Diabetic Nephropathy Research Articles

Simultaneous pancreas and kidney transplantation: A qualitative study of partners’ experiences

Chronic health conditions often affect the lives of family members as well as the patient themselves. The current study aimed to explore the experiences of partners of individuals with diabetes and chronic kidney disease (CKD) who received a simultaneous pancreas and kidney transplant (SPKT) to understand the wider impact of SPKTs. Eight partners of recipients of SPKT were interviewed about their experiences before and after the transplant. Interviews were transcribed verbatim and analysed thematically. Participants described how they navigated life with an unwell partner; sub-themes included a) living with pervasive worry, b) the challenge of enhanced responsibilities, and c) the buffering effect of social support. Diabetes complications, such as the experience of severe hypoglycaemia, particularly fuelled worry. Participants felt great relief after their partner’s successful transplant but also faced certain realities around the potential for their partner’s health to deteriorate again. The study highlights the impact of diabetes and CKD on patients’ families and the wider benefit of transplantation, not just for the patient. The pancreas transplant, in addition to the kidney, relieved partners of their worry about hypoglycaemic events and the development of diabetes complications. Partners may benefit from being encouraged to seek support and to maintain their own health and wellbeing.

A novel role of peroxiredoxin 2 in diabetic kidney disease progression by activating the classically activated macrophages.

Diabetic kidney disease (DKD) is the main cause of deaths due to diabetes mellitus (DM). Due to the complexity of its onset, it is difficult to achieve accurate prevention and treatment. The classically activated macrophage (M1) polarization is a crucial proinflammatory mechanism of DKD, while the interaction and cascade effects of oxidative stress and inflammatory response remain to be elucidated. A urine proteomic analysis of patients with DM indicated that peroxiredoxin 2 (PRDX2) had the higher abundance in DKD. We recently found that PRDX of parasitic protozoa Entamoeba histolytica, which was similar to human PRDX2 in amino acid sequence and spatial structure, could activate the inflammatory response of macrophages through toll-like receptor 4 (TLR4). Hence, our study was designed to explore the role of PRDX2 in chronic inflammation during DKD. Combined with in vivo and in vitro experiments, results showed that the PRDX2 was positively correlated with DKD progression and upregulated by high glucose or recombinant tumor necrosis factor-α in renal tubular epithelial cells; Besides, recombinant PRDX2 could promote M1 polarization of macrophages, and enhance the migration as well as phagocytic ability of macrophages through TLR4. In summary, our study has explored the novel role of PRDX2 in DKD to provide a basis for further research on the diagnosis and treatment of DKD.

The advance of single cell transcriptome to study kidney immune cells in diabetic kidney disease.

Diabetic kidney disease (DKD) is a prevalent microvascular complication of diabetes mellitus and a primary cause of end-stage renal disease (ESRD). Increasing studies suggest that immune cells are involved in regulating renal inflammation, which contributes to the progression of DKD. Compared with conventional methods, single-cell sequencing technology is more developed technique that has advantages in resolving cellular heterogeneity, parallel multi-omics studies, and discovering new cell types. ScRNA-seq helps researchers to analyze specifically gene expressions, signaling pathways, intercellular communication as well as their regulations in various immune cells of kidney biopsy and urine samples. It is still challenging to investigate the function of each cell type in the pathophysiology of kidney due to its complex and heterogeneous structure and function. Here, we discuss the application of single-cell transcriptomics in the field of DKD and highlight several recent studies that explore the important role of immune cells including macrophage, T cells, B cells etc. in DKD through scRNA-seq analyses. Through combing the researches of scRNA-seq on immune cells in DKD, this review provides novel perspectives on the pathogenesis and immune therapeutic strategy for DKD.

Discussion on the treatment of diabetic kidney disease based on the "gut-fat-kidney" axis.

Diabetic kidney disease is the main cause of end-stage renal disease, and its prevention and treatment are still a major clinical problem. The human intestine has a complex flora of hundreds of millions of microorganisms, and intestinal microorganisms, and their derivatives are closely related to renal inflammatory response, immune response, and material metabolism. Brown adipose tissue is the main part of adaptive thermogenesis. Recent studies have shown that activating brown fat by regulating intestinal flora has good curative effects in diabetic kidney disease-related diseases. As an emerging medical concept, the "gut-fat-kidney" axis has received increasing attention in diabetic kidney disease and related diseases. However, the specific mechanism involved needs further study. A new theoretical basis for the prevention and treatment of diabetic kidney disease is presented in this article, based on the "gut-fat-kidney" axis.

Relationship of serum calcium concentration with chronic kidney disease and mortality in type 2 diabetes mellitus patients: evidence from the NHANES 1999-2018.

This study aims to explore the relationship of serum calcium (Ca) concentration with diabetic kidney disease (DKD) and all-cause mortality among type 2 diabetes mellitus (T2DM) patients using National Health and Nutrition Examination Surveys (NHANES). Data of T2DM patients aged ≥ 40 years were screened from the NHANES database from 1999 to 2018. The outcomes were the risk of DKD diagnosed by urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 and the risk of all-cause mortality ascertained by linkage to National Death Index (NDI) records through 31 December 2019. The weighted univariate and multivariate logistic regression model and cox proportional hazard model were utilized to explore the relationships of serum Ca concentration with DKD and all-cause mortality, respectively, with odds ratios (ORs), hazard ratios (HRs) and 95% confidence interval. The relationships were further explored stratified by age, gender, body mass index (BMI), the duration of T2DM, and the history of cardiovascular disease (CVD), cancer and DKD. Totally, 6595 T2DM patients were included. Of these patients, 2441 (37.01%) had DKD and 1868 (28.32%) deaths occurred over a mean follow-up of 104.50 (± 1.61) months. In fully adjusted model, we observed high serum Ca concentration was associated with high risk of DKD (OR = 1.45, 95% CI 1.18-1.77) and high all-cause mortality risk (HR = 1.33, 95% CI 1.16-1.52). These relationships remained significant after performing subgroup analyses. The Restricted cubic spline curves shown that linear correlations were observed between serum Ca concentration and DKD as well as all-cause mortality (P < 0.05). Elevated serum Ca concentration may predict the high risk of DKD and poor prognosis in T2DM patients, and future large-scale and well-designed prospective cohort study is needed to explore the association of serum Ca concentration and DKD and prognosis in T2DM patients.

The diagnostic utility of urinary Transferrin excretion rate as predictor for micro albuminuria in patients with Type 2 Diabetes Mellitus among Karbala province

One of the factors responsible of end-stage renal disease and chronic kidney disease is diabetic nephropathy. Microalbuminuria itself is regarded as the initial indication of diabetic nephropathy, and it affects 20% to 40% of patients with diabetes mellitus. Because of the limited accuracy and precision of microalbuminuria, more susceptible markers may be developed to more accurately identify diabetic nephropathy early on. The purpose of this research was to ascertain whether urine transferrin could be used as a marker for diabetic nephropathy. In our research, 80 subjects with type 2 diabetes were divided into two categories: 10 healthy controls and group 1 (normoalbuminuric, with albumin excretion up to 30 mg/d) and group 2 (microalbuminuric, with albumin excretion between 30 and 300 mg/d). all subjects was over the age of 18, had diabetes for further than a year, and had a glomerular filtration rate greater than 60 mL/min/1.73 m2. The concentration of transferrin, serum creatinine, and glycosylated hemoglobin (HbA1c) in both spot urine and 24-hour urine samples were assessed using a super accurate sandwich enzyme - linked immunosorbent assay kit. subjects with microalbuminuria had substantially greater urinary transferrin levels than both normoalbuminuric and healthy control participants. We discovered a significantly positive correlation r = 0.584 (p &lt; 0.001) when we compared these categories based on the urinary transferrin concentration. Urinary transferrin levels did not correlate with glycoregulation, and neither did transferrin levels and the length of diabetes. Urinary transferrin levels may be utilized as an important indicator of diabetic nephropathy, according to the findings of the research.

Tiliroside protects against diabetic nephropathy in streptozotocin-induced diabetes rats by attenuating oxidative stress and inflammation

BACKGROUND Diabetic nephropathy (DN), affecting half of diabetic patients and contributing significantly to end-stage kidney disease, poses a substantial medical challenge requiring dialysis or transplantation. The nuanced onset and clinical progression of kidney disease in diabetes involve consistent renal function decline and persistent albuminuria. AIM To investigate Tiliroside's (Til) protective effect against diabetic nephropathy (DN) in rats under diabetic conditions. METHODS Five groups of six rats each were included in this study: Rats treated with DMSO by intraperitoneal injection as controls, those treated with STZ by intraperitoneal injection, those treated with STZ + Til (25 mg/kg body weight [bwt]) or Til (50 mg/kg bwt), and those treated with anti-diabetic medication glibenclamide (600 μg/kg bwt). Biochemical markers, fasting blood glucose, food intake, kidney weight, antioxidant enzymes, inflammatory and fibrotic markers, and renal injury were monitored in different groups. Molecular docking analysis was performed to identify the interactions between Til and its targeted biomarkers. RESULTS Til significantly reduced biochemical markers, fasting blood glucose, food intake, and kidney weight and elevated antioxidant enzymes in diabetic rats. It also mitigated inflammatory and fibrotic markers, lessened renal injury, and displayed inhibitory potential against crucial markers associated with DN as demonstrated by molecular docking analysis. CONCLUSION These findings suggest Til's potential as a therapeutic agent for DN treatment, highlighting its promise for future drug development.

The association between plasma lipidome and diabetic microangiopathy: a mendelian randomization study.

Current studies have identified severe lipid metabolism diseases in diabetic microangiopathy patients, especially in diabetic kidney disease (DKD), diabetic retinopathy (DR) and diabetic neuropathy (DN), with unclear causal relationships. We employed a large-scale dataset containing 179 lipid species as the exposure and large-scale public summary-level datasets of DKD, DR and DN as the outcome. We applied Mendelian randomization (MR) approach to explore causal associations between circulating liposomes and diabetic microangiopathy. A sequence of sensitivity tests was conducted to verify the stability of the MR analysis. We manifest that diacylglycerol (18:1_18:3) (OR = 0.716, 95%CI = 0.559-0.917, P = 0.008), triacylglycerol (OR:0.741-0.763, P < 0.05) and phosphatidylcholine (OR:0.620-1.247, P < 0.05) have a potential association with DKD. And there is a nominal causal effect of phosphatidylinositol (16:0_18:2) (OR = 0.617, 95%CI = 0.401-0.948, P = 0.028), phosphatidylcholine (OR:0.499-0.672, P < 0.05) and sphingomyelin (OR:0.652-1.850, P < 0.05) to DR. In addition, phosphatidylethanolamine (18:1_0:0) (OR = 0.616, 95%CI = 0.405-0.935, P = 0.023), diacylglycerol (16:0_18:1) (OR = 0.675, 95%CI = 0.463-0.984, P = 0.041) and phosphatidylcholine (OR = 0.720-1.619, P < 0.05) nominally associate with DN. It is noteworthy that plasma lipidome of different structures show different effects. We establish a possible causal connection between certain plasma lipidome and major diabetic microangiopathies. Implementing intervention strategies targeting different lipid molecules may provide novel approaches for preventing and treating diabetic microangiopathies.

β-cryptoxanthin suppresses oxidative stress via activation of the Nrf2/HO-1 signaling pathway in diabetic kidney disease

ObjectivesThis study aims to explore the role and investigate mechanisms of β-Cryptoxanthin (BCX) in high glucose (HG)-induced podocyte injury and renal dysfunction.MethodsIn this study, db/db mice were orally treated with BCX. Blood glucose, body weight, urinary albumin creatinine ratio (ACR) were recorded to evaluate the mice renal function. The H&amp;amp;E, PAS staining, and transmission electron microscopy (TEM) were utilized to examine the effect of BCX on the morphological changes of glomeruli in db/db mice. In addition, reactive oxygen species (ROS) content, mitochondrial membrane potential (MMP) level, ATP level, and SA-β-gal staining were used to assess the podocyte oxidative damage, mitochondrial dysfunction and senescence. Furthermore, the effects of BCX on Nrf2/HO-1 signaling pathway were evaluated in vivo and in vitro through Western blotting, immunohistochemistry and immunofluorescence analysis.ResultsIn vivo, BCX reversed glomerular mesangial matrix expansion and reduced proteinuria in db/db mice, as well as decreased glomerular oxidative stress and kidney aging. Similarly, in vitro study showed that BCX effectively alleviated the oxidative stress, mitochondrial dysfunction, and senescence induced by HG in podocytes. Furthermore, we identified that the antioxidative effects of BCX are associated with the activation of Nrf2/HO-1 signaling pathway, and that Nrf2 knockdown partially abrogated the protective effects of BCX in vitro.ConclusionOur study demonstrated for the first time that BCX alleviates podocyte injury in DKD by promoting Nrf2/HO-1 signaling pathways. BCX may be a potential candidate compound for preventing Diabetic kidney disease (DKD).

Integrated Health Monitoring System using Fingerprint and Disease Risk Prediction

Recent developments in machine learning and biometric systems have had a big influence on healthcare applications. In order to provide a holistic approach to health monitoring, this research introduces a unique method that combines disease risk prediction with fingerprint-based blood group recognition. Based on user-provided health data, the system uses machine learning algorithms to determine the risk of common illnesses including diabetes, cardiovascular disease, and chronic kidney disease (CKD) and convolutional neural networks (CNNs) to identify blood type from fingerprint photos. Through the integration of fingerprint biometric data with health risk modelling, the suggested approach seeks to increase the precision and usability of health forecasts. The system's effectiveness is demonstrated by the evaluation's excellent classification accuracy for blood groups and trustworthy estimates of illness risk.This work demonstrates the possibility of integrating biometric data with predictive health models and offers a promising step toward customized healthcare solutions

J-shaped association of serum uric acid with all-cause and cardiovascular mortality in patients with diabetic kidney disease.

The association of serum uric acid (SUA) with mortality remains unclear in patients with diabetic kidney disease (DKD). Thus, this prospective cohort study aimed to explore the association of SUA with all-cause and cardiovascular disease (CVD) mortality among patients with DKD in a large, nationally representative sample. This cohort study included data from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 and the National Death Index mortality data until 31 December 2019. The restricted cubic spline and the Cox proportional hazards regression were conducted to describe the association of SUA with all-cause and CVD mortality and evaluate potential nonlinear associations. The analysis included 3470 patients with DKD from NHANES 1999-2018. During the follow-up time of 24,633 person-years, we recorded 1489 all-cause deaths, including 542 CVD deaths. We identified a J-shaped association of SUA with all-cause and CVD mortality. The corresponding inflection points were observed at 5.1 and 5.7mg/dL. When SUA were higher than inflection points, each 1mg/dL increase in SUA was linked to a 13% and 22% higher risk of all-cause (HR: 1.13; 95% CI: 1.07-1.20;P < 0.001) and CVD (HR: 1.22; 95% CI: 1.06-1.41;P = 0.006) mortality, respectively. This study indicated the J-shaped association of SUA with all-cause and CVD mortality in patients with DKD. The corresponding inflection points were 5.1 mg/dL for all causes and 5.7mg/dL for CVD, respectively. More clinical randomized trials are needed to confirm the optimal uric acid-lowering target.

Cinnamaldehyde ameliorates diabetes-induced biochemical impairments and AGEs macromolecules in a pre-clinical model of diabetic nephropathy.

Cinnamaldehyde, has various therapeutic potentials including glucose-lowering effect, and insulinotropic effect; however, its glycation inhibitory mechanism is not known yet. In this study, we explored the effects of cinnamaldehyde for its AGEs inhibitory mechanism in a streptozotocin-complete Freund's adjuvant (STZ-CFA) induced diabetic nephropathy (DN) rat model. Pre-clinical DN model was developed by the administration of multiple low doses of STZ-CFA in rats, mainly characterized by abnormal blood parameters and nephrotic damages. Diabetes-related systemic profile and histopathological hallmarks were evaluated using biochemical assays, microscopic imaging, immunoblot, and real-time PCR analyses, supported by cinnamaldehyde-albumin interaction assessed using STD-NMR and in silico site-directed interactions in the presence of glucose. Cinnamaldehyde-treatment significantly reversed DN hallmarks, fasting blood glucose (FBG), serum insulin, glycated hemoglobin (HbA1c), urinary microalbumin, and creatinine contrasted to non-treated DN rats and aminoguanidine, a positive reference advanced glycation end products (AGEs) inhibitor. The pathological depositions of AGEs, receptor for advanced glycation end products (RAGE), and carboxymethyl lysine (CML), and transcriptional levels of AGE-RAGE targeted immunomodulatory factors (IL1β, TNF-α, NF-κB, TGF-β) were significantly improved in cinnamaldehyde treated rats as compared to aminoguanidine. Cinnamaldehyde post-treatment improved pancreatic pathology and systemic glycemic index (0.539 ± 0.01 vs. 0.040 ± 0.001, P < 0.001) in DN rats. Subsequently, in silico profiling of cinnamaldehyde defined the competitive binding inhibition with glucose in AGE and RAGE receptors that was further confirmed by in vitro STD-NMR analysis. These findings suggest potential role of cinnamaldehyde in reversing STZ-induced diabetic nephropathic impairments; therefore, appears promising candidate for further pharmacological explorations towards diabetes-associated complications.

Molecular Mechanism of Finerenone in Treating Diabetic Nephropathy Based on Bioinformatics

Background: Diabetic Nephropathy (DN) is the leading cause of the end-stage renal disease (ESRD). Finerenone (with the molecular formula C21H22N4O3) is an oral non-steroidal mineralocorticoid antagonist (ns-MRA) that is both highly potent and has strong selectivity for the MR. At present, it has been used to treat DN. However, the molecular mechanism of finerenone in the treatment of diabetic nephropathy remains unclear. Objective: In this study, we employed bioinformatics approaches to investigate the molecular mechanism of finerenone as a novel therapeutic agent for the treatment of DN. Methods: We examined a number of databases, including GEO, DisGeNET, Genecards, and OMIM, to find putative genes linked to DN. We then employed the PubChem database and PharmMapper service platform to identify targets of finerenone. Further analysis was conducted using the DAVID database for enrichment analysis and the STRING database for protein-protein interaction (PPI) networks. Molecular docking (MD) was performed using AutoDockTools software, and results were visualized using PyMOL software. Results: In total, we identified 82 drug-disease targets, primarily associated with lipid and atherosclerosis, diabetic cardiomyopathy, MAPK signaling pathway, and PI3K-Akt signaling pathway. Our PPI network analysis and docking studies demonstrated good binding ability of finerenone to specific targets such as AKT1, MMP-9, IGF1, EGFR, CASP3, PPARG, ESR1, MMP-2, and KDR. Conclusion: Finerenone has the potential to reduce the progression of DN through various pathways, including lipid and atherosclerosis, diabetic cardiomyopathy, MAPK signaling pathway, and PI3KAkt signaling pathway. Moreover, it could exert anti-inflammatory and antifibrotic effects on specific targets, such as AKT1, MMP-9, IGF1, EGFR, CASP3, PPARG, ESR1, MMP-2, and KDR.

Role of epigenetic changes in the pathophysiology of diabetic kidney disease

Background: Diabetic kidney disease (DKD) is a global health issue. Epigenetic changes play an important role in the pathogenesis of this disease. Summary: DKD is currently the leading cause of kidney failure worldwide. Although much is known about the pathophysiology of DKD, the research field of epigenetics is relatively new. Several recent studies have demonstrated that diabetes-induced dysregulation of epigenetic mechanisms alters the expression of pathological genes in kidney cells. If these changes persist for a long time, the so-called “metabolic memory” could be established. In this review, we highlight diabetes-induced epigenetic modifications associated with DKD. While there is a substantial amount of literature on epigenetic changes, only a few studies describe the underlying molecular mechanisms. Detailed analyses have shown that epigenetic changes play an important role in known pathological features of DKD, such as podocyte injury, fibrosis, accumulation of extracellular matrix, or oxidative injury, all of which contribute to the pathophysiology of disease. The transforming growth factor-b plays a key role, as it is involved in all mentioned epigenetic types of regulation. Key messages: Epigenetic is crucial for the development and progression of diabetic kidney disease, but the detailed molecular mechanisms have to be further analyzed more in detail.

Protective Effect of Mesenchymal Stromal Cells in Diabetic Nephropathy: The In vitro and In vivo Role of the M-Sec-Tunneling Nanotubes.

&#160;Mitochondrial dysfunction plays an important role in the development of podocyte injury in diabetic nephropathy (DN). Tunnelling nanotubes (TNTs) are long channels that connect cells and allow organelle exchange. Mesenchymal stromal cells (MSCs) can transfer mitochondria to other cells through the M-Sec-TNTs system. However, it remains unexplored whether MSCs can form heterotypic TNTs with podocytes, thereby enabling the replacement of diabetes-damaged mitochondria. In this study, we analysed TNT formation, mitochondrial transfer, and markers of cell injury in podocytes that were pre-exposed to diabetes-related insults and then co-cultured with diabetic or non-diabetic MSCs. Furthermore, to assess the in vivo relevance, we treated DN mice with exogenous MSCs, either expressing or lacking M-Sec, carrying fluorescent-tagged mitochondria. MSCs formed heterotypic TNTs with podocytes, allowing mitochondrial transfer, via a M-Sec-dependent mechanism. This ameliorated mitochondrial function, nephrin expression, and reduced apoptosis in recipient podocytes. However, MSCs isolated from diabetic mice failed to confer cytoprotection due to Miro-1 downregulation. In experimental DN, treatment with exogenous MSCs significantly improved DN, but no benefit was observed in mice treated with MSCs lacking M-Sec. Mitochondrial transfer from exogenous MSCs to podocytes occurred in vivo in a M-Sec-dependent manner. These findings demonstrate that the M-Sec-TNT-mediated transfer of mitochondria from healthy MSCs to diabetes-injured podocytes can ameliorate podocyte damage. Moreover, M-Sec expression in exogenous MSCs is essential for providing renoprotection in vivo in experimental DN.

Cell Division Cycle 42 Improves Renal Functions, Fibrosis, Th1/Th17 Infiltration and Inflammation to Some Degree in Diabetic Nephropathy.

Our two previous studies observed that cell division cycle 42 (CDC42) was lower and correlated with improved renal function and inflammation in diabetic nephropathy (DN) patients, and CDC42 inhibited renal tubular epithelial cell fibrosis and inflammation under high glucose condition. Sequentially, this current study aimed to investigate the effect of CDC42 on improving renal function, fibrosis, and inflammation in DN mice, and its interaction with T cell receptor (TCR) related pathways. Mice were treated by streptozotocin to construct early-stage DN model, then transfected with CDC42 overexpression adenovirus, followed by simultaneous treatment of LY294002 (PI3K/AKT inhibitor) and CI-1040 (ERK inhibitor), respectively. CDC42 reduced blood glucose, creatinine, and 24h urine protein in DN mice, but only showed a tendency to decrease blood urea nitrogen without statistical significance. Hematoxylin&eosin staining revealed that CDC42 descended the glomerular volume, basement membrane thickness, and inflammatory cell infiltration in kidney. Meanwhile, CDC42 lowered fibronectin, TGF-β1, and Collagen I expressions in kidney, but not decreased α-SMA significantly. Besides, CDC42 decreased T-helper (Th) 1 and Th17 cells in kidney, and reduced serum IFN-γ, IL-1β, IL-17A, and TNF-α but not IL-6. Regarding TCR-related pathways, CDC42 activated AKT and ERK pathways but not JNK pathway. However, the treatment of LY294002 and CI-1040 had limited effect on attenuating CDC42's functions on renal function and fibrotic markers. CDC42 improves renal functions, fibrosis, Th1/Th17 infiltration and inflammation to some degree in DN mice, these functions may be independent to AKT and ERK pathways.

A machine learning model for predicting worsening renal function using one-year time series data in patients with type 2 diabetes.

To prevent end-stage renal disease caused by diabetic kidney disease, we created a predictive model for high-risk patients using machine learning. The reference point was the time at which each patient's estimated glomerular filtration rate (eGFR) first fell below 60 mL/min/1.73 m2. The input period spanned the reference point to 1 year prior. The primary endpoint was a 50% decrease in eGFR from the mean of the input period over the 3 year evaluation period. We created predictive models for patients' primary endpoints using time series data of various variables over the input period. Among 2,533 total patients, 1,409 had reference points, 31 had records for their input and evaluation periods and had reached their primary endpoints, and 317 patients had not. The area under the curve (AUC) of the predictive model peaked (0.81) when the minimum eGFR, the difference between maximum and minimum eGFR, and both maximum and minimum urinary protein values were included in the features. The accuracy of prognosis prediction can be improved by considering the variable components of urinary protein and eGFR levels. This model will allow us to identify patients whose renal functions are relatively preserved with eGFR of more than 60 mL/min/1.73 m2 and are likely to benefit clinically from immediate treatment intensification.

Primary glomerular diseases and long-term adverse health outcomes: A nationwide cohort study.

Although glomerular diseases are the third most frequent cause of end-stage kidney disease worldwide, little is known about their long-term outcomes. In patients with chronic kidney disease (CKD) stage 3-5 enrolled in the Swedish Renal Registry, we compared risks of hospitalization, kidney replacement therapy (KRT), major cardiovascular events (MACE), and death of the four most frequent primary glomerular diseases (IgA nephropathy [IgAN], focal segmental glomerulosclerosis [FSGS], minimal change disease [MCD], and membranous nephropathy [MN]), and patients with CKD due to the most common non-communicable diseases (control-CKD). We identified 2396 patients with glomerular disease (97% biopsy-proven, 69% men, 57 years, eGFR 29mL/min/1.73m2, uACR 88mg/mmol, 1524 with IgAN, 398 FSGS, 94 MCD, and 380 MN) and 37,697 controls (64% men, 74 years, eGFR 25mL/min/1.73m2, uACR 23mg/mmol), mainly with diabetic nephropathy and nephroangiosclerosis. The median follow-up was 6.3 (3.3; 9.9) years. Compared with control-CKD, patients with primary glomerular diseases generally had a lower risk of hospitalization, MACE (adjusted hazard ratios [HRs] ranging from 0.44 to 0.88 depending on the etiology) and death (HRs ranging 0.45-0.76). Patients with IgAN and FSGS had a faster eGFR decline and a higher rate of KRT (HRs 1.26 [95%CI: 1.15-1.37] and 1.34 [1.15-1.57], respectively). Conversely, patients with MN and MCD had a lower KRT rate and slower eGFR decline. Despite having a lower relative risk of hospitalization, cardiovascular events and mortality, patients with IgAN and FSGS are at higher risk of CKD progression than the most common etiologies of CKD, emphasizing the need for more stringent treatment strategies in these patients.

Factors Associated With Adverse Outcomes Among Patients Undergoing Endovascular Revascularization for Iliac Artery Lesions TASC II A and B: A Single-Center Study.

This prospective study from October 2016 to September 2020 aimed to identify the factors associated with non-revascularization and mortality rates in patients who underwent endovascular interventions for Trans-Atlantic Inter-Society Consensus (TASC) II A/B iliac artery occlusions at the Department of Vascular Surgery. Patients with TASC II A/B iliac artery occlusions who underwent endovascular intervention, including balloon angioplasty and stent placement, were included. The primary outcomes were factors associated with non-revascularization and mortality rate. A total of 133 patients were enrolled in this study. Univariable analysis revealed significant associations between non-revascularization and diabetes (hazard ratio [HR]=2.61, 95% confidence interval [CI], p=0.03), chronic kidney disease (HR=16.2, 95% CI, p=0.01), and severe calcifications (HR=8.56, 95% CI, p<0.001). Subsequent multivariable analysis confirmed the significance of these factors, showing HRs of 3.04 (95% CI, p=0.02), 13.12 (95% CI, p=0.03), and 8.62 (95% CI, p<0.001), respectively. The overall mortality rate observed was 20.3%. Severe calcifications emerged as a significant risk factor for mortality in both univariable (HR=2.47, 95% CI, p=0.02) and multivariable (HR=3.01, 95% CI, p<0.001) analyses. Severe calcifications correlate with non-revascularization and mortality, while comorbidities like diabetes mellitus and chronic kidney disease are also associated with non-revascularization. Recognizing these identified factors holds substantial promise in enhancing patient selection and procedural approaches, potentially bolstering the success rates of endovascular interventions. However, further research aimed at comprehending the underlying mechanisms and devising strategies to mitigate these risks is imperative for continued improvement in patient outcomes. The study provides valuable insights into patient selection and procedural planning for endovascular interventions in TASC II A/B iliac artery occlusions. Identifying severe calcifications, diabetes, and chronic kidney disease as key risk factors for non-revascularization and mortality equips clinicians with essential predictive tools, potentially improving outcomes by tailoring treatment approaches. The innovation lies in highlighting the impact of comorbidities and calcification severity, offering a pathway to refine patient eligibility criteria and optimize procedural decisions. This underscores the importance of further research to develop strategies that mitigate these risk factors and enhance intervention success rates.

Modulators of Alpha-2 Macroglobulin Upregulation by High Glucose in Glomerular Mesangial Cells

Up to 40% of patients with diabetes mellitus will develop diabetic kidney disease (DKD), characterized pathologically by the accumulation of extracellular matrix proteins, which leads to the loss of kidney function over time. Our previous studies showed that the pan-protease inhibitor alpha 2-macroglobulin (A2M) is increased in DKD and is a critical regulator of the fibrotic response in glomerular mesangial cells (MC), an initial site of injury during DKD development. How A2M is regulated by high glucose (HG) has not yet been elucidated and is the focus of this investigation. Using serial deletions of the full A2M promoter, we identified the −405 bp region as HG-responsive in MC. Site-directed mutagenesis, siRNA, and ChIP studies showed that the transcription factor, nuclear factor of activated T cells 5 (NFAT5), regulated A2M promoter activity and protein expression in response to HG. Forkhead box P1 (FOXP1) served as a cooperative binding partner for NFAT5, required for A2M upregulation. Lastly, we showed that Smad3, known for its role in kidney fibrosis, regulated A2M promoter activity and protein production independently of HG. The importance of NFAT5, FOXP1, and Smad3 in A2M regulation was confirmed in ex vivo studies using isolated glomeruli. In conclusion, Smad3 is required for basal and HG-induced A2M expression, while NFAT5 and FOXP1 cooperatively regulate increased A2M transcription in response to HG. Inhibition of NFAT5/FOXP1 will be further evaluated as a potential therapeutic strategy to inhibit A2M production and attenuate profibrotic signaling in DKD.