Types Of Chronic Kidney Disease Research Articles

A multi-center randomized controlled trial to investigate potential effects of exercise therapy on renal function stratified by renal disorders and renal pathology: beneficial or harmful effect in immunoglobulin a nephropathy.

The effects of exercise therapy (ET) on renal function in chronic kidney disease (CKD) remain unclear. In a randomized controlled trial (UMIN-CTR number: UMIN000038415), we investigated whether ET affects renal function in CKD; eligible patients had undergone renal biopsy in the past 3months. We stratified patients by disease (immunoglobulin A [IgA] nephropathy, n = 16; diabetic nephropathy, n = 4; benign nephrosclerosis, n = 13; and other CKD types, n = 13) and randomized them to 12weeks' observation and 24weeks' ET comprising home-based aerobic exercise 3×/week and resistance training 2×/week (intervention group) or usual care (non-intervention group). Primary endpoint was creatinine-based estimated glomerular filtration rate (eGFR) or serum cystatin C-based eGFR (eGFRcys). Secondary endpoints included urinary protein and exercise tolerance. Seventy patients were enrolled, 50 fulfilled the inclusion criteria, but 4 discontinued before randomization. No items significantly differed between week 0 to 24 in either group (intervention group, n = 23; non-intervention group, n = 23) or between groups at week 24 (intention-to-treat population) in the total study population. The eGFRcys slope showed no significant intergroup difference in the observation period, but eGFRcys improved significantly in IgA nephropathy patients (n = 16) in the intervention group (stratified comparison; week 0, 48.3 ± 18.2; week 24, 51.6 ± 17.6; p = 0.043). In these patients, urinary protein was significantly worse at week 24 in the non-intervention group (p = 0.046) and worsened significantly less in the intervention group (p = 0.039). ET did not improve renal function overall in CKD patients but might help maintain renal function in patients with IgA nephropathy.

Diosmin ameliorates renal fibrosis through inhibition of inflammation by regulating SIRT3-mediated NF-κB p65 nuclear translocation

BackgroundRenal fibrosis is considered an irreversible pathological process and the ultimate common pathway for the development of all types of chronic kidney diseases and renal failure. Diosmin is a natural flavonoid glycoside that has antioxidant, anti-inflammatory, and antifibrotic activities. However, whether Diosmin protects kidneys by inhibiting renal fibrosis is unknown. We aimed to investigate the role of Diosmin in renal interstitial fibrosis and to explore the underlying mechanisms.MethodsThe UUO mouse model was established and gavaged with Diosmin (50 mg/kg·d and 100 mg/kg·d) for 14 days. HE staining, Masson staining, immunohistochemistry, western blotting and PCR were used to assess renal tissue injury and fibrosis. Elisa kits were used to detect the expression levels of IL-1β, IL-6, and TNF-α and the activity of SIRT3 in renal tissues. In addition, enrichment maps of RNA sequencing analyzed changes in signaling pathways. In vitro, human renal tubular epithelial cells (HK-2) were stimulated with TGF-β1 and then treated with diosmin (75 μM). The protein and mRNA expression levels of SIRT3 were detected in the cells. In addition, 3-TYP (selective inhibitor of SIRT3) and SIRT3 small interfering RNA (siRNA) were used to reduce SIRT3 levels in HK-2.ResultsDiosmin attenuated UUO-induced renal fibrosis and TGF-β1-induced HK-2 fibrosis. In addition, Diosmin reduced IL-1β, IL-6, and TNF-α levels in kidney tissues and supernatants of HK-2 medium. Interestingly, Diosmin administration increased the enzymatic activity of SIRT3 in UUO kidneys. In addition, Diosmin significantly increased mRNA and protein expression of SIRT3 in vitro and in vivo. Inhibition of SIRT3 expression using 3-TYP or SIRT3 siRNA abolished the anti-inflammatory effects of diosmin in HK-2 cells. Enrichment map analysis by RNA sequencing indicates that the nuclear factor-kappa B (NF-κB) signaling pathway was inhibited in the Diosmin intervention group. Furthermore, we found that TGF-β1 increased the nuclear expression of nuclear NF-κB p65 but had little significant effect on the total intracellular expression of NF-κB p65. Additionally, Diosmin reduced TGF-β1-caused NF-κB p65 nuclear translocation. Knockdown of SIRT3 expression by SIRT3 siRNA increased the nuclear expression of NF-κB p65 and abolished the inhibition effect of Diosmin in NF-κB p65 expression.ConclusionsDiosmin reduces renal inflammation and fibrosis, which is contributed by inhibiting nuclear translocation of NF-κB P65 through activating SIRT3.

Identification of common and specific fibrosis-related genes in three common chronic kidney diseases

Background Kidney fibrosis is the common final pathway of virtually all advanced forms of chronic kidney disease (CKD) including diabetic nephropathy (DN), IgA nephropathy (IgAN) and membranous nephropathy (MN), with complex mechanism. Comparative gene expression analysis among these types of CKD may shed light on its pathogenesis. Therefore, we conducted this study aiming at exploring the common and specific fibrosis-related genes involved in different types of CKD. Methods Kidney biopsy specimens from patients with different types of CKD and normal control subjects were analyzed using the NanoString nCounter® Human Fibrosis V2 Panel. Genes differentially expressed in all fibrotic DN, IgAN and MN tissues compared to the normal controls were regarded as the common fibrosis-related genes in CKD, whereas genes exclusively differentially expressed in fibrotic DN, IgAN or MN samples were considered to be the specific genes related to fibrosis in DN, IgAN and MN respectively. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression of the selected genes. Results Protein tyrosine phosphatase receptor type C (PTPRC), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), interleukin 10 receptor alpha (IL10RA) and CC chemokine receptor 2 (CCR2) were identified as the potential common genes for kidney fibrosis in different types of CKD, while peroxisome proliferator-activated receptor alpha (PPARA), lactate oxidase (LOX), secreted phosphoprotein 1 (SPP1) were identified as the specific fibrosis-associated genes for DN, IgAN and MN respectively. qRT-PCR demonstrated that the expression levels of these selected genes were consistent with the NanoString analysis. Conclusions There were both commonalities and differences in the mechanisms of fibrosis in different types of CKD, the commonalities might be used as the common therapeutic targets for kidney fibrosis in CKD, while the differences might be used as the diagnostic markers for DN, IgAN and MN respectively. Inflammation was highly relevant to the pathogenesis of fibrosis. This study provides further insight into the pathophysiology and treatment of fibrotic kidney disease.

Abstract P372: Global Burden Of Chronic Kidney Disease Due To Hypertension In 38 Oecd Countries: A Benchmarking Analysis For The Global Burden Of Disease Study 2019

Background: Chronic Kidney Disease (CKD) due to hypertension (HTN) ranks as the leading cause of death among all types of CKD in Organization for Economic Cooperation and Development (OECD) countries. Method: Using the Global Burden of Disease methodology, CKD due to HTN prevalence, incidence, deaths, Disability adjusted life years were analyzed by age, sex, year across the 38 OECD countries between 1990-2019. Results: Total prevalence of CKD due to HTN doubled from 4933515 (95%UI4543,520-5382155) in 1990 to 10871399 (95%UI10055175-11754447) in 2019. Age-standardized incidence rate (ASIR) increased from 21/100000 in 1990 to 25/100000 in 2019. The highest ASMR was observed in Mexico (16/100000), ASIR in Turkey (36/100000) in 2019. The highest annual percentage of change (APC) increased in ASMR observed in Estonia 341% (0.8-3.6) per 100000 from 1990-2019. Conclusion: CKD due to HTN has remained a leading cause of deaths in OECD countries. The escalating prevalence of CKD due to HTN underscores the urgency for proactive strategies aimed at prevention, early detection, and effective management of HTN.

Abstract P126: The Single-cell And Spatial Transcriptional Landscape Of Advanced Diabetic And Hypertensive Kidney Disease In Humans

Diabetes and hypertension, the two most common causes of chronic kidney disease (CKD), can both lead to renal inflammation and fibrosis through a complex interplay among multiple cell types. However, the similarities and differences between the two pathogenic mechanisms remain understudied, including the involvement of cell organization and related biological processes. We generated an integrative cell landscape of CKD using single-nucleus gene expression and spatial transcriptome profiling in kidney samples from three patients with advanced diabetic nephropathy (ADN), three patients with advanced hypertensive nephropathy (AHN), and two normal controls. We obtained a total of 56,131 nuclei and 3,992 spatial spots to investigate the cell composition and the context of spatial niches. Significant hallmark changes were observed in both types of CKD, including the presence of an average of 60% (SD 12%) proximal tubule cells showing injured status, fibroblasts activation, mitochondria dysfunction, and a 2.9-fold increased inflammatory immune cell infiltration such as activated T cells and macrophages. Some alterations were more pronounced in AHN, such as a notable podocyte loss, which averaged 89% in AHN versus 66% in ADN, mesangial cell activation by increased collagen production, and a 34% higher proportion of natural killer T cells. Among the predominant cell communication, integrin coding gene ITGB8 was up-regulated in diseased thick ascending limbs (combined p.adj=2.3e-139) and injured proximal tubules (combined p.adj=4.4e-92), which acts as the receptor for collagen and laminin that may play a central role in extracellular matrix remodeling surrounding tubular cells. Additionally, the SPP1-CD44 axis established a broad connection between various tubular cells and pan-immune cells, potentially leading to the wide range of inflammatory responses. The co-localization pattern of this interaction was further supported by contextual evidence derived from spatial niches. Our findings provide a cell landscape of advanced diabetic and hypertensive CKD in humans, shedding light on the cellular and molecular basis of these diseases.

#4869 ULTRASOUND IMAGING PATTERNS OF KIDNEY DISEASE IN PATIENTS WITH METABOLIC SYNDROME

Abstract Background and Aims Meeting definition of metabolic syndrome (MetS) requires detection of central obesity (increasing waist circumference, WC) plus any two of the other four factors (hyperglycemia, dyslipidemia, cardiovascular disease, hypertension) [1]. Up to date, kidney evaluation is not fully reflected in MetS evaluation. Multiparameter ultrasound (US) can provide accurate information on every MetS sign [2] and for specific detecting type of chronic kidney disease (CKD) [3]. The Aim was to study added diagnostic value of ultrasound diagnosis of chronic kidney disease in patients with MetS for precise diagnosis and patients stratification. Method We included 48 overweight subjects patients (27-75 years; 25 women) with signs of MetS, BMI > 30, waist circumference (WC) > 110. The control group included 50 healthy individuals (26 women), mean age 43 ± 7 years without clinical, laboratory signs of MetS, nephropathy and liver pathology. All patients underwent general clinical, lab tests; abdominal US including precise multiparameter US of kidneys as in [3] measuring shear wave elastography (SWE), Doppler in parenchyma and vessels. We determined fat accumulations measuring VF and subcutaneous (SF) fat thickness (cm) and areas (cm2) on US. Results We detected hypertension (in 62%); hypercholesterolemia (in 45%); hyperuricemia (in 28%); hyperglycemia (in 32%); nephropathy (in 37%), portal hypertension (in 32%) in obese individuals (vs controls p < 0.05). In all patients we found increasing of visceral fat and various abnormalities in kidneys on US, we distinguished patterns in according to constituents of MetS by its definition s follows: Diabetic nephropathy included mild decresing or normal kidneys size, thinning parenchyma, low differentiation, clear smooth margings, Doppler showed mild decreasing velocities, increasing of RI in segmental arteries over 0.7 (Figure 1). Ischemic pattern associated with advanced atherosclerosis included severe decreasing of size, thinned, hyperechoic parenchyma; decreasing velocities under 25 cm/s., severe increasing of RI over 0.8. Hypertension associated nephropathy: mild changes in structure, normal velocities, increased RI (Figure 2). Hypertension correlated with levels of RI. Nephropathy in hyperuricemia and gout: signs as in [3] included thinning, increasing echogenicity of kidney parenchyma (P < 0.05), detection of fibrotic changes and small hyperechoic inclusions, hilly margins, anaechoic strips under the capsule, RI increasing in segmental arteries over 0.7. “Circular pyramyds pattern” included hyoerechoic circles around pyramids (white pyramid sign, hyperdense renal pyramids sign) with normal size, normal / mild increase of RI. SWE showed increased parenchyma stiffness to 10 ± 1.7 kPa (6–17 kPa) versus 4.2 ± 1.2 kPa (P < .05), showed differences among patterns, highest values were in nephropathy in gout and ischemia. Conclusion Multiparameter ultrasound is effective for detecting and distinguishing patterns of kidney disease in MetS provides additional value for differentiation and modification treatment and targeted prevention. Kidney involvement should be considered in management of MetS.

The effects of cold region meteorology and specific environment on the number of hospital admissions for chronic kidney disease: An investigate with a distributed lag nonlinear model

Abstract Objective To explore the effects of daily mean temperature (°C), average daily air pressure (hPa), humidity (%), wind speed (m/s), particulate matter (PM) 2.5 (μg/m3) and PM10 (μg/m3) on the admission rate of chronic kidney disease (CKD) patients admitted to the Second Affiliated Hospital of Harbin Medical University in Harbin and to identify the indexes and lag days that impose the most critical influence. Methods The R language Distributed Lag Nonlinear Model (DLNM), Excel, and SPSS were used to analyze the disease and meteorological data of Harbin from 01 January 2010 to 31 December 2019 according to the inclusion and exclusion criteria. Results Meteorological factors and air pollution influence the number of hospitalizations of CKD to vary degrees in cold regions, and differ in persistence or delay. Non-optimal temperature increases the risk of admission of CKD, high temperature increases the risk of obstructive kidney disease, and low temperature increases the risk of other major types of chronic kidney disease. The greater the temperature difference is, the higher its contribution is to the risk. The non-optimal wind speed and non-optimal atmospheric pressure are associated with increased hospital admissions. PM2.5 concentrations above 40 μg/m3 have a negative impact on the results. Conclusion Cold region meteorology and specific environment do have an impact on the number of hospital admissions for chronic kidney disease, and we can apply DLMN to describe the analysis.

Urine Metabolomic Signature of People Diagnosed with Balkan Endemic Nephropathy and Other Types of Chronic Kidney Disease Compared with Healthy Subjects in Romania

Metabolomic analysis methods were employed to determine biomarkers for various chronic kidney diseases (CKDs). Modern analytical methods were developed and applied successfully to find a specific metabolomic profile in urine samples from CKD and Balkan endemic nephropathy (BEN) patients. The aim was to explore a specific metabolomic profile defined by feasible/easy-to-identify molecular markers. Urine samples were collected from patients with CKDs and BEN, and from healthy subjects from endemic and nonendemic areas in Romania. Metabolomic analysis of urine samples, extracted by the liquid-liquid extraction (LLE) method, was performed by gas chromatography-mass spectrometry (GC-MS). The statistical exploration of the results was performed through a principal component analysis (PCA) evaluation. Urine samples were statistically analyzed using a classification based on six types of metabolites. Most urinary metabolites are distributed in the center of a loading plot, meaning that these compounds do not represent significant markers for BEN. One of the most frequent and higher-concentration urinary metabolites in BEN patients was p-Cresol, a phenolic compound that implies a severe injury of the renal filtration function. The presence of p-Cresol was associated with protein-bound uremic toxins, which have specific functional groups such as indole and phenyl. In prospective studies for future investigation, prevention, and disease treatment, we suggest a larger sample size, sample extraction using other methods, and analysis using other chromatography techniques coupled with mass spectrometry, which can generate a more significant data set for statistical analysis.

The Long-Term Survival Outcome in Older Patients with Different Pathological Types of Chronic Kidney Disease

Introduction: Chronic kidney diseases (CKDs) are prevalent in older people, and renal pathological manifestations are important for diagnosis, treatment, and prognosis. However, the long-term survival outcome and risk factors for older CKD patients with different pathological types are not fully understood and need to be further investigated. Methods: Medical data were recorded and all-cause mortality was followed up in patients who underwent renal biopsy diagnosed in Guangdong Provincial People’s Hospital from 2005 to 2015. Kaplan-Meier analysis was used to identify the incidence of survival outcomes. Multivariate Cox regression models and nomograms were applied to analyze pathological types and other factors for overall survival outcomes. Results: 368 cases were included and the median follow-up was 85 (46.5, 111) months. Overall mortality was 35.6%. The highest mortality was in the mesangioproliferative glomerulonephritis (MPGN) group (88.9%), followed by amyloidosis (AMY) group (84.6%), and the lowest mortality was in the minimal change disease (MCD) group (21.9%). Moreover, multivariate Cox regression model showed that survival times of MPGN {hazard ratio (HR) = 8.215 (95% confidence interval [CI]: 2.735–24.674), p < 0.001} and AMY (HR = 6.130 [95% CI: 2.219–16.94], p < 0.001) were significantly shorter than MCD. In addition, age, lower baseline estimated glomerular filtration rate (eGFR), history of chronic obstructive pulmonary disease (COPD) and cerebrovascular accidents (CVA)/transient ischemic attack (TIA), MPGN, and AMY were independent risk factors for the mortality of older patients with CKD. Conclusion: The long-term survival outcome of older CKD patients showed differences among different pathological types, and MPGN, AMY, age, baseline eGFR, CVA/TIA, and COPD were independent predictors for mortality.

Characteristics of Acupoint Selection and Therapeutic Effect Analysis of Acupuncture Treatment for Patients with Chronic Kidney Disease.

The therapeutic effect of acupuncture treatment on chronic kidney disease (CKD) was assessed, and the characteristics of acupoint selection in different CKD types were summarised. A total of 100 patients with CKD were enrolled in this retrospective cohort study, of whom 50 received acupuncture treatment for 12 weeks (acupuncture group) and 50 received routine treatment for 12 weeks (control group). Routine treatment included appropriate rest, low-salt and low-protein diet and correction of the disturbance in water, electrolyte and acid-base balance. Hypertensive patients received antihypertensive treatment, and patients with hyperuricaemia received uric acid lowering treatment. Acupuncture acupoints were selected in accordance with traditional Chinese medicine (TCM) theory. Baseline characteristics, therapeutic effects and adverse events were assessed, and kidney function indexes, urine albumin creatine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were compared at different time points (before acupuncture treatment, T1; Immediately after acupuncture treatment, T2; After 3 months of follow-up, T3). The baseline data were slightly different between the groups (p > 0.05), specifically gender, age, duration time, TCM syndrome, CKD stage, systolic blood pressure (SBP), diastolic blood pressure (DBP), and cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). The acupuncture group presented better therapeutic effects than the control group (82.00% vs. 60.00%, p = 0.015). At T2 or T3, the value of UACR in both groups obviously decreased (p < 0.05), whereas the eGFRs markedly increased (p < 0.05). In addition, at T2 or T3, the UACRs were significantly lower in the acupuncture group than in the control group (p < 0.01), whereas an opposite result was obtained for eGFR (p < 0.05). The adverse event rate barely differed between the groups (8.00% vs. 6.00%, p = 0.695). Acupuncture treatment can effectively treat CKD and can improve kidney function. This study provides a theoretical basis for clinical application.

Endoglin Is an Important Mediator in the Final Common Pathway of Chronic Kidney Disease to End-Stage Renal Disease.

Chronic kidney disease (CKD) is a slow-developing, progressive deterioration of renal function. The final common pathway in the pathophysiology of CKD involves glomerular sclerosis, tubular atrophy and interstitial fibrosis. Transforming growth factor-beta (TGF-β) stimulates the differentiation of fibroblasts towards myofibroblasts and the production of extracellular matrix (ECM) molecules, and thereby interstitial fibrosis. It has been shown that endoglin (ENG, CD105), primarily expressed in endothelial cells and fibroblasts, can function as a co-receptor of TGF signaling. In several human organs, endoglin tends to be upregulated when chronic damage and fibrosis is present. We hypothesize that endoglin is upregulated in renal interstitial fibrosis and plays a role in the progression of CKD. We first measured renal endoglin expression in biopsy samples obtained from patients with different types of CKD, i.e., IgA nephropathy, focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN) and patients with chronic allograft dysfunction (CAD). We showed that endoglin is upregulated in CAD patients (p &lt; 0.001) and patients with DN (p &lt; 0.05), compared to control kidneys. Furthermore, the amount of interstitial endoglin expression correlated with eGFR (p &lt; 0.001) and the amount of interstitial fibrosis (p &lt; 0.001), independent of the diagnosis of the biopsies. Finally, we investigated in vitro the effect of endoglin overexpression in TGF-β stimulated human kidney fibroblasts. Overexpression of endoglin resulted in an enhanced ACTA2, CCN2 and SERPINE1 mRNA response (p &lt; 0.05). It also increased the mRNA and protein upregulation of the ECM components collagen type I (COL1A1) and fibronectin (FN1) (p &lt; 0.05). Our results suggest that endoglin is an important mediator in the final common pathway of CKD and could be used as a possible new therapeutic target to counteract the progression towards end-stage renal disease (ESRD).

Sodium-glucose cotransporter inhibitors and kidney fibrosis: review of the current evidence and related mechanisms.

Sodium-glucose cotransporter inhibitors (SGLT2i) are a new class of anti-diabetic drugs that have beneficial cardiovascular and renal effects. These drugs decrease proximal tubular glucose reabsorption and decrease blood glucose levels as a main anti-diabetic action. Furthermore, SGLT2i decreases glomerular hyperfiltration by a tubuloglomerular feedback mechanism. However, the renal benefits of these agents are independent of glucose-lowering and hemodynamic factors, and SGLT2i also impacts the kidney structure including kidney fibrosis. Renal fibrosis is a common pathway and pathological marker of virtually every type of chronic kidney disease (CKD), and amelioration of renal fibrosis is of utmost importance to reduce the progression of CKD. Recent studies have shown that SGLT2i impact many cellular processes including inflammation, hypoxia, oxidative stress, metabolic functions, and renin-angiotensin system (RAS) which all are related with kidney fibrosis. Indeed, most but not all studies showed that renal fibrosis was ameliorated by SGLT2i through the reduction of inflammation, hypoxia, oxidative stress, and RAS activation. In addition, less known effects on SGLT2i on klotho expression, capillary rarefaction, signal transducer and activator of transcription signaling and peptidylprolyl cis/trans isomerase (Pin1) levels may partly explain the anti-fibrotic effects of SGLT2i in kidneys. It is important to remember that some studies have not shown any beneficial effects of SGLT2i on kidney fibrosis. Given this background, in the current review, we have summarized the studies and pathophysiologic aspects of SGL2 inhibition on renal fibrosis in various CKD models and tried to explain the potential reasons for contrasting findings.

Bacteroides plebeius improves muscle wasting in chronic kidney disease by modulating the gut-renal muscle axis.

Chronic kidney disease (CKD) affects approximately 10% of the global population. Muscle atrophy occurs in patients with almost all types of CKD, and the gut microbiome is closely related to protein consumption during chronic renal failure (CRF). This study investigated the effects of Bacteroides plebeius on protein energy consumption in rats with CKD, and our results suggest that Bacteroides plebeius may combat muscle atrophy through the Mystn/ActRIIB/SMAD2 pathway. A total of 5/6 Nx rats were used as a model of muscle wasting in CKD. The rats with muscle wasting were administered Bacteroides plebeius (2 × 108 cfu/0.2 ml) for 8 weeks. The results showed that Bacteroides plebeius administration significantly inhibited muscle wasting in CKD. High-throughput 16 S rRNA pyrosequencing revealed that supplementation with Bacteroides plebeius rescued disturbances in the gut microbiota. Bacteroides plebeius could also enhance the barrier function of the intestinal mucosa. Bacteroides plebeius may modulate the gut microbiome and reduce protein consumption by increasing the abundance of probiotics and reducing damage to the intestinal mucosal barrier. Our findings suggest that Bacteroides plebeius may combat muscle atrophy through the Mystn/ActRIIB/SMAD2 pathway.

Renal tubular epithelial cell necroptosis promotes tubulointerstitial fibrosis in patients with chronic kidney disease.

Renal fibrosis, a common pathological manifestation of virtually all types of chronic kidney disease (CKD), ultimately predisposes patients to end-stage renal disease. However, there is no effective therapy for renal fibrosis. Our earlier studies proved that RIP3-mediated necroptosis might be an important mode of renal tubular cell death in rats with chronic renal injury. Under transmission electron microscopy (TEM), we found morphological changes in the necrosis of human renal tissue, and the percentage of necrotic cells increased significantly in patients with stages 2 and 3a CKD. Immunofluorescence analyses showed that the percentages of TUNEL+ /RIP3+ double-positive and TUNEL+ /MLKL+ double-positive tubular epithelial cells in renal tubules of patients with stages 2 and 3a CKD were significantly increased compared to those in control patients without renal disease. Immunohistochemistry analyses of renal biopsy specimens from patients with CKD revealed RIP3, MLKL, and p-MLKL upregulation in patients with stages 2 and 3a CKD, suggesting that necroptosis of renal tubular epithelial cells in CKD patients occurs, and the peak of necroptosis was in stages 2 and 3a CKD. We showed that profibrotic factor proteins (TGF-β1, Smad2 and Smad3) and fibroblast activation markers (α-SMA and Vimentin) were specifically upregulated in stage 2 and 3a CKD patients. In addition, Pearson correlation analysis showed that the percentage of necroptotic renal tubular epithelial cells was positively correlated with TGF-β1 and collagen-I. We also showed that RIP1/3 or MLKL inhibitors decreased the expression of RIP3, MLKL, TGF-β1, and Smad3 in HK-2 cells treated with TNF-α. FGF-2, α-SMA, Vimentin and FN were overexpressed in the hRIFs cultured with the supernatant of necroptotic HK-2 cells, whereas necroptosis blockers (Nec-1s, GSK'872 and NSA) and TGF-β1/Smad3 pathway antagonists (LY364947 and SIS3) reduced FGF-2, α-SMA, Vimentinand FN levels. Collectively, necroptosis of renal tubular epithelial cells in CKD patients occurs, and the peak of necroptosis was in stages 2 and 3a CKD. Renal tubular epithelial cell necroptosis mediates renal tubulointerstitial fibrosis in patients with chronic kidney disease, which is related to the TGF-β1/Smad3 signaling pathway.

The Smad3-dependent microRNA let-7i-5p promoted renal fibrosis in mice with unilateral ureteral obstruction.

Renal fibrosis is a common feature of all types of chronic kidney disease (CKD) and is tightly regulated by the TGF-β/Smad3 pathway. Let-7i-5p belongs to the let-7 microRNA family with diverse biological functions. It has been reported that let-7i-5p suppresses fibrotic disease in the heart, lungs, and blood vessels, while the role of let-7i-5p in renal fibrosis remains limited. In this study, we aimed to investigate the role of let-7i-5p in renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) and TGF-β1–stimulated renal tubular cell line TCMK1. The RNA-targeting CRISPR/Cas13d system was used to knock down let-7i-5p. Renal injury and fibrosis were determined by histological analysis, RT-PCR, Western blot, and immunostaining. Our results have shown that in the kidneys after UUO, the expression of let-7i-5p was significantly increased along with notable tubular injury and interstitial fibrosis. Electroporation of let-7i–targeting Cas13d plasmid efficiently knocked down let-7i-5p in kidneys after UUO with reduced tubular injury, fibrotic area, and expression of fibrotic marker genes α-SMA, fibronectin, and Col1a1. In TGF-β1–stimulated TCMK1 cells, knockdown of let-7i-5p by Cas13d plasmid transfection also blunted the expression of fibrotic marker genes. Most importantly, the genomic locus of let-7i showed enriched binding of Smad3 as revealed by chromatin immunoprecipitation. In TCMK1 cells, the overexpression of Smad3 can directly induce the expression of let-7i-5p. However, the deletion of Smad3 abolished TGF-β1–stimulated let-7i-5p expression. Collectively, these findings suggest that let-7i-5p is a Smad3-dependent microRNA that plays a pathogenic role in renal fibrosis. Let-7i-5p could be a promising target for the treatment of CKD-associated renal fibrosis.

Plasma Galectin-9 Is a Useful Biomarker for Predicting Renal Function in Patients Undergoing Native Kidney Biopsy.

Galectin-9 reduces tissue damage in certain immune-mediated glomerular diseases. However, its role in structural and functional renal changes in patients with varying types of chronic kidney disease (CKD) is less clear. To investigate the association between plasma galectin-9 levels, proteinuria, tubulointerstitial lesions, and renal function in different CKD stages. We measured plasma galectin-9 levels in 243 patients undergoing renal biopsy for determining the CKD etiology. mRNA and protein expression levels of intrarenal galectin-9 were assessed by quantitative real-time polymerase chain reaction and immunostaining. Relationships between plasma galectin-9, clinical characteristics, and tubulointerstitial damage were analyzed with logistic regression. We investigated galectin-9 expression patterns in vitro in murine J774 macrophages treated with differing stimuli. To analyze the relationship between galectin-9 and clinical features, we divided the patients into 2 groups according to median plasma galectin-9 levels. The high galectin-9 group tended to be older and to have decreased renal function, higher proteinuria, and greater interstitial fibrosis. After multivariable adjustment, elevated plasma galectin-9 levels were independently associated with stage 3b or higher CKD. An analysis of gene expression in the tubulointerstitial compartment in the biopsy samples showed a significant positive correlation between intrarenal galectin-9 mRNA expression and plasma galectin-9 levels. Immunohistochemistry confirmed increased galectin-9 expression in the renal interstitium of patients with advanced CKD, and most galectin-9-positive cells were macrophages, as determined by double-immunofluorescence staining. In vitro experiments showed that galectin-9 expression in macrophages was significantly increased after interferon-γ stimulation. Our findings suggest that plasma galectin-9 is a good biomarker for diagnosing advanced CKD.

THIRSTY FOR FRUCTOSE: Arginine Vasopressin, Fructose, and the Pathogenesis of Metabolic and Renal Disease.

We review the pathways by which arginine vasopressin (AVP) and hydration influence the sequelae of the metabolic syndrome induced by high fructose consumption. AVP and inadequate hydration have been shown to worsen the severity of two phenotypes associated with metabolic syndrome induced by high fructose intake–enhanced lipogenesis and insulin resistance. These findings have implications for those who frequently consume sweeteners such as high fructose corn syrup (HFCS). Patients with metabolic syndrome are at higher risk for microalbuminuria and/or chronic kidney disease; however, it is difficult to discriminate the detrimental renal effects of the metabolic syndrome from those of hypertension, impaired glucose metabolism, and obesity. It is not surprising the prevalence of chronic renal insufficiency is growing hand in hand with obesity, insulin resistance, and metabolic syndrome in those who consume large amounts of fructose. Higher AVP levels and low hydration status worsen the renal insufficiency found in patients with metabolic syndrome. This inter-relationship has public health consequences, especially among underserved populations who perform physical labor in environments that place them at risk for dehydration. MesoAmerican endemic nephropathy is a type of chronic kidney disease highly prevalent in hot ambient climates from southwest Mexico through Latin America. There is growing evidence that this public health crisis is being spurred by greater fructose consumption in the face of dehydration and increased dehydration-dependent vasopressin secretion. Work is needed at unraveling the mechanism(s) by which fructose consumption and increased AVP levels can worsen the renal disease associated with components of the metabolic syndrome.

Corni Fructus Alleviates UUO-Induced Renal Fibrosis via TGF-β/Smad Signaling.

Renal fibrosis is a type of chronic kidney disease (CKD) induced by infiltration of inflammatory cells, myofibroblast accumulation, and ECM production in the kidney. From a long time ago, Corni Fructus (CF) is known to supplement the liver and kidney with its tepid properties. In this study, we investigated the renal protective mechanism of CF, which is known to supplement the kidney, in rat model of unilateral ureteral obstruction (UUO). After inducing UUO through surgery, the group was separated (n = 8) and the drug was administered for 2 weeks; normal rats (normal), water-treated UUO rats (control), CF 100 mg/kg-treated UUO rats (CF100), and CF 200 mg/kg-treated UUO rats (CF200). As a result of histopathological examination of kidney tissue with H&E, MT, and PAS staining, it was confirmed that the infiltration of inflammatory cells and the erosion of collagen were relatively decreased in the kidneys treated with CF. Also, CF significantly reduced the levels of MDA and BUN in serum. As a result of confirming the expression of the factors through western blotting, CF treatment significantly reduced the expression of NADPH oxidase and significantly regulated the AMPK/LKB1/NF-κB pathway associated with inflammation. In addition, it downregulated the expression of major fibrotic signaling factors, such as α-SMA, collagen I, MMP-2, and TIMP-1, and significantly regulated the TGF-β1/Smad pathway, which is known as a major regulator of renal fibrosis. Taken together, these findings indicate that CF can alleviate renal fibrosis by regulating the TGF-β1/Smad pathway through inhibition of oxidative stress in UUO.

Imbalance of circulating innate lymphoid cell subpopulations in patients with chronic kidney disease

Innate lymphoid cells (ILCs) are a newly identified heterogeneous family of innate immune cells. We conducted this study to investigate the frequency of circulating ILC subsets in various chronic kidney diseases (CKD). In DN, the proportion of total ILCs and certain ILC subgroups increased significantly. Positive correlations between proportion of total ILCs, ILC1s and body mass index, glycated hemoglobin were observed in DN. In LN, a significantly increased proportion of ILC1s was found in parallel with a reduced proportion of ILC2s. The proportions of total ILCs and ILC1s were correlated with WBC count and the level of C3. In all enrolled patients, the proportion of total ILCs and ILC1s was significantly correlated with the levels of ACR and GFR. In the present study, the proportion of circulating ILC subsets increased significantly in various types of CKD and correlated with clinico-pathological features, which suggests a possible role for ILCs in CKD.

Efficacy and safety of Abelmoschus manihot in treating chronic kidney diseases: A multicentre, open-label and single-arm clinical trial

Rationale and objectiveThe efficacy of Abelmoschus manihot (AM) in treating of chronic kidney disease (CKD) has been confirmed by prior trials. AM is also commonly combined to other medicines among CKD patients in clinic. This trial aimed at evaluating the safety of AM combination application, and further verifying the efficacy of AM in treating various types of CKD. Study designA multicentre, prospective, open-label, single-arm trial Setting and participantsApproximately 2000 CKD patients with proteinuria (≥ 150 mg/d), from 105 centres across China InterventionsAM was administered to patients three times per day for 24 weeks: the daily dose was based on age (> 12 years old: 2.5 g tid; 6∼12 years old: 1.5 g tid; 2∼6 years old: 1 g tid) OutcomesThe efficacy outcomes were the change in 24-hour proteinuria and estimated glomerular filtration rate (eGFR) from baseline to week 24. Safety outcomes included adverse events and laboratory tests. Results2054 CKD patients from 105 centres were enrolled in this trial, with 1843 (89.7%) completing the 24-week follow-up. The participants’ median age was 44 years old and 44.6% were female. Compared to baseline, 24-hour proteinuria decreased 471 mg (95% confident interval, 367 to 575, p < 0.001) at week 24. eGFR did not change significantly relative to baseline with the mean increase as 1.7 ml/min/1.73 m2 (95% confident interval, -0.3 to 3.7, p = 0.09). 902 (43.9%) participants combined medication to AM during follow-up. The total incidence of adverse events was 12.9%; and the most common adverse events were hyperlipidaemia (4.1%), abnormal liver function (2.3%), upper respiratory infection (1.8%), and hyperglycaemia (1.1%). Combined medications did not change the risk for hyperlipidaemia and upper respiratory infection. The combination application with antiplatelet reagents increased the risk of abnormal liver function, and with calcium channel blockers increased the risk of hyperglycaemia. LimitationsSingle-arm clinical trial and short observation time ConclusionWe have provided safety information of AM on various types of CKD in a large trial, especially when combination to medications most commonly prescribed to CKD patients. AM also showed to decrease proteinuria with stable kidney function during follow up. AM is a promising treatment for CKD patients.