disease (DKD). Serum periostin is a biomarker for the early detection of fibrosis in DKD. Moreover, shear wave elastography (PSWE) and the renal resistivity index (RRI) are widely used to evaluate renal fibrosis. We aimed to evaluate periostin’s role as an indicator for detecting renal fibrosis in the early stages of DKD, alongside RRI and PSWE.MethodsSeventy-two type 2 diabetes mellitus patients were subdivided into four groups dependent on glomerular filtration rate (GFR) categories (G1–G4), and eighteen healthy participants were enrolled. Creatinine, HbA1c, eGFR, albumin-creatinine ratio (ACR), and serum periostin were measured. RRI and PSWE values were recorded.ResultsPeriostin levels increased significantly with DKD progression. Periostin’s diagnostic performance of cutoff value, which was 39.92 ng/mL for early detection of DKD, with 97.2% sensitivity and 100% specificity. Both RRI and PSWE values increased significantly with DKD progression. RRI and PSWE cutoff values were 0.5 and 1.52 kPa, respectively, with sensitivity of 83.3% and specificity of 100% for RRI, and for PSWE values demonstrated a sensitivity of 80.6%, and specificity of 100%. Strong positive correlations were observed between periostin levels and both RRI and PSWE values (p < 0.001).ConclusionsPeriostin, RRI and PSWE provide valuable insight into the combined use of biochemical and imaging markers for early detection of renal fibrosis in DKD monitoring of DKD progression.Trial registration noMS-132-2024.

ObjectiveThe assessment of the grade of renal fibrosis in diabetic kidney disease (DKD) requires renal biopsy, which may be associated with certain risks. To assess the severity of chronic pathologic changes in DKD, we performed a quantitative analysis of renal parenchymal stiffness in advanced DKD, using shear wave elastography (SWE) imaging.Patients and methodsTwenty-nine diabetic patients with chronic kidney disease (CKD) grades 3–4 due to DKD, and 23 healthy subjects were enrolled. Combined conventional ultrasound and SWE imaging were performed on all participants. The length, width, and cortical thickness and stiffness were recorded for each kidney.ResultsCortical thickness was lower in patients with DKD than in healthy subjects (13.8±2.2 vs 14.8±1.6 mm; P=0.002) and in DKD patients with CKD grade 4 than in those with grade 3 (13.0±3.5 vs 14.7±2.1 mm; P<0.001). Cortical stiffness was greater in patients with DKD than in healthy subjects (23.72±14.33 vs 9.02±2.42 kPa; P<0.001), in DKD patients with CKD grade 4 than in those with grade 3 (30.4±16.2 vs 14.6±8.1 kPa; P<0.001), and in DKD patients with CKD grade 3b, than in those with CKD grade 3a (15.7±6.7 vs 11.0±4.2 kPa; P=0.03). Daily proteinuria was higher in DKD patients with CKD grade 4 than in those with grade 3 (5.52±0.96 vs 1.13±0.72; P=0.001), and in DKD patients with CKD grade 3b, than in those with CKD grade 3a (1.59±0.59 vs 0.77±0.48; P<0.001). Cortical stiffness was inversely correlated with the estimated glomerular filtration rate (r=−0.65, P<0.001) and with cortical thickness (r=−0.43, P<0.001) in patients with DKD.ConclusionsIn patients with advanced DKD, SWE imaging may be utilized as a simple and practical method for quantitative evaluation of the chronic morphological changes and for the differentiation between CKD grades.

Diabetic kidney disease (DKD) is characterized by progressive fibrosis, oxidative stress, and mitochondrial dysfunction, contributing to renal dysfunction. EphrinB2, a cell surface protein, has been implicated in tissue repair and fibrosis, but its role in DKD remains poorly understood. This study investigates the impact of EphrinB2 expression on renal fibrosis, mitochondrial dynamics, and cellular signaling pathways in DKD. EphrinB2 expression and function were investigated in renal tissues from DKD patients, STZ-induced diabetic mice, and HG-treated HK-2 cells. EphrinB2 overexpression was achieved using AAV in vivo and lentiviral vectors in vitro. Functional assessments included histological and biochemical evaluations, while mechanistic studies utilized siRNA knockdown, pathway-specific inhibitors and activators, and co-immunoprecipitation to explore the role of the Epac1-Rap1 signaling pathway in EphrinB2-mediated antifibrotic and mitochondrial protective effects. EphrinB2 expression was significantly downregulated in the kidneys of DKD patients and STZ-induced diabetic mice, correlating with increased fibrosis and tubular injury. Overexpression of EphrinB2 (EphrinB2-OE) in diabetic mice restored renal function, reduced fibrosis, alleviated oxidative stress, and preserved mitochondrial structure. In HK-2 cells, EphrinB2-OE mitigated HG-induced fibrosis, reduced ROS levels, and restored MMP and ATP production. Mechanistically, EphrinB2-OE enhanced the Epac1-Rap1 pathway, stabilizing Epac1 protein and promoting mitochondrial biogenesis via PGC-1α. Additionally, EphrinB2-OE modulated the E-cadherin/β-catenin complex and preventing β-catenin nuclear translocation, and preserving epithelial integrity and epithelial-to-mesenchymal transition (EMT). EphrinB2 exerts protective effects against renal fibrosis and dysfunction in diabetic conditions by regulating fibrosis pathways, mitochondrial dynamics, and epithelial stability. Targeting EphrinB2 signaling presents a promising therapeutic strategy for diabetic kidney disease.

Objectives: Chronic kidney disease (CKD) and its progression is associated with a number of complications, including thyroid dysfunction, in particular hypothyroidism.The objective of the study was to compared the thyroid profiles in diabetic and nondiabetic chronic kidney disease.Also, thyroid profiles were compared in different stages of CKD and in dialyzed versus non -dialyzed patients.Methods: An observational study was conducted among 150 CKD patients at DY Patil Hospital, Nerul. of the patients were of diabetic kidney disease. Demographic features, medical history of diabetes mellitus, hypertension and renal disease of each patient were noted, and blood samples were analyzed for free triiodothyronine (T3), free thyroxine (T4), thyroid stimulating hormone (TSH). Results: Thyroid dysfunction was found in 48.7 % CKD patients, the most common was subclinical hypothyroidism (45.3%). When compared to non -diabetic chronic kidney disease patients, diabetic kidney disease patients had higher prevalence of subclinical hypothyroidism (32% vs 58.6%). Stage 4 and 5 CKD patients had higher prevalence of having subclinical hypothyroidism as compared to stage 3 patients (54.1% vs 48.9% vs 30.5% respectively). Subclinical hypothyroidism was found to be more in patients undergoing hemodialysis as compared to those not under hemodialysis (61.5% vs 32.65%). Conclusions: CKD patients of diabetic origin were more prone to thyroid abnormalities as compared to CKD patients of non -diabetic origin. Stage 4 and 5 CKD patients had significantly higher risk of having thyroid dysfunction as compared to stage 3 patients. Thyroid dysfunction was found to be more in patients undergoing hemodialysis as compared to those not under hemodialysis

Multimodality Prevention of Contrast-Induced Acute Kidney Injury

Disease-specific trajectories of renal function in advanced chronic kidney disease (CKD) are not well defined. Here, we compared these trajectories in the estimated glomerular filtration rate (eGFR) by CKD stages. Patients with multiple eGFR measurements during the 5-year preregistration period of the REACH-J study were enrolled. Mean annual eGFR declines were calculated from linear mixed effect models with the adjustment variables of baseline CKD stage, age, sex and the current CKD stage and the level of proteinuria (CKDA1-3). Among 1,969 eligible patients with CKDG3b-5, the adjusted eGFR decline (ml/min/1.73m2/year) was significantly faster in diabetic kidney disease (DKD) patients and polycystic kidney disease (PKD) patients than in patients with other kidney diseases (DKD, -2.96 ± 0.13; PKD, -2.82 ± 0.17; and others, -1.95 ± 0.05, p < 0.01). The declines were faster with higher CKD stages. In DKD patients, the eGFR decline was significantly faster in CKDG5 than CKDG4 (-4.10 ± 0.18 vs -2.76 ± 0.20, p < 0.01), while these declines in PKD patients were similar. The eGFR declines in PKD patients were significantly faster than DKD patients in CKDG4 (-2.92 ± 0.23 vs -2.76 ± 0.20, p < 0.01) and in CKDA2 (-3.36 ± 0.35 vs -1.40 ± 0.26, p < 0.01). Our study revealed the disease-specific annual eGFR declines by CKD stages and the level of proteinuria. Comparing to the other kidney diseases, the declines in PKD patients were getting faster from early stages of CKD. These results suggest the importance of CKD managements in PKD patients from the early stages.

Supplemented Gegen Qinlian Decoction Formula attenuates podocyte mitochondrial fission and renal fibrosis in diabetic kidney disease by inhibiting TNF-α-mediated necroptosis, compared with empagliflozin

Chronic kidney disease (CKD) and diabetic kidney disease (DKD) are major public health problems, and their burden is growing relentlessly with the aging of the global population. Their early recognition is now a public health priority, and there is an unmet need for the identification of specific biomarkers in minimally invasive or non-invasive samples. Mitochondrial dysfunction plays a pivotal role in the development and progression of both CKD and DKD and circulating platelets have emerged as an ideal candidate for the assessment of the respiratory function. The present study assessed mitochondrial respiration in platelets isolated from the peripheral blood of patients with DKD and CKD compared to healthy controls. The study included a total number of 89 subjects, as follows: 30 DKD patients divided into three subgroups based on the urinary albumin-to-creatinine ratio (uACR): 20 normoalbuminuric, 10 microalbuminuric, and 10 macroalbuminuric, 29 CKD patients (positive controls) and 20 healthy individuals (negative controls). Platelets were isolated by differential centrifugations and a high-resolution respirometry protocol was adapted to assess mitochondrial respiration dependent on complex I (CI) and complex II (CII). A significant reduction of the CI-supported active respiration was found in the normoalbuminuric DKD patients and further decreased in the microalbuminuric DKD subgroup. Both CI and CII-dependent coupled respiration and the maximal uncoupled respiration were significantly reduced in the macroalbuminuric DKD subgroup. In conclusion, mitochondrial respiration impairment in peripheral platelets is evident from the early stages of DKD. Moreover, platelet mitochondrial respiration was more severely impaired in patients with macroalbuminuric DKD as compared to those with CKD. Further, more extensive follow-up studies are warranted to determine whether platelet respiratory mitochondrial dysfunction could serve as a peripheral biomarker for kidney mitochondrial dysfunction and/or as a prognostic tool in DKD.