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.].

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.

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.

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.

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.

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.

Cinacalcet attenuated bone loss via inhibiting parathyroid hormone-induced endothelial-to-adipocyte transition in chronic kidney disease rats.

BACKGROUND: Recently, cinacalcet (CINA) has been shown to be effective for attenuating bone loss in the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD), which might be associated with the reduction in serum parathyroid hormone (PTH) levels. However, the exact mechanism is largely unclear. Emerging studies have revealed that an increased number of bone marrow adipocytes (BMAs) are involved in bone loss and the endothelial-to-adipocyte transition via the endothelial-to-mesenchymal transition (EndMT) might play a key role in this pathological process. Here, we assessed whether CINA could attenuate bone loss via inhibiting endothelial-to-adipocyte transition in CKD rats. METHODS: A rat model of CKD was induced by adenine and a high phosphorus diet. CINA was orally administrated to CKD animals (10 mg/kg once a day). Dual energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and bone mechanical tests were used to determine the skeletal changes. The bone marrow expression of EndMT markers was also examined. The effect of elevated PTH levels on the endothelial-to-adipocyte transition was studied in endothelial cells (ECs). RESULTS: Elevation of serum PTH levels, remarkable bone loss and increased numbers of BMAs were observed in rats with CKD compared with the controls, and these changes were attenuated after treatment with CINA. Furthermore, the CINA treatment abolished the upregulation of mesenchymal markers (FSP1 and α-SMA) and the downregulation of an endothelial marker (CD31) in bone tissues from rats with CKD. The serum PTH concentrations were correlated with the bone marrow protein levels of these EndMT-related proteins. An in vitro treatment in ECs demonstrated that PTH induced the EndMT in a concentration- and time-dependent manner. Accordingly, ECs treated with PTH exhibited adipogenic potential following growth in adipogenic culture medium. CONCLUSIONS: Our study indicated CINA treatment attenuated bone loss in CKD rats, which might be associated with inhibiting PTH-induced endothelial-to-adipocyte transition in CKD rats.

Efficacy and safety of cinacalcet and active vitamin D in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease: a network meta-analysis.

BACKGROUND: We conducted a network meta-analysis (NMA) to evaluate the efficacy and safety of cinacalcet, active vitamin D and cinacalcet plus active vitamin D in the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). METHODS: A systematic literature search was performed using the Cochrane Library, PubMed, EMBASE, Web of Science, Google Scholar, China National Knowledge Internet (CNKI) and Wanfang databases. In total, eight randomized controlled trials (RCTs) with 1,443 patients were eligible for this meta-analysis. Pairwise meta-analysis was performed to evaluate the compliance of intact parathyroid hormone (iPTH), Ca, P, etc., and the mortality and safety of cinacalcet plus active vitamin D and active vitamin D alone. Then, NMA was used to estimate the safety and efficacy of the administration of active vitamin D and different drugs in the control group. RESULTS: The results of the pairwise meta-analysis revealed that compared with active vitamin D monotherapy, cinacalcet plus active vitamin D did not improve the survival of patients but significantly improved the blood calcium compliance rate [relative risk (RR) =1.82, 95% confidence interval (CI): 1.51-2.21, P<0.00001]. Furthermore, it is worth noting that compared with the corresponding incidence with other treatments, the incidence of vomiting was significantly increased with cinacalcet plus active vitamin D treatment (RR =2.07, 95% CI: 1.18-3.65, P=0.01). Through direct and indirect comparisons, the NMA revealed the following results: (I) compared with oral or intravenous (IV) administration of vitamin D, the solely oral administration of active vitamin D increased mortality, and (II) cinacalcet monotherapy increased the risk of hypocalcemia, and that risk was even higher for cinacalcet plus active vitamin D. However, the results should be treated with caution because the prediction interval (PrI) crossed the invalid line. CONCLUSIONS: This pairwise meta-analysis and NMA provided a comprehensive analysis of the currently utilized CKD-SHPT treatment interventions. This network identified some highly ranked interventions through analyses that were included in a small number of trials; these interventions merit further examination on a larger scale in the context of well-designed RCTs.

The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway.

The discovery of hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) has revolutionized the treatment strategy for renal anemia. However, the presence of multiple transcription targets of HIF raises safety concerns regarding HIF-PHI. Here, we explored the dose-dependent effect of MK-8617 (MK), a kind of HIF-PHI, on renal fibrosis. MK was administered by oral gavage to mice for 12 wk at doses of 1.5, 5, and 12.5 mg/kg. In vitro, the human proximal tubule epithelial cell line HK-2 was treated with increasing doses of MK administration. Transcriptome profiling was performed, and fibrogenesis was evaluated. The dose-dependent biphasic effects of MK on tubulointerstitial fibrosis (TIF) were observed in chronic kidney disease mice. Accordingly, high-dose MK treatment could significantly enhance TIF. Using RNA-sequencing, combined with in vivo and in vitro experiments, we found that Krüppel-like factor 5 (KLF5) expression level was significantly increased in the proximal tubular cells, which could be transcriptionally regulated by HIF-1α with high-dose MK treatment but not low-dose MK. Furthermore, our study clarified that HIF-1α-KLF5-TGF-ß1 signaling activation is the potential mechanism of high-dose MK-induced TIF, as knockdown of KLF5 reduced TIF in vivo. Collectively, our study demonstrates that high-dose MK treatment initiates TIF by activating HIF-1α-KLF5-TGF-ß1 signaling. These findings provide novel insights into TIF induction by high-dose MK (HIF-PHI), suggesting that the safety dosage window needs to be emphasized in future clinical applications.-Li, Z.-L., Lv, L.-L., Wang, B., Tang, T.-T., Feng, Y., Cao, J.-Y., Jiang, L.-Q., Sun, Y.-B., Liu, H., Zhang, X.-L., Ma, K.-L., Tang, R.-N., Liu, B.-C. The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway.

FK506 prevented bone loss in streptozotocin-induced diabetic rats via enhancing osteogenesis and inhibiting adipogenesis.

BACKGROUND: Type 1 diabetes mellitus (DM) is associated with severe osteoporosis, which is still a great challenge in the clinic. This work aimed to investigate the skeletal effects of FK506 in a rat model of streptozocin induced type 1 DM. METHODS: Rats were divided into three groups: control (CTL), DM rats and DM rats treated with FK506. Dual energy X-ray absorption, micro-computed tomography, bone mechanics and bone histology were used for skeletal analysis. Bone marrow adipocytes infiltrations were detected by oil red O stain and H&E stain. In addition, the protein expression of adipocyte-specific makers (PPAR-γ, C/EBP-αß), osteoblast-specific markers (Runx2, Osterix) and nuclear translocation of ß-catenin in femurs were determined by western blot. RESULTS: In the study, bone mineral density of femurs and lumbar vertebras in diabetic rats were increased after FK506 administration. FK506 treatment resulted in higher cancellous bone volume but had no significant effect on cortical bones in diabetic rats. The ultimate force and work to failure were increased in DM+FK506 group, while they were reduced in the DM group. Compared with the CTL, the infiltration of bone marrow adipocytes was significantly increased in the DM group, which was reduced after the treatment of FK506. Besides, the expression levels of Runx2 and Osterix were up-regulated, and that of PPAR-γ and C/EBP-α were down-regulated in diabetic rats after FK506 treatment. In addition, the nuclear translocation of ß-catenin protein levels were increased in diabetic rats after the treatment of FK506. CONCLUSIONS: Our study indicated that FK506 could alleviate bone loss in diabetic rats. This effects could be due to the results of enhancing osteogenesis and inhibiting adipogenesis, which might be regulated by activation the nuclear translocation of ß-catenin.

Artemisinin attenuates tubulointerstitial inflammation and fibrosis via the NF-κB/NLRP3 pathway in rats with 5/6 subtotal nephrectomy.

Artemisinin (Art) is isolated from Artemisia annua L. and known as the most effective antimalaria drugs. Previous studies demonstrated that it could exert an immune-regulatory effect on autoimmune diseases. In this study, we first investigated its potential role in tubulointerstitial inflammation and fibrosis in rats with 5/6 nephrectomy. Subtotal nephrectomized (SNx) rats were orally administered Art (100 mg·kg -1 ·d - 1) for 16 weeks. Blood and urine samples were collected for biochemical examination. Kidney tissues were collected for immunohistochemistry and Western blot analyses. Ang II-induced injury of the human kidney 2 (HK-2) cells was used for in vitro study. It was shown that Art could significantly attenuate the renal function decline in SNx rats compared with control. More importantly, Art treatment significantly reduced the tubulointerstitial inflammation and fibrosis, as demonstrated by the evaluation of renal pathology. Furthermore, Art inhibited the activation of NLRP3 inflammasome and NF-κB in the kidneys. In in vitro study, Art pretreatment could significantly prevent the activation of NLRP3 inflammasome and NF-κB in Ang II-treated HK-2 cells, while BAY11-7082 (an inhibitor of NF-κB) significantly inhibited Ang II-induced NLRP3 inflammasome activation. This study suggested that Art could provide renoprotective role by attenuating the tubulointerstitial inflammation and fibrosis in SNx rats by downregulating the NF-κB/NLRP3 signaling pathway.