Roxadustat on Renal Anemia with Macroinflammation: A Retrospective Cohort Study.

Introduction: Roxadustat, the first-in-class drug for the treatment of renal anemia, has demonstrated efficacy in renal anemia with microinflammation. Additional data are needed regarding the efficacy of roxadustat on renal anemia with systemic macroinflammation. Methods: Three cohorts of renal anemia based on the basic level of high-sensitivity CRP were included. Patients with hsCRP ≤2 mg/L were selected as non-inflammation (NI) group; 2< hsCRP ≤10 mg/L as microinflammation (MI) group; hsCRP≥10 mg/L as macroinflammation (MA) group. Patients received oral roxadustat three times per week for 52 weeks. The primary end point was the hemoglobin level over weeks 12-52. The second end point was the cumulative proportion of patients achieving hemoglobin response by the end of week 12. Results: A total of 107 patients with chronic kidney diseases (CKDs) were enrolled. Overall, the baseline hemoglobin level of patients was 79.99 ± 11.20 g/L. Roxadustat could significantly increase the hemoglobin level in all of the three groups and did not show any significant difference (p > 0.05, respectively). Meanwhile, compared with that of the NI group, there was no significant difference in hemoglobin response rate in the MA group both at week 12 (p = 0.06; 95% confidence interval [CI], 0.9531-13.75) and week 52 (p = 0.37; 95% CI, 0.5080-7.937). Moreover, the hemoglobin response was independent of baseline hsCRP level (p = 0.72, 95% CI, -0.1139 to 0.0794). More importantly, roxadustat significantly reduced ferritin and serum iron levels and increased total iron-binding capacity in the three groups, which showed no significant differences among the three groups (p > 0.05, respectively). Conclusion: Roxadustat significantly improves anemia in CKD patients with systemic macroinflammation.

Erratum: Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury: Erratum.

[This corrects the article DOI: 10.7150/thno.54550.].

Bioelectrical impedance analysis-derived phase angle predicts sarcopenia in patients on maintenance hemodialysis.

BACKGROUND: This study aimed to investigate the association between phase angle (PhA) and sarcopenia and evaluate its performance as a sarcopenia predictor in patients receveing maintenance hemodialysis (MHD). METHODS: All enrolled patients underwent handgrip strength (HGS) and the 6-m walk test, and muscle mass was measured using bioelectrical impedance analysis. Sarcopenia was diagnosed according to the diagnostic criteria of the Asian Sarcopenia Working Group. Logistic regression analysis was used to evaluate the PhA as an independent predictor of sarcopenia after adjusting for confounding factors. The receiver operating characteristic (ROC) curve was used to analyze the predictive value of PhA in sarcopenia. RESULTS: Two hundred forty-one patients receiving hemodialysis were enrolled in this study, and the prevalence of sarcopenia was 28.2%. Patients with sarcopenia presented a lower PhA value (4.7° vs 5.5°; P < 0.001), lower muscle mass index (6.0 vs 7.2 [kg/m2 ]; P < 0.001), lower HGS (19.7 vs 26.0 [kg]; P < 0.001), and lower walk speed (0.83 ± 0.27 vs 0.92 ± 0.23 [m/s]; P = 0.007) than patients without sarcopenia. The odds of patients receiving MHD presenting with sarcopenia increased as PhA decreased, even after adjustment (odds ratio = 0.39; 95% CI, 0.18-0.85; P = 0.019). ROC analysis revealed that the best cutoff value of PhA for sarcopenia was 4.95° in patients receiving MHD. CONCLUSION: PhA may be a useful and simple predictor for predicting patients undergoing hemodialysis who are at risk of sarcopenia. To further facilitate the application of PhA in the diagnosis of sarcopenia, more research need to be conducted.

The analysis of low-dose glucocorticoid maintenance therapy in patients with primary nephrotic syndrome suffering from COVID-19.

Objectives: This study aimed to describe the effects of low-dose (prednisolone acetate 2.5-7.5 mg/day) glucocorticoids (GCs) maintenance therapy in patients with primary nephrotic syndrome (NS) suffering from coronavirus disease 2019 (COVID-19). Methods: A single-center retrospective study of NS patients with COVID-19 infection in Zhongda Hospital Affiliated to Southeast University from 1 February 2022 to 31 March 2023 was conducted. All enrolled patients underwent renal biopsy for the pathological diagnosis and reached complete remission (CR) or near-CR before COVID-19 infection. According to the maintained therapy regimen, patients were divided into low-dose GCs group and non-GCs group. Results: A total of 125 patients were enrolled in the study. Their median age was 46.0 ± 15.6 years, and the median value of 24-h urine protein was 0.77 g. The majority of these patients received treatment for more than 6 months, with a significant portion achieving CR (29.6%) or near-CR (43.2%). The leading cause of NS was membranous nephropathy (52%). There were no significant differences in the baseline characteristics between low-dose GCs and non-GCs group. As compared to those in the non-GCs group, patients receiving low-dose GCs treatment showed less fatigue or muscle weakness, smell disorder, palpitations, decreased appetite, taste disorder, dizziness, sore throat or difficult to swallow and fever (p < 0.05). Moreover, patients in the low-dose GCs group were with higher median quality of life scores (85.0) than in the non-GCs group (p = 0.001). Further serum inflammatory factor analysis indicated that interleukin-6 (IL-6) levels in the non-GCs group were significantly higher than that in the low-dose GCs group (p < 0.05). Conclusion: Patients with NS in low-dose GCs maintenance therapy stage showed milder symptom, higher quality of life and decreased serum IL-6 levels compared to those, who were not on GCs maintenance therapy. These results suggest the beneficial effect of low-dose GCs therapy in NS patients with CR/near-CR suffering from COVID-19 infection.

Weekly pattern of dialysis unit blood pressure is a promising marker for prognosis evaluation in hemodialysis population.

BACKGROUND: Dialysis unit blood pressure (BP) pattern showed superiority in prognostic evaluation and interdialytic BP burden assessment. However previous studies mainly focused on the recurrent BP pattern within a session (intradialytic BP change or intradialytic BP slope), the clinical value of the weekly pattern of dialysis unit BP is unknown. METHODS: We performed a prospective cohort study in adult end stage renal disease (ESRD) patients on thrice weekly hemodialysis (HD). The slope and the change of the postdialysis systolic BP (SBP) in the course of a week (post-SBP slope and post-SBP change) were used to characterize the weekly pattern of dialysis unit BP. Outcomes included all-cause mortality, cardiovascular mortality, and first cardiovascular event. We also measured the home BP in our cohort. RESULTS: One hundred and twenty-nine subjects were followed over a median of 31 months. Higher post-SBP slope (≥0.185) was independently associated with increased risk of all-cause mortality, cardiovascular mortality, and first cardiovascular event. Results were similar for increased post-SBP change. HD patients with a higher post-SBP slope or an increased post-SBP change also had significant increased interdialytic BP burden measured by home SBP on both dialysis days and non-dialysis days. CONCLUSIONS: Post-SBP slope and post-SBP change might be promising dialysis unit BP markers for prognostic evaluation and interdialytic BP burden assessment.

Urinary small extracellular vesicles derived CCL21 mRNA as biomarker linked with pathogenesis for diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a leading cause of renal failure, whereas the effective and early diagnostic biomarkers are still lacking. METHODS: Fourteen cytokines and chemokines mRNA were detected in urinary extracellular vesicles (EVs) from the screening cohort including 4 healthy controls (HC), 4 diabetes mellitus (DM) and 4 biopsy-proven DN patients, and was validated in another 16 HC and 15 DM and 28 DN patients. Correlation analysis was performed between the candidate biomarkers and clinic parameters as well as kidney histological changes. The findings were also confirmed in DN rat model with single injection of STZ. RESULTS: The number of small EVs secreted in urine was increased in DN patients compared to DM patients and healthy controls, with expression of AQP1 (a marker of proximal tubules) and AQP2 (a marker of distal/collecting tubules). Small EVs derived CCL21 mRNA increased significantly in DN patients and correlated with level of proteinuria and eGFR. Interestingly, elevated CCL21 mRNA from urine small EVs was observed in DN patients with normal renal function and could discriminate early DN patients from DM more efficiently compared to eGFR and proteinuria. CCL21 also showed an accurate diagnostic ability in distinguishing incipient from overt DN. Histologically, CCL21 mRNA expression increased progressively with the deterioration of tubulointerstitial inflammation and showed the highest level in nodular sclerosis group (class III) in DN patients. Remarkable infiltration of CD3 positive T cells including both CD4 and CD8 positive T cell population were observed in DN patients with high-CCL21 expression. Besides, accumulation of CD3 positive T cells correlated with level of urinary small EVs derived CCL21 and co-localized with CCL21 in the tubulointerstitium in DN patients. Finally, the correlation of CCL21 expression in renal cortex and urinary small EVs was confirmed in STZ-induced DN rat model. CONCLUSIONS: Urinary small EVs derived CCL21 mRNA may serve as early biomarker for identifying DN linked with pathogenesis. CCL21 mRNA mediated T cell infiltration may constitute the key mechanism of chronic inflammation in DN.

PTH-induced EndMT via miR-29a-5p/GSAP/Notch1 pathway contributed to valvular calcification in rats with CKD.

BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) is a common pathophysiology in valvular calcification (VC) among non-chronic kidney disease (CKD) patients. However, few studies were investigated in CKD-induced VC. Parathyroid hormone (PTH) was considered to be an important component of EndMT in CKD-induced cardiovascular diseases. Therefore, determining whether PTH could induce valvular EndMT and elucidating corresponding mechanism involved further study. METHODS: Performing a 5/6 nephrectomy with a high phosphorus diet was done to construct VC models in rats with CKD. miRNA sequencing was used to ascertain changes in microRNA in human umbilical vein endothelial cells (HUVECs) intervened by PTH. VC was observed by Von Kossa staining and scanning electron microscope. RESULTS: PTH induced valvular EndMT in VC. Global microRNA expression profiling of HUVECs was examined in PTH versus the control in vitro, in which miR-29a-5p was most notably decreased and was resumed by PTHrP(7-34) (PTH-receptor1 inhibitor). Overexpression of miR-29a-5p could inhibit PTH-induced EndMT in vitro and valvular EndMT in vivo. The dual-luciferase assay verified that γ-secretase-activating protein (GASP) served as the target of miR-29a-5p. miR-29a-5p-mimics, si-GSAP and DAPT (γ-secretase inhibitor) inhibited PTH-induced γ-secretase activation, thus blocking Notch1 pathway activation to inhibit EndMT in vitro. Moreover, Notch1 pathway activation was observed in VC. Blocking Notch1 pathway activation via AAV-miR-29a and DAPT inhibited valvular EndMT. In addition, blocking Notch1 pathway activation was also shown to alleviate VC. CONCLUSION: PTH activates valvular EndMT via miR-29a-5p/GSAP/Notch1 pathway, which can contribute to VC in CKD rats.

Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury.

Mesenchymal stem cells-derived exosomes (MSC-exos) have attracted great interest as a cell-free therapy for acute kidney injury (AKI). However, the in vivo biodistribution of MSC-exos in ischemic AKI has not been established. The potential of MSC-exos in promoting tubular repair and the underlying mechanisms remain largely unknown. Methods: Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of human umbilical cord mesenchymal stem cells (hucMSCs) derived exosomes. The biodistribution of MSC-exos in murine ischemia/reperfusion (I/R) induced AKI was imaged by the IVIS spectrum imaging system. The therapeutic efficacy of MSC-exos was investigated in renal I/R injury. The cell cycle arrest, proliferation and apoptosis of tubular epithelial cells (TECs) were evaluated in vivo and in HK-2 cells. The exosomal miRNAs of MSC-exos were profiled by high-throughput miRNA sequencing. One of the most enriched miRNA in MSC-exos was knockdown by transfecting miRNA inhibitor to hucMSCs. Then we investigated whether this candidate miRNA was involved in MSC-exos-mediated tubular repair. Results:Ex vivo imaging showed that MSC-exos was efficiently homing to the ischemic kidney and predominantly accumulated in proximal tubules by virtue of the VLA-4 and LFA-1 on MSC-exos surface. MSC-exos alleviated murine ischemic AKI and decreased the renal tubules injury in a dose-dependent manner. Furthermore, MSC-exos significantly attenuated the cell cycle arrest and apoptosis of TECs both in vivo and in vitro. Mechanistically, miR-125b-5p, which was highly enriched in MSC-exos, repressed the protein expression of p53 in TECs, leading to not only the up-regulation of CDK1 and Cyclin B1 to rescue G2/M arrest, but also the modulation of Bcl-2 and Bax to inhibit TEC apoptosis. Finally, inhibiting miR-125b-5p could mitigate the protective effects of MSC-exos in I/R mice. Conclusion: MSC-exos exhibit preferential tropism to injured kidney and localize to proximal tubules in ischemic AKI. We demonstrate that MSC-exos ameliorate ischemic AKI and promote tubular repair by targeting the cell cycle arrest and apoptosis of TECs through miR-125b-5p/p53 pathway. This study provides a novel insight into the role of MSC-exos in renal tubule repair and highlights the potential of MSC-exos as a promising therapeutic strategy for AKI.

Risk factors for calciphylaxis in Chinese hemodialysis patients: a matched case-control study.

INTRODUCTION: Calciphylaxis is a rare but potentially fatal disease commonly occurred in dialysis patients. Despite some previous studies on risk factors for calciphylaxis, there is still a lack of data from Chinese population. METHODS: The retrospective matched case-control study about calciphylaxis was performed in Zhongda Hospital affiliated to Southeast University. The case group involved 20 hemodialysis patients who were newly diagnosed with calciphylaxis from October 2017 to December 2018. The 40 noncalciphylaxis patients undergoing dialysis with the same age and duration of dialysis were randomly selected as controls. RESULTS: Most of calciphylaxis patients were male and elderly, while overweight people were more susceptible to the disease. Although incidence of secondary hyperparathyroidism was higher in calciphylaxis patients, the differences in duration of elevated serum intact parathyroid hormone (iPTH) and its highest value did not reach statistical significance compared with controls. No significant difference in warfarin therapy was discernible between two groups. The univariate regression analysis indicated that male, score of use of activated vitamin D and its analogues, corrected serum calcium level, serum phosphate, Ca × P product, iPTH, albumin, and alkaline phosphatase (ALP) level were significantly associated with calciphylaxis. Elevated levels of serum phosphate (OR 4.584, p = 0.027) and ALP (OR 1.179, p = 0.036), decreased level of serum albumin (OR 1.330, p = 0.013) were independent risk factors after multivariate analysis. CONCLUSION: This is the first report of risk factors associated with calciphylaxis in China. Increased levels of serum phosphate and ALP, decreased level of serum albumin were vital high-risk factors for calciphylaxis in Chinese hemodialysis population.

Role of crosstalk between endothelial cells and smooth muscle cells in vascular calcification in chronic kidney disease.

Chronic kidney disease (CKD) is a severe health problem worldwide, and vascular calcification (VC) contributes substantially to the cardiovascular morbidity and high mortality of CKD. CKD is often accompanied by a variety of pathophysiological states, such as inflammation, oxidative stress, hyperglycaemia, hyperparathyroidism and haemodynamic derangement, that can cause injuries to smooth muscle cells (SMCs) and endothelial cells (ECs) to promote VC. Similar to SMCs, whose role has been widely explored in VC, ECs may contribute to VC via osteochondral transdifferentiation, apoptosis, etc. In addition, given their location in the innermost layer of the blood vessel lumen and preferential reception of various pro-calcification stimuli, ECs can pass messages to vascular wall cells and communicate with them. Crosstalk between ECs and SMCs via cytokines through a paracrine mechanism, extracellular vesicles, miRNAs and myoendothelial gap junctions also plays a role in VC. In this review, we emphasize the role of intercellular crosstalk between ECs and SMCs in VC associated with CKD.

Effect of hypoxia-inducible factor-prolyl hydroxylase inhibitors on anemia in patients with CKD: a meta-analysis of randomized controlled trials including 2804 patients.

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are orally active first-in-class new generation drugs for renal anemia. This extensive meta-analysis of randomized controlled trials (RCTs) was designed to provide clear information on the efficacy and safety of HIF-PHIs on anemia in chronic kidney disease (CKD) patients. Searches included PubMed, Web of Science, Ovid MEDLINE, and Cochrane Library database up to October 2019. RCTs of patients with CKD comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in the treatment of anemia. The primary outcome was hemoglobin change from baseline (Hb CFB); the secondary outcomes included iron-related parameters and the occurrence of each adverse event. 26 trials in 17 articles were included, with a total of 2804 dialysis or patients with CKD. HIF-PHIs treatment produced a significant beneficial effect on Hb CFB compared with the placebo group (MD, 0.69; 95% CI, 0.36 to 1.02). However, this favored effect of HIF-PHIs treatment was not observed in subgroup analysis among trials compared with ESAs (MD, 0.06; 95% CI, -0.20 to 0.31). The significant reduction in hepcidin by HIF-PHIs was observed in all subgroups when compared with the placebo group, whereas this effect was observed only in NDD-CKD patients when compared with ESAs. HIF-PHIs increased the risk of nausea (RR, 2.20; 95% CI, 1.06 to 4.53) and diarrhea (RR, 1.75; 95% CI, 1.06 to 2.92). We conclude that orally given HIF-PHIs are at least as efficacious as ESAs treatment to correct anemia short term in patients with CKD. In addition, HIF-PHIs improved iron metabolism and utilization in patients with CKD.

Extracellular vesicle-encapsulated IL-10 as novel nanotherapeutics against ischemic AKI.

Recently, extracellular vesicles (EVs) have been attracting strong research interest for use as natural drug delivery systems. We report an approach to manufacturing interleukin-10 (IL-10)-loaded EVs (IL-10+ EVs) by engineering macrophages for treating ischemic acute kidney injury (AKI). Delivery of IL-10 via EVs enhanced not only the stability of IL-10, but also its targeting to the kidney due to the adhesive components on the EV surface. Treatment with IL-10+ EVs significantly ameliorated renal tubular injury and inflammation caused by ischemia/reperfusion injury, and potently prevented the transition to chronic kidney disease. Mechanistically, IL-10+ EVs targeted tubular epithelial cells, and suppressed mammalian target of rapamycin signaling, thereby promoting mitophagy to maintain mitochondrial fitness. Moreover, IL-10+ EVs efficiently drove M2 macrophage polarization by targeting macrophages in the tubulointerstitium. Our study demonstrates that EVs can serve as a promising delivery platform to manipulate IL-10 for the effective treatment of ischemic AKI.

Rab27a dependent exosome releasing participated in albumin handling as a coordinated approach to lysosome in kidney disease.

Exosomes are increasingly recognized as vehicles of intercellular communication. However, the role of exosome in maintaining cellular homeostasis under stress conditions remained unclear. Here we show that Rab27a expression was upregulated exclusively in tubular epithelial cells (TECs) during proteinuria nephropathy established by adriamycin (ADR) injection and 5/6 nephrectomy as well as in chronic kidney disease patients, leading to the increased secretion of exosomes carrying albumin. The active exosome production promoted tubule injury and inflammation in neighboring and the producing cells. Interferon regulatory factor 1 (IRF-1) was found as the transcription factor contributed to the upregulation of Rab27a. Albumin could be detected in exosome fraction and co-localized with exosome marker CD63 indicating the secretion of albumin into extracellular space by exosomes. Interestingly, inhibition of exosome release accelerated albumin degradation which reversed tubule injury with albumin overload, while lysosome suppression augmented exosome secretion and tubule inflammation. Our findings revealed that IRF-1/Rab27a mediated exosome secretion constituted a coordinated approach to lysosome degradation for albumin handling, which lead to the augment of albumin toxicity as a maladaptive response to maintain cell homeostasis. The findings may suggest a novel therapeutic strategy for proteinuric kidney disease by targeting exosome secretion.

Association Between the Serum Uric Acid Level and the Severity of Coronary Artery Disease in a Retrospective Study of China Nondialysis CKD Patients.

Introduction: Hyperuricemia has been associated with increased cardiovascular events in the general population. However, the role of serum uric acid (SUA) level on the severity of coronary artery stenosis (CAS) in nondialysis chronic kidney disease (CKD) patients is obscure. Methods: We implement a retrospective cohort study of 734 patients diagnosed with stage 3-5 CKD. All selected patients underwent coronary artery angiography. The associations of SUA with the present, and severity of coronary artery disease (CAD) were analyzed. Results: Of these 734 patients, 511 patients had angiographically proven CAD. Compared with non-CAD group, the SUA level in CAD group was much higher (388.00 vs. 363.00 µmol/l, P < 0.01). After adjusting for multiple confounding factors, a multivariate logistic regression analysis demonstrated that SUA was relevant to the presence of CAD when SUA as a continuous variable. However, this relationship was not observed with SUA as a categorical variable. In a subgroup analysis for the CAD group, we found that the rates of severe CAS in the third tertile of SUA (58.6%) was higher than that in the first tertile (41.6%) (P < 0.01). Compared with the first tertile of SUA, the third tertile of SUA was an independent risk factor for severe arterial stenosis (odds ratio, OR, 1.976 [1.203-3.248]), a pattern that was recapitulated by multivariate logistic regression analysis with SUA as a continuous variable (1.002 [1.000-1.004]). Conclusions: The SUA level may serve as a predictor of the severity of CAS among nondialysis CKD patients with CAD.

Crosstalk between tubular epithelial cells and glomerular endothelial cells in diabetic kidney disease.

In recent years, although the development of clinical therapy for diabetic kidney disease (DKD) has made great progress, the progression of DKD still cannot be controlled. Therefore, further study of the pathogenesis of DKD and improvements in DKD treatment are crucial for prognosis. Traditional studies have shown that podocyte injury plays an important role in this process. Recently, it has been found that glomerulotubular balance and tubuloglomerular feedback (TGF) may be involved in the progression of DKD. Glomerulotubular balance is the specific gravity absorption of the glomerular ultrafiltrate by the proximal tubules, which absorbs only 65% to 70% of the ultrafiltrate. This ensures that the urine volume will not change much regardless of whether the glomerular filtration rate (GFR) increases or decreases. TGF is one of the significant mechanisms of renal blood flow and self-regulation of GFR, but how they participate in the development of DKD in the pathological state and the specific mechanism is not clear. Injury to tubular epithelial cells (TECs) is the key link in DKD. Additionally, injury to glomerular endothelial cells (GECs) plays a key role in the early occurrence and development of DKD. However, TECs and GECs are close to each other in anatomical position and can crosstalk with each other, which may affect the development of DKD. Therefore, the purpose of this review was to summarize the current knowledge on the crosstalk between TECs and GECs in the pathogenesis of DKD and to highlight specific clinical and potential therapeutic strategies.

A Rat Model with Multivalve Calcification Induced by Subtotal Nephrectomy and High-Phosphorus Diet.

BACKGROUND: Chronic kidney disease (CKD) with known valve calcification (VC) places individuals at high risk of cardiovascular disease. The study of VC in CKD is challenging due to the lack of a suitable research model. Here, we established a rat model of multivalve calcification induced by subtotal nephrectomy and a high-phosphate (HP) diet and analyzed the valve characteristics. METHODS: We established a CKD model in Sprague-Dawley rats by performing 5/6 nephrectomy (5/6Nx) followed by feeding with chow containing different phosphate concentrations for 8, 12, or 16 weeks. The rats were divided into 4 groups: sham+normal phosphate (NP, 0.9% P), sham+high phosphate (HP, 2.0% P), 5/6Nx+NP, and 5/6Nx+HP. Serum creatinine (Scr), blood urea nitrogen (BUN), parathyroid hormone (PTH), calcium, phosphorus, and 24-h urine protein levels were investigated. Pathological examinations included histological characterization, safranin staining, Alcian blue staining, and von Kossa staining at different time points. Using nanoanalytical electron microscopy, we examined valves from rats in the 5/6Nx+HP and sham+HP groups and detected spherical particles using energy-dispersive spectroscopy (EDS) to observe microscopic changes in the valves. In addition, the calcified tissues were analyzed for phase and crystallization properties using an X-ray powder diffractometer. RESULTS: The rats in the 5/6Nx+HP and 5/6Nx+NP groups presented with increased levels of Scr, BUN, and 24-h urine protein compared with those of the rats in the sham+HP and sham+NP groups. High levels of PTH were observed, and hematoxylin and eosin staining and immunohistochemistry for proliferating cell nuclear antigen showed parathyroid hyperplasia in rats in the 5/6Nx+HP group but not in the 5/6Nx+NP group. In rats in the 5/6Nx+HP group, extracellular matrix glycosylation was observed in the aortic valve in the 12th week and the mitral valve in the 16th week. In the 16th week, chondrocytes appeared in the aortic valve, as confirmed by immunofluorescence and Western blotting. Calcified particles mainly composed of phosphorus and calcium were observed in both the aortic and mitral valves by transmission electron microscopy and scanning electron microscopy (SEM). The main mineral component of the calcified aortic valve particles was hydroxyapatite [Ca5(PO4)3(OH)], as shown by X-ray diffraction. However, there were no obvious differences in heart function between rats in the 5/6Nx+HP and sham+HP groups. CONCLUSIONS: Our findings demonstrate that multivalve calcification is involved in CKD following 16-week HP and that hydroxyapatite [Ca5(PO4)3(OH)] is the main component of the calcified aortic valve particles of rats in the 5/6Nx+HP group.

MicroRNA26a inhibits cisplatin-induced renal tubular epithelial cells apoptosis through suppressing the expression of transient receptor potential channel 6 mediated dynamin-related protein 1.

Acute kidney injury (AKI) is a common adverse reaction of the anticancer drug. Among these chemotherapeutic agents, cisplatin, an effective chemotherapeutic drug, is extensively applied to the treatment of solid tumours, yet various adverse reactions, especially AKI, often limit their use. However, the pathogenesis of AKI caused by cisplatin remains poorly clarified. Therefore, we tested whether microRNAs, which have been certified as key regulators of disease are involved in this process. AKI mouse and HK2 cells were treated with cisplatin. Annexin V/PI staining and cleaved caspase-3 were used to assess apoptosis. Western blot analyses and qRT-PCR were used to evaluate the protein and mRNA level of TRPC6 and DRP1. miR-26a was remarkably decreased in cisplatin-induced AKI and in cisplatin co-cultured HK2 cells. Furthermore, we used a miR-26a mimics in vitro and found that apoptosis was alleviated than that in the control cells. We further verified that miR-26a protected against cisplatin-induced cell apoptosis by acting on transient receptor potential channel 6 (TRPC6) which can regulate the expression of dynamin-related protein 1 (DRP1), thus inhibited the mitochondrial apoptosis pathway. Therefore, the study unveiled that miR-26a/TRPC6/DRP1 is a novel protective pathway in cisplatin-induced AKI and may be targeted for the prevention and treatment of drug-related renal injury. SIGNIFICANCE OF THE STUDY: Our study found that miR-26a was significantly downregulated during cisplatin-induced AKI and during cisplatin co-cultured HK2 cells. Further, in vitro we used miR-26a mimic to intervene cells and found that apoptosis alleviated compared with control group. We further verified that miR-26a protected cisplatin-induced apoptosis by target transient receptor potential channel 6 (TRPC6) which can regulate the expression of dynamic-related protein 1 (DRP1) and inhibit the mitochondrial apoptosis pathway. Thus, miR-26a/TRPC6/DRP1 is a new protective pathway in cisplatin-induced AKI and may be targeted for the prevention and treatment of drug-related acute kidney injury.

Exosomal miRNA-19b-3p of tubular epithelial cells promotes M1 macrophage activation in kidney injury.

Tubulointerstitial inflammation is a common characteristic of acute and chronic kidney injury. However, the mechanism by which the initial injury of tubular epithelial cells (TECs) drives interstitial inflammation remains unclear. This paper aims to explore the role of exosomal miRNAs derived from TECs in the development of tubulointerstitial inflammation. Global microRNA(miRNA) expression profiling of renal exosomes was examined in a LPS induced acute kidney injury (AKI) mouse model and miR-19b-3p was identified as the miRNA that was most notably increased in TEC-derived exosomes compared to controls. Similar results were also found in an adriamycin (ADR) induced chronic proteinuric kidney disease model in which exosomal miR-19b-3p was markedly released. Interestingly, once released, TEC-derived exosomal miR-19b-3p was internalized by macrophages, leading to M1 phenotype polarization through targeting NF-κB/SOCS-1. A dual-luciferase reporter assay confirmed that SOCS-1 was the direct target of miR-19b-3p. Importantly, the pathogenic role of exosomal miR-19b-3p in initiating renal inflammation was revealed by the ability of adoptively transferred of purified TEC-derived exosomes to cause tubulointerstitial inflammation in mice, which was reversed by inhibition of miR-19b-3p. Clinically, high levels of miR-19b-3p were found in urinary exosomes and were correlated with the severity of tubulointerstitial inflammation in patients with diabetic nephropathy. Thus, our studies demonstrated that exosomal miR-19b-3p mediated the communication between injured TECs and macrophages, leading to M1 macrophage activation. The exosome/miR-19b-3p/SOCS1 axis played a critical pathologic role in tubulointerstitial inflammation, representing a new therapeutic target for kidney disease.

Diaphragmatic dysfunction associates with dyspnoea, fatigue, and hiccup in haemodialysis patients: a cross-sectional study.

Muscle wasting is associated with increased mortality and morbidity in chronic kidney disease (CKD) patients, especially in the haemodialysis (HD) population. Nevertheless, little is known regarding diaphragm dysfunction in HD patients. We conducted a cross-sectional study at the Institute of Nephrology, Southeast University, involving 103 HD patients and 103 healthy volunteers as normal control. Ultrasonography was used to evaluate diaphragmatic function, including diaphragm thickness and excursion during quiet and deep breathing. HD patients showed lower end-inspiration thickness of the diaphragm at total lung capacity (0.386 ± 0.144 cm vs. 0.439 ± 0.134 cm, p < 0.01) and thickening fraction (TF) (0.838 ± 0.618 vs. 1.127 ± 0.757; p < 0.01) compared to controls. The velocity and excursion of the diaphragm were significantly lower in the HD patients during deep breathing (3.686 ± 1.567 cm/s vs. 4.410 ± 1.720 cm/s, p < 0.01; 5.290 ± 2.048 cm vs. 7.232 ± 2.365 cm; p < 0.05). Changes in diaphragm displacement from quiet breathing to deep breathing (△m) were lower in HD patients than in controls (2.608 ± 1.630 vs. 4.628 ± 2.110 cm; p < 0.01). After multivariate adjustment, diaphragmatic excursion during deep breathing was associated with haemoglobin level (regression coefficient = 0.022; p < 0.01). We also found that the incidence of dyspnoea and hiccup and the fatigue scores, all of which were related to diaphragmatic dysfunction, were significantly higher in HD patients than in controls (all p < 0.01). Improving diaphragm function through targeted therapies may positively impact clinical outcomes in HD patients.