Mass spectrometry-based proteomic analysis of proteins adsorbed by hexadecyl-immobilized cellulose bead column for the treatment of dialysis-related amyloidosis.

BACKGROUND: Dialysis-related amyloidosis (DRA) is a severe complication in end-stage kidney disease (ESKD) patients undergoing long-term dialysis treatment, characterized by the deposition of ß2-microglobulin-related amyloids (Aß2M amyloid). To inhibit DRA progression, hexadecyl-immobilized cellulose bead (HICB) columns are employed to adsorb circulating ß2-microglobulin (ß2M). However, it is possible that the HICB also adsorbs other molecules involved in amyloidogenesis. METHODS: We enrolled 14 ESKD patients using HICB columns for DRA treatment; proteins were extracted from HICBs following treatment and identified using liquid chromatography-linked mass spectrometry. We measured the removal rate of these proteins and examined the effect of those molecules on Aß2M amyloid fibril formation in vitro. RESULTS: We identified 200 proteins adsorbed by HICBs. Of these, 21 were also detected in the amyloid deposits in the carpal tunnels of patients with DRA. After passing through the HICB column and hemodialyzer, the serum levels of proteins such as ß2M, lysozyme, angiogenin, complement factor D and matrix Gla protein were reduced. These proteins acted in the Aß2M amyloid fibril formation. CONCLUSIONS: HICBs adsorbed diverse proteins in ESKD patients with DRA, including those detected in amyloid lesions. Direct hemoperfusion utilizing HICBs may play a role in acting Aß2M amyloidogenesis by reducing the amyloid-related proteins.

Renal transcriptome analysis of uninephrectomized db/db mice identified a mechanism for the transition to severe diabetic nephropathy.

Diabetic nephropathy (DN), included in diabetic kidney disease (DKD), is a primary driver of end-stage renal disease (ESRD) leading to dialysis treatment. To develop new therapeutic drugs to prevent ESRD and avoid dialysis treatment, insight into DKD pathophysiology and animal models suitable for drug efficacy testing are needed. In this study, transcriptome analysis of kidneys from 26-week-old and 35-week-old uninephrectomized (UNX) db/db mice was used to identify the pathways that affect the deterioration of renal function in db/db mice. Differentially expressed genes suggested that there was increased interferon (IFN)-γ signaling during the 26 to 35-week period. Modules that changed between 26 and 35 weeks of age extracted by weighted gene co-expression network analysis (WGCNA) suggested increased the tumor necrosis factor (TNF)-α and nuclear factor-kappa B (NF-κB) signaling pathway in component cells of glomeruli. The protein-protein interaction (PPI) network analysis identified Cxcl16 as a hub gene for those signaling pathways, and it was shown that the pathways in this module changed when the glomerular filtration rate decreased in patients with DN. These results suggested the possibility that signaling mediated by Cxcl16 induced by IFN-γ and TNF-α between 26 and 35 weeks of age leads to renal fibrosis, resulting in severe disease. Drugs that target such pathways can be options for developing drugs for DN. We also think that the uninephrectomized db/db mouse can be used as an animal model of severe DKD and to evaluate efficacy in patients with DN.

End-stage kidney disease: a never healing wound leading to another never healing wound, renal cancer.

BACKGROUND: End-stage kidney disease and acquired cystic kidney disease are the final stages of chronic kidney disease, leading to loss of kidney function and frequent development of tumours. It has been suggested that an inflammatory microenvironment may be responsible for the progressive kidney remodelling and cancer development. METHODS: Our aim was to analyse gene expression suggested to be involved in the remodelling of kidneys in end-stage kidney disease, and in the development of preneoplastic lesions and tumours. Immunohistochemistry was employed to assess the cellular localisation of different genes involved in these pathways on representative tissue sections. RESULTS: Cellular (αSMA positive naïve activated fibroblasts, endothelial cells, macrophages) and non-cellular components (cytokines IL6, TGFß, IL1ß, CSF2, fibronectin, laminin, and matrix modifier proteases MMP9 and MMP12) of the inflammatory microenvironment were expressed in the kidneys of patients with end-stage kidney disease. IL6 and FN1 expressing naïve activated fibroblasts and recruited inflammatory cells were the most abundant cellular components of the inflammatory microenvironment. CONCLUSION: The progressive inflammatory and fibrotic processes in end-stage kidney disease have features recalling those of  a never healing wound and may explain the frequent development of kidney cancer.

The Interplay of Autophagy and Oxidative Stress in the Kidney: What Do We Know?

BACKGROUND: Autophagy, as an indispensable metabolism, plays pivotal roles in maintaining intracellular homeostasis. Nutritional stress, amino acid deficiency, oxidative stress, and hypoxia can trigger its initiation. Oxidative stress in the kidney activates essential signal molecules, like mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK), and silent mating-type information regulation 2 homolog-1 (SIRT1), to stimulate autophagy, ultimately leading to degradation of intracellular oxidative substances and damaged organelles. Growing evidence suggests that autophagy protects the kidney from oxidative stress during acute ischemic kidney injury, chronic kidney disease, and even aging. SUMMARY: This review emphasizes the cross talk between reactive oxygen species (ROS) signaling pathways and autophagy during renal homeostasis and chronic kidney disease according to the current latest research and provides therapeutic targets during kidney disorders by adjusting autophagy and suppressing oxidative stress. KEY MESSAGES: ROS arise through an imbalance of oxidation and antioxidant defense mechanisms, leading to impaired cellular and organ function. Targeting the overproduction of ROS and reactive nitrogen species, reducing the antioxidant enzyme activity and the recovery of the prooxidative-antioxidative balance provide novel therapeutic regimens to contribute to recovery in acute and chronic renal failure. Although, in recent years, great progress has been made in understanding the molecular mechanisms of oxidative stress and autophagy in acute and chronic renal failure, the focus on clinical therapies is still in its infancy. The growing number of studies on the interactive mechanisms of oxidative stress-mediated autophagy will be of great importance for the future treatment and prevention of kidney diseases.

Expression pattern of peritoneum IL-6 is associated with baseline peritoneal transport function in uremic patients before dialysis.

OBJECTIVE: This study aimed to investigate the biological factors associated with baseline peritoneal transport in uremic patients before dialysis. METHODS: Thirty patients with uremia were grouped according to their peritoneal dialysate creatinine/serum creatinine ratio (D/P) as high-transport (H, 16 cases) with D/P>0.65 and low-transport (L, 14 cases) with D/P≤0.65 one month after continuous ambulatory peritoneal dialysis treatment. Multi-inflammatory levels such as serum IL-6 and albumin, peritoneal IL-6 level, and microvessel density (MVD) of visceral peritoneal were compared and correlated between the two groups to determine the associated factors. RESULTS: There were no significant differences in clinical parameters between the two groups (p < 0.05). There were no significant differences in serum IL-6 and albumin between the two groups. However, peritoneal IL-6 and MVD in group H were significantly higher than group L (p=0.012, p=0.044), and they were positively correlated (r=0.368, p=0.045). Furthermore, baseline D/P was positively correlated with IL-6 expressions (r=0.640, p=0.000) and peritoneal MVD (r=0.476, p=0.008), and independently associated with peritoneal IL-6 expression (p=0.004). CONCLUSIONS: The baseline peritoneal transport performance is associated with peritoneal IL-6 expression and MVD but not circulatory IL-6.

Study on the Relationship Between Peritoneal Dialysis Ultrafiltration Failure and Aquaporin 1, Aquaporin 3, and Vascular Endothelial Growth Factor A Expression.

INTRODUCTION: The aim of this study was to investigate the expression of aquaporin 1 (AQP-1), AQP-3 and vascular endothelial growth factor A (VEGF-A) in peritoneal tissues of patients without kidney disease, chronic kidney disease at stages 5 (CKD 5) and patients on prolonged peritoneal dialysis with ultrafiltration failure (PDUFF), and elucidate the possible mechanism of peritoneal dialysis ultrafiltration failure. METHODS: Peritoneal specimens were collected from the following patient groups at Xianju People's hospital: CKD 5, PD-UFF and normal control groups. Routine staining and immunohistochemical analyses were performed on samples obtained from the three groups. RESULTS: The expression of AQP-1 and AQP-3 on peritoneal mesothelial cells, peritoneal vessels and in the interstitium was significantly lower in the PD-UFF group than the CKD 5 and control groups (P < .01), while no statistically significant difference was found between the CKD 5 and control groups (P > .05). In contrast, VEGF-A expression was significantly higher in peritoneal mesothelial cells, peritoneal vessels and the interstitium in the PD-UFF group than the CKD 5 and control groups (P < .01). No statistically significant difference was found between the CKD 5 and control groups (P > .05). CONCLUSION: AQP-1 and AQP-3 expression levels decrease in peritoneal mesothelial cells and the vascular interstitium of patients with a prolonged peritoneal dialysis course, while VEGF-A expression gradually increases. The formation of peritoneal neovascularization and the decrease in AQP expression may be primarily associated with peritoneal dialysis ultrafiltration failure.  DOI: 10.52547/ijkd.6928.

Disruption of mitochondrial functions involving mitochondrial permeability transition pore opening caused by maleic acid in rat kidney.

Propionic acid (PA) predominantly accumulates in tissues and biological fluids of patients affected by propionic acidemia that may manifest chronic renal failure along development. High urinary excretion of maleic acid (MA) has also been described. Considering that the underlying mechanisms of renal dysfunction in this disorder are poorly known, the present work investigated the effects of PA and MA (1-5 mM) on mitochondrial functions and cellular viability in rat kidney and cultured human embryonic kidney (HEK-293) cells. Mitochondrial membrane potential (∆ψm), NAD(P)H content, swelling and ATP production were measured in rat kidney mitochondrial preparations supported by glutamate or glutamate plus malate, in the presence or absence of Ca2+. MTT reduction and propidium iodide (PI) incorporation were also determined in intact renal cells pre-incubated with MA or PA for 24 h. MA decreased Δψm and NAD(P)H content and induced swelling in Ca2+-loaded mitochondria either respiring with glutamate or glutamate plus malate. Noteworthy, these alterations were fully prevented by cyclosporin A plus ADP, suggesting the involvement of mitochondrial permeability transition (mPT). MA also markedly inhibited ATP synthesis in kidney mitochondria using the same substrates, implying a strong bioenergetics impairment. In contrast, PA only caused milder changes in these parameters. Finally, MA decreased MTT reduction and increased PI incorporation in intact HEK-293 cells, indicating a possible association between mitochondrial dysfunction and cell death in an intact cell system. It is therefore presumed that the MA-induced disruption of mitochondrial functions involving mPT pore opening may be involved in the chronic renal failure occurring in propionic acidemia.

Hirudin Regulates Vascular Function in Chronic Renal Failure through Modulating Macrophage Polarization.

Excessive inflammation is responsible for arteriovenous fistula (AVF) failure, which determines the therapeutic effect of chronic renal failure (CRF). Macrophage polarization is of great significance in the inflammatory response. Hirudin (Hiru) has been reported to possess a definite anti-inflammatory effect. This study is to uncover the impacts of Hiru on classically (M1)/alternatively (M2) macrophage polarization in the CRF rat model and rat vascular smooth muscle cells (VSMCs). After the CRF rat model was administrated with different concentrations of Hiru, blood urea nitrogen (BUN) and serum creatinine (Scr) levels were tested. H&E staining was to detect vascular injury, and IHC assay was to analyze inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) expressions in vascular tissues. Levels of inflammatory factors were examined by ELISA. Besides, western blot was to estimate the levels of marker proteins related to macrophage, proliferation, and apoptosis. CCK-8 was to measure cell viability. We discovered that Hiru alleviated renal function injury and vascular injury, exacerbated VSMC hyperplasia, and stimulated the differentiation and activation of M1 macrophage towards M2 macrophage in vivo. Moreover, after treatment with lipopolysaccharide (LPS)/IFN-gamma (IFN-γ), the increased M1/M2 ratio and enhanced levels of inflammatory factors were observed. Furthermore, Hiru boosted the proliferation and ameliorated the inflammatory response and apoptosis of rat VSMCs during the process of coincubation of M1-conditioned medium (CM). Collectively, Hiru played a protective role against vascular injury in CRF directly or through its influence on M1 macrophage polarization and inflammation.

Quercetin regulates vascular endothelium function in chronic renal failure via modulation of Eph/Cav-1 signaling.

Arteriovenous fistula (AVF) is frequently believed to be the best vascular access for chronic renal failure (CRF) patients. Vascular endothelial cell dysfunction has been implicated in AVF maturation. Quercetin (Quer) is a natural polyphenolic compound widely used in traditional Chinese medicine. We aimed to uncover the impacts of Quer on vascular endothelial cells in a CRF rat model and human umbilical vein endothelial cells (HUVECs) stimulated by lipopolysaccharide (LPS) and serum from rat with CRF. Blood urea nitrogen and serum creatinine levels were tested in CRF rat model after administration of Quer. H&E staining was used to estimate endothelial damage. Nitric oxide (NO), endothelial NO synthase (eNOS), EPH receptor B4 (EphB4), EphrinB2, and p-caveolin-1 (p-Cav-1) levels in the serum were examined by enzyme-linked immunosorbent assay. Western blot was employed to analyze the expressions of eNOS, phosphorylated (p)-eNOS, EphB4, and Cav-1 in arterial tissues and HUVECs. Cell counting kit-8 was applied for assessing cell proliferation. TUNEL (terminal-deoxynucleotidyl transferase-mediated nick end labeling) assay was employed to estimate cell apoptosis. Results showed that Quer ameliorated renal function impairment and endothelial injury in vivo. Meanwhile, Quer boosted the proliferation and suppressed the apoptosis of HUVECs stimulated by LPS and serum from rat with CRF. Additionally, Quer elevated NO and eNOS levels, upregulated p-eNOS expression but downregulated EphB4, EphrinB2, and p-Cav-1 expressions. Moreover, EphB4 inhibitor had the similar effect as Quer treatment in HUVECs stimulated by LPS and serum from rat with CRF. Collectively, Quer might effectively regulate vascular function to prevent AVF failure in CRF via modulation of Eph/Cav-1 signaling.

Urinary Matrix Metalloproteinase 7 Activated by Oxidative Stress Predicts Kidney Prognosis in Myeloperoxidase-Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Aims: Effective and applicable predictors of end-stage kidney disease (ESKD) are needed for patients with myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis (MPO-AAV) and kidney involvement. We investigated whether urinary matrix metalloproteinase-7 (uMMP7) was associated with kidney injury severity and incident ESKD in MPO-AAV. Results: A prospective two-stage study was conducted in 150 patients with newly diagnosed MPO-AAV in two independent cohorts. uMMP7 was measured on the days of initial and repeat kidney biopsies. In stage I, a higher initial uMMP7 level was associated with a lower estimated glomerular filtration rate (eGFR), higher level of proteinuria, and greater extent of kidney pathologic lesions. This elevated uMMP7 protein level is activated and potentially derived from the enhanced kidney production induced by oxidative stress. In stage II, uMMP7 at initial biopsy was independently associated with the incidence of ESKD over 6 years. The higher uMMP7 group (vs. lower) had an adjusted hazard ratio of 3.79 (95% confidence interval [CI], 1.49-6.09) for ESKD in the test cohort. Findings were similar in the validation cohort. A combination of data from the two cohorts revealed that adding uMMP7 into clinical or clinicopathologic models significantly improved risk discrimination for future ESKD. Innovation: An elevated uMMP7 level in MPO-AAV was independently associated with severe kidney injury and incident ESKD. Conclusions: uMMP7 in MPO-AAV improves identification of patients at risk of ESKD and may enable early and optimized therapy to improve outcomes. Antioxid. Redox Signal. 37, 246-256.

Association between bone mineral metabolism and vascular calcification in end-stage renal disease.

BACKGROUND: Development of vascular calcification is accelerated in patients with end-stage renal disease. In addition to traditional risk factors of cardiovascular disease (CVD) abnormal bone and mineral metabolism together with many other factors contribute to the excess cardiovascular burden in patients on dialysis. Aortic calcification score and coronary calcification score are predictive of CVD and mortality. The aim of this study was to evaluate the possible relationship between arterial calcification and bone metabolism. METHODS: Thirty two patients on dialysis were included. All patients underwent a bone biopsy to assess bone histomorphometry and a 18F-NaF PET scan. Fluoride activity was measured in the lumbar spine (L1 - L4) and at the anterior iliac crest. Arterial calcification scores were assessed by computerized tomography for quantification of coronary artery calcification score and lateral lumbar radiography for aortic calcification score. RESULTS: This study group showed high prevalence of arterial calcification and 59% had verified CVD. Both CAC and AAC were significantly higher in patients with verified CVD. Only 22% had low turnover bone disease. There was a weak association between fluoride activity, which reflects bone turnover, measured in the lumbar spine, and CAC and between PTH and CAC. There was also a weak association between erosion surfaces and AAC. No significant association was found between calcification score and any other parameter measured. CONCLUSIONS: The results in this study highlight the complexity, when evaluating the link between bone remodeling and vascular calcification in patients with multiple comorbidities and extensive atherosclerosis. Several studies suggest an impact of bone turnover on development of arterial calcification and there is some evidence of reduced progression of vascular calcification with improvement in bone status. The present study indicates an association between vascular calcification and bone turnover, even though many parameters of bone turnover failed to show significance. In the presence of multiple other factors contributing to the development of calcification, the impact of bone remodeling might be diminished. TRIAL REGISTRATION: The study is registered in ClinicalTrials.gov protocol registration and result system, ID is NCT02967042 . Date of registration is 17/11/2016.

Pharmacokinetics and Safety of Intravenous Ferric Pyrophosphate Citrate: Equivalence to Administration via Dialysate.

Ferric pyrophosphate citrate (FPC) is indicated to maintain hemoglobin in patients with stage 5 hemodialysis-dependent chronic kidney disease on chronic hemodialysis by addition to the dialysate. An intravenous (IV) FPC presentation containing 6.75 mg of iron in 4.5 mL was developed. The objective was to establish the equivalence of iron delivery via dialysate and IV infusion using a pharmacokinetic approach. An open-label, randomized, multiple-period, single-dose, crossover study was conducted in 27 patients with CKD-5HD. Each patient received (1) a basal iron profile over 12 hours, (2) FPC 6.75 mg Fe IV predialyzer, (3) FPC 6.75 mg Fe IV postdialyzer, and (4) FPC 2 µM (110 µg Fe/L of hemodialysate). Serum and plasma iron was analyzed for total Fe and transferrin bound iron (TBI). Equivalence was determined by comparing maximum observed concentration and area under the concentration-time curve from time 0 to the last observation of 110 µg Fe/L of hemodialysate (reference) and test treatments Fe predialyzer and postdialyzer iron profiles. The main outcome measure was the measurement of bioequivalence between the reference and test treatments. Bioequivalence parameters showed that infusion of FPC iron IV, predialyzer and postdialyzer delivered equivalent iron as via hemodialysate. The increment in serum total Fe from predialysis to postdialysis was the same as observed in the long-term clinical studies of FPC. FPC IV was well tolerated. IV infusion of 6.75 mg iron as FPC during 3 hours of HD delivers an equivalent amount of iron as when Triferic is delivered via hemodialysate. The IV presentation of FPC extends the ability to provide FPC iron to all patients receiving hemodialysis or hemodiafiltration.

Metformin improves relevant disease parameters in an autosomal dominant polycystic kidney disease mouse model.

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the polycystin 1 (PKD1) or polycystin 2 genes, presents with progressive development of kidney cysts and eventual end-stage kidney disease with limited treatment options. Previous work has shown that metformin reduces cyst growth in rapid ADPKD mouse models via inhibition of cystic fibrosis transmembrane conductance regulator-mediated fluid secretion, mammalian target of rapamycin, and cAMP pathways. The present study importantly tested the effectiveness of metformin as a therapy for ADPKD in a more clinically relevant Pkd1RC/RC mouse model, homozygous for the R3277C knockin point mutation in the Pkd1 gene. This mutation causes ADPKD in humans. Pkd1RC/RC male and female mice, which have a slow progression to end-stage kidney disease, received metformin (300 mg/kg/day in drinking water vs. water alone) from 3 to 9 or 12 mo of age. As previously reported, Pkd1RC/RC females had a more severe disease phenotype as compared with males. Metformin treatment reduced the ratio of total kidney weight-to-body weight relative to age-matched and sex-matched untreated controls at both 9 and 12 mo and reduced the cystic index in females at 9 mo. Metformin also increased glomerular filtration rate, lowered systolic blood pressure, improved anemia, and lowered blood urea nitrogen levels relative to controls in both sexes. Moreover, metformin reduced gene expression of key inflammatory markers and both gene and protein expression of kidney injury marker-1 and cyclin-dependent kinase-1 versus untreated controls. Altogether, these findings suggest several beneficial effects of metformin in this highly relevant slowly progressive ADPKD mouse model, which may help inform new ADPKD therapies in patients.NEW & NOTEWORTHY Metformin treatment improved ADPKD disease severity in a relevant, slowly progressive ADPKD mouse model that recapitulates a PKD-associated PKD1 mutation. Relative to controls, metformin reduced kidney weight/body weight, cystic index and BUN levels, while improving GFR, blood pressure and anemia. Metformin also reduced key inflammatory and injury markers, along with cell proliferation markers. These findings suggest several beneficial effects of metformin in this ADPKD mouse model, which may help inform new ADPKD therapies in patients.

Efficacy and safety of mesenchymal stem cell in Chinese patients with chronic renal failure: A pilot study in Shandong province, China.

This study designed to evaluate efficacy and safety profile of Mesenchymal stem cells (MSCs) versus Acetyl cysteine (NACys) in the Chinese patients with Chronic renal failure (CRF). The CRF patients having eGFR less than 60ml per minute per 1.73m2 randomly assigned to MSCs (N=100) or NACys (N=100) (1:1) for 8 weeks. MSCs administered as intravenous infusion of marrow-derived autologous MSCs (1 × 106 to 2 × 106/kg) reperfusion, whereas, another group received NACys 600mg orally twice a day for 8 weeks. The efficacy variables include: creatinine; cystatin C; TGF-ß levels; oxidants/reactive oxygen species production induced by TGF-ß; collagen levels (type 1 and 4); urinary albumin/creatinine ratio and Glomerular area. Safety was also assesed. Both the treatments significantly decreased creatinine, cystatin C and reactive oxygen species from baseline, however, reduction in creatinine, cystatin C, and reactive oxygen species level from baseline was significantly higher in patient treated with MSCs (N=100) as compared to NACys (N=100). Moreover, improvement in renal and systemic functional parameters from baseline was significantly higher in patient treated with MSCs as compared to NACys. Overall, MSCs offer significantly greater improvement in renal function as compared to NACys in Chinese CRF patients.

Quercetin alleviates chronic renal failure by targeting the PI3k/Akt pathway.

Chronic renal failure (CRF) threatens human health greatly and attracts worldwide concerns of health professionals in the public health sector. In our preliminary study, we found that Compound capsule (Shengqing Jiangzhuo Capsule, SQJZJN) had a significant therapeutic effect on CRF. Quercetin is one of the main components of this Compound capsule. In this study, we investigated the effect of Quercetin monomer on CRF and the regulation of PI3k/Akt pathway. Network pharmacology analysis methods were employed to analyze the SQJZJN/Quercetin/PIK3R1 network relationships. In this study, a CRF rat model was prepared using the gavage adenine solution method and detected the indicators of Creatinine (Cr), Blood Urea Nitrogen (BUN), and Uric Acid (UA). After treating the rat model with Quercetin and PIK3R1-interfering lentivirus, respectively, we observed the changes on the histological morphology of the kidney and detected apoptosis using TUNEL staining. Gene and protein expression associated with renal function were detected using qPCR, WB and immunofluorescence. Quercetin was identified as the main ingredient of SQJZJN by the network pharmacological screening and Quercetin at 1.5 and 3 g/(kg.d) concentrations could effectively alleviate the CRF symptoms, reduce the levels of Cr, BUN, and UA, and markedly inhibit cell apoptosis demonstrated by the intragastric administration. Furthermore, the protein expression of p-PI3K, p-AKT, NLRP3, caspase1, AQP1, and AQP2 in all groups was detected by immunofluorescence and western blot assays, indicating that Quercetin could reduce the expression of NLRP3, caspase1, p-PI3k, and p-Akt, and increase the expression of AQP1 and AQP2 in the renal tissues of CRF rats. Being labeled with biotin and incubated with the total protein extracted from kidney tissues, Quercetin could bind to PIK3R1. Following the PIK3R1 interference lentivirus was injected into the CRF model rats by tail vein, the CRF symptoms were effectively alleviated in the PIK3R1 interference group, consistent with the effect of Quercetin. Taken together, Quercetin, a major component of SQJZJN, might minimize renal fibrosis and apoptosis in CRF rats by inhibiting the PI3k/Akt pathway through targeting PIK3R1. By regulating AQP1 and AQP2, both water retention and toxin accumulation were reduced.

Bone responsiveness to parathyroid hormone is negatively associated with parathyroid hormone-lowering drug use in patients undergoing hemodialysis: a cross-sectional study.

BACKGROUND: Parathyroid hormone (PTH) acts on bone to indirectly increase the number and activity of osteoclasts. Thus, PTH has a stimulatory effect on bone resorption and upregulates bone turnover. However, the responsiveness of bone to PTH varies widely among patients receiving dialysis. In fact, relative to the serum PTH level, the level of serum tartrate-resistant acid phosphatase-5b (TRACP-5b), a bone resorption marker derived from osteoclasts, varies as well. This study aimed to examine factors related to bone responsiveness to PTH in patients undergoing chronic hemodialysis (HD). METHODS: This study included patients receiving chronic HD in Kawasaki Municipal Tama Hospital (Kanagawa, Japan) and Yonaha Medical Clinic (Okinawa, Japan) and excluded patients who received HD for less than 6 months, those who received a combination of HD and peritoneal dialysis, and those who had cancer bone metastases or myeloma. The TRACP-5b/intact PTH (iPTH) ratio was created as an index of bone responsiveness to PTH, categorized into tertiles (low, medium, and high), and a cross-sectional study was conducted. P < 0.05 indicated statistically significant differences. RESULTS: One hundred and six patients were analyzed. Age (P = 0.010), body mass index (BMI) (P = 0.003), use of calcium-sensing receptor (CaSR) agonists (P = 0.008), use of vitamin D receptor activators (VDRAs) (P = 0.012), plasma iPTH level (P < 0.001), serum 1,25(OH)2D level (P = 0.003), and serum TRACP-5b level (P < 0.001) were significantly different among the three categories. In the single linear regression analysis, age (P = 0.016), corrected serum calcium level (P = 0.007), and ln [1,25(OH)2D] (P = 0.044) showed a significant positive correlation with ln [TRACP-5b/iPTH], whereas BMI (P = 0.026), use of CaSR agonists (P = 0.001), use of VDRAs (P = 0.009), and serum phosphorus level (P = 0.018) showed a significant negative correlation. Upon conducting multiple linear regression analysis incorporating significant variables in the single linear regression analysis, a significant negative correlation was observed between the TRACP-5b/iPTH ratio and intravenous administration of a CaSR agonist (etelcalcetide) and/or a VDRA (calcitriol or maxacalcitol) in all the adjusted models. CONCLUSIONS: Bone responsiveness to PTH is negatively correlated with the intravenous administration of a CaSR agonist and/or a VDRA in patients undergoing chronic HD.

Ellagic acid protects rats from chronic renal failure via MiR-182/FOXO3a axis.

Studies showed that ellagic acid (EA) can significantly improve kidney function, but the renal-protective effects of EA and the potential mechanism require adequate elucidation. This study investigated the mechanisms of EA in chronic renal failure (CRF) injury. A rat model of CRF was established by 5/6 nephrectomy. The body weight, urine volume and urine protein content of the rat model of CRF with EA treatment (0/20/40 mg/kg/day) were recorded. Hematoxylin&eosin (H&E) staining, Masson staining and TUNEL were used for histopathological observation. Serum levels of creatinine value, blood urea nitrogen, superoxide dismutase, glutathione, malondialdehyde, tumor necrosis factor-α, interleukin-6 and intercellular cell adhesion molecule-1 were determined using enzyme-linked immunosorbent assay (ELISA) kits. The expressions of genes involved in CRF damage were detected by quantitative real-time PCR (qRT-PCR) and western blot. The relationships among EA, miR-182 and FOXO3a were verified by TargetScan 7.2, dual-luciferase assay and rescue experiments. In this study, EA treatment significantly increased the body weight, but reduced urination and urine protein content, renal tissue damage, collagen deposition, inflammation and the contents of serum creatinine (Scr), blood urea nitrogen (BUN), and malondialdehyde (MDA), and improved the antioxidant capacity of CRF rats. Moreover, EA treatment inhibited miR-182, TGF-ß1, fibronectin and Bax levels, and promoted those of FOXO3a and Bcl-2 in CRF rats. Additionally, miR-182 specifically targeted FOXO3a, and effectively reduced the renal-protective effect of EA. Further research found that overexpressed FOXO3a partially reversed the inhibitory effect of miR-182 on CRF rats. Our results suggest that EA might reduce CRF injury in rats via miR-182/FOXO3a.

Significance of Adipose Tissue Maintenance in Patients Undergoing Hemodialysis.

In the general population, obesity is known to be associated with adverse outcomes, including mortality. In contrast, high body mass index (BMI) may provide a survival advantage for hemodialysis patients, which is known as the obesity paradox. Although BMI is the most commonly used measure for the assessment of obesity, it does not distinguish between fat and lean mass. Fat mass is considered to serve as an energy reserve against a catabolic condition, while the capacity to survive starvation is also thought to be dependent on its amount. Thus, fat mass is used as a nutritional marker. For example, improvement of nutritional status by nutritional intervention or initiation of hemodialysis is associated with an increase in fat mass. Several studies have shown that higher levels of fat mass were associated with better survival in hemodialysis patients. Based on body distribution, fat mass is classified into subcutaneous and visceral fat. Visceral fat is metabolically more active and associated with metabolic abnormalities and inflammation, and it is thus considered to be a risk factor for cardiovascular disease and mortality. On the other hand, subcutaneous fat has not been consistently linked to adverse phenomena and may reflect nutritional status as a type of energy storage. Visceral and subcutaneous adipose tissues have different metabolic and inflammatory characteristics and may have opposing influences on various outcomes, including mortality. Results showing an association between increased subcutaneous fat and better survival, along with other conditions, such as cancer or cirrhosis, in hemodialysis patients have been reported. This evidence suggests that fat mass distribution (i.e., visceral fat and subcutaneous fat) plays a more important role for these beneficial effects in hemodialysis patients.

High Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Are Associated with Poor Survival in Patients with Hemodialysis.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers for systemic inflammation condition. Although NLR has emerged as a risk factor for poor survival in end-stage renal disease (ESRD) patients, the relationship between PLR and mortality is still unknown. We aimed to explore the interaction of NLR and PLR in predicting mortality in hemodialysis (HD) patients. METHOD: We enrolled 360 HD patients for a 71-month follow-up. The endpoint was all-cause and cardiovascular (CV) mortality. Pearson correlation analysis was conducted to evaluate the relationship between factors and NLR or PLR. Kaplan-Meier curves and Cox proportional analysis were used to assess the prognostic value of NLR and PLR. RESULTS: NLR was positively correlated with neutrophil and negatively correlated with lymphocyte, hemoglobin, and serum albumin. PLR was positively correlated with neutrophil and platelet and negatively correlated with lymphocyte and hemoglobin. In multivariate Cox regression, a higher NLR level was independently associated with all-cause mortality (OR 2.011, 95% CI 1.082-3.74, p = 0.027), while a higher PLR level might predict CV mortality (OR 2.768, 95% CI 1.147-6.677, p = 0.023) in HD patients. CONCLUSION: NLR and PLR are cheap and reliable biomarkers for all-cause and CV mortality to predict survival in HD patients.

Expression of renal vitamin D receptors and metabolizing enzymes in IgA nephropathy.

AIM: One of the main causes of end-stage renal disease (ESRD) in the world is IgA nephropathy (IgAN). Since kidney is a key player in vitamin D metabolism, we investigated the expression of renal vitamin D receptors (VDR) and metabolizing enzymes in IgA nephropathy patients (IgAN-P). METHODS: The sample included twelve IgAN-P who underwent ultrasound-guided renal biopsies and five controls who underwent nephrectomy due to clear renal carcinoma. Immunofluorescent staining was used to determine the expression of VDR, 25-hydroxyvitamin D3 -alpha-hydroxylase (1alpha-OHase) and vitamin D3 24-hydroxylase (CYP24A1). RESULTS: Significant increase in expression of VDR, which was prominent in distal tubular cells (DTCs) in tissues from IgAN-P, was found in comparison to the controls (p = 0.0368). The expression of 1alpha-OHase, calcitriol synthesizing enzyme, was significantly lower in IgAN-P, in comparison with controls (p < 0.0001). The opposite, expression of CYP24A1 (vitamin D degrading enzyme), was significantly higher in IgAN-P in comparison with controls (p = 0.0003). Additionally, we found significant negative correlation between percentage of CYP24A1 immunoreactive nuclei in proximal tubular cells (PTCs) and estimated glomerular filtration rate (eGFR) in IgAN-P (r = -0.6139; p = 0.0337). CONCLUSIONS: Our research indicates substantially decreased renal calcitriol production and increased vitamin D degradation in kidneys of IgAN-P, but larger studies are needed to confirm our results.