Iron Supplements Concomitant within Hypoxia-Inducible Factor Prolyl Hydroxylase Domain Inhibitors in the Treatment of Chronic Kidney Disease Anemia.

Background: Anemia is a common and important complication in patients with chronic kidney disease (CKD). Accordingly, the current treatment is based on erythropoiesis-stimulating agents (ESAs) and iron. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain inhibitors (HIF-PHIs) have been developed to treat renal anemia through a novel mechanism. HIF-PHIs increase erythropoietin at physiologic blood concentrations and also improve the supply of hematopoietic iron. Iron is the main component of hemoglobin, and ensuring efficient iron metabolism is essential in the treatment of anemia. Summary: HIF-PHIs may have advantages in improving iron utilization and mobilization compared to ESAs. Most HIF-PHI trials revealed a significant decline of hepcidin, increase in transferrin level and total iron binding capacity in patients. From a clinical point of view, improvements in iron metabolism should translate into reductions in iron supplementation. There are differences in the iron treatment regimentation currently used, so it is important to evaluate and timely iron supplementation across studies. Key Messages: This review summarizes the mechanism of HIF-PHIs on improved iron metabolism and the route of iron usage in the trials for dialysis-dependent CKD and non-dialysis CKD. And this review also makes an interpretation of the clinical practice guidelines in China and recommendation by Asia Pacific Society of Nephrology.

The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII.

BACKGROUND: Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-ß1 (TGF-ß1) is a well-known cytokine that drives PMT. However, the underlying mechanism has not been fully established, and little is known about the associated metabolic changes. METHODS: Bioinformatics analysis was used to identify transcriptomic changes during PMT. PDGFRß + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-ß1. Metabolites were analyzed by ultraperformance liquid chromatography (UPLC) and tandem mass spectrometry (MS). 2-Deoxyglucose (2-DG) was used to inhibit glycolysis via its actions on hexokinase (HK). The hexokinase II (HKII) plasmid was transfected into pericytes for HKII overexpression. LY294002 or rapamycin was used to inhibit the PI3K-Akt-mTOR pathway for mechanistic exploration. RESULTS: An increase in carbon metabolism during PMT was detected through bioinformatics and metabolomics analysis. We first detected increased levels of glycolysis and HKII expression in pericytes after stimulation with TGF-ß1 for 48 h, accompanied by increased expression of α-SMA, vimentin and desmin. Transdifferentiation was blunted when pericytes were pretreated with 2-DG, an inhibitor of glycolysis. The phosphorylation levels of PI3K, Akt and mTOR were elevated during PMT, and after inhibition of the PI3K-Akt-mTOR pathway with LY294002 or rapamycin, glycolysis in the TGF-ß1-treated pericytes was decreased. Moreover, PMT and HKII transcription and activity were blunted, but the plasmid-mediated overexpression of HKII rescued PMT inhibition. CONCLUSIONS: The expression and activity of HKII as well as the level of glycolysis were increased during PMT. Moreover, the PI3K-Akt-mTOR pathway regulates PMT by increasing glycolysis through HKII regulation.

A Prediction Model for Acute Kidney Injury in Adult Patients With Minimal Change Disease.

Background: Early prediction of acute kidney injury (AKI) can allow for timely interventions, but there are still few methods that are easy and convenient to apply in predicting AKI, specially targeted at patients with minimal change disease (MCD). Motivated by this, we aimed to develop a predicting model for AKI in patients with MCD within the KDIGO criteria. Methods: Data on 401 hospitalized adult patients, whose biopsy was diagnosed as MCD from 12/31/2010 to 15/7/2021, were retrospectively collected. Among these data, patients underwent biopsy earlier formed the training set (n = 283), while the remaining patients formed the validation set (n = 118). Independent risk factors associated with AKI were analyzed. From this, the prediction model was developed and nomogram was plotted. Results: AKI was found in 55 of 283 patients (19%) and 15 of 118 patients (13%) in the training and validation cohorts, respectively. According to the results from lasso regression and logistic regression, it was found that four factors, including mean arterial pressure, serum albumin, uric acid, and lymphocyte counts, were independent of the onset of AKI. Incorporating these factors, the nomogram achieved a reasonably good concordance index of 0.84 (95%CI 0.77-0.90) and 0.75 (95%CI 0.62-0.87) in predicting AKI in the training and validation cohorts, respectively. Decision curve analysis suggested clinical benefit of the prediction models. Conclusions: Our predictive nomogram provides a feasible approach to identify high risk MCD patients who might develop AKI, which might facilitate the timely treatment.

Krϋppel-like factor 15 suppresses renal glomerular mesangial cell proliferation via enhancing P53 SUMO1 conjugation.

Mesangial cell (MC) proliferation is a key pathological feature in a number of common human renal diseases, including mesangial proliferative nephritis and diabetic nephropathies. Knowledge of MC responses to pathological stimuli is crucial to the understanding of these disease processes. We previously determined that Krϋppel-like factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, was required for inhibition of MC proliferation. In the present study, we investigated the direct target gene and the underlying mechanism by which KLF15 regulated mesangial proliferation. First, we screened small ubiquitin-related modifier 1 (SUMO1) as the direct transcriptional target of KLF15 and validated this finding with ChIP-PCR and luciferase assays. Furthermore, we demonstrated that overexpressing KLF15 or SUMO1 enhanced the stability of P53, which blocked the cell cycle of human renal MCs (HRMCs) and therefore abolished cell proliferation. Conversely, knockdown of SUMO1 in HRMCs, even those overexpressed with KLF15, could not inhibit HRMC proliferation rates and increase SUMOylation of P53. Finally, the results showed that the levels of SUMOylated P53 in the kidney cortices of anti-Thy 1 model rats were decreased during proliferation periods. These findings reveal the critical mechanism by which KLF15 targets SUMO1 to mediate the proliferation of MCs.

Clinical features of acute kidney injury in patients with nephrotic syndrome and minimal change disease: a retrospective, cross-sectional study.

BACKGROUND: Minimal change nephropathy (MCD) is a common pathological type of nephrotic syndrome and is often associated with acute kidney injury (AKI). This study aimed to investigate the clinical characteristics and related factors of AKI in patients with MCD and nephrotic syndrome. METHODS: Patients from Chinese People's Liberation Army General Hospital who were diagnosed with pathological renal MCD with clinical manifestations of nephrotic syndrome were included from January 1, 2013 to December 31, 2017. Patients diagnosed with membranous nephropathy (MN) by renal biopsy from January 1, 2013 to December 31, 2017 are included as a control population. We retrospectively analyzed the clinical and pathological characteristics of patients as well as the percentages and clinical characteristics of AKI in different age groups. We assessed the correlation of pathological characteristics with serum creatinine using multivariate linear regression analysis. RESULTS: A total of 367 patients with MCD were included in the analysis, with a sex ratio of 1.46: 1 (male: female) and an age range of 6 to 77 years. Among all the patients, 109 developed AKI (29.7%), and of these patients, 85 were male (78.0%). In the 586 patients with MN, 27 (4.6%) patients developed AKI. The percentage of AKI in MCD patients was significantly higher than that in MN patients (χ2 = 41.063, P < 0.001). The percentage of AKI increased with age in the MCD patients. The percentage of AKI in patients aged 50 years or older was 52.9% (46/87), which was significantly higher than that [22.5% (63/280)] in patients under 50 years (χ2 = 6.347, P = 0.013). We observed statistically significant differences in age (43 [27, 59] years vs. 28 [20, 44] years, Z = 5.487, P < 0.001), male (78.0% vs. 51.4%, χ2 = 22.470, P < 0.001), serum albumin (19.9 ±â€Š6.1 g/L vs. 21.5 ±â€Š5.7 g/L, t = 2.376, P = 0.018), serum creatinine (129.5 [105.7, 171.1] µmol/L vs. 69.7 [57.7, 81.9] µmol/L, Z = 14.190, P < 0.001), serum urea (10.1 [6.2, 15.8] mmol/L vs. 4.7 [3.6, 6.4] mmol/L, Z = 10.545, P < 0.001), IgE (266.0 [86.7, 963.0] IU/ml vs. 142.0 [35.3, 516.5] IU/ml, Z = 2.742, P = 0.007), history of diabetes (6.4% vs. 1.2%, P = 0.009), and history of hypertension (23.9% vs. 5.1%, χ2 = 28.238, P < 0.001) between the AKI group and the non-AKI group. According to multivariate linear regression analysis, among the renal pathological features analyzed, renal tubular epithelial cell damage (ß = 178.010, 95% CI: 147.888-208.132, P < 0.001) and renal interstitial edema (ß = 28.833, 95% CI: 11.966-45.700, P = 0.001) correlated with serum creatinine values. CONCLUSIONS: The percentage of AKI in MCD patients is significantly higher than that in MN patients. Patients over 50 years old are more likely to develop AKI. Renal tubular epithelial cell injury and renal interstitial edema may be the main pathological lesions that are associated with elevated serum creatinine in patients with MCD.

STAT3 Inhibition Partly Abolishes IL-33-Induced Bone Marrow-Derived Monocyte Phenotypic Transition into Fibroblast Precursor and Alleviates Experimental Renal Interstitial Fibrosis.

Previous studies of Jak-STAT inhibitors have shown promise in treating kidney diseases. The activation of Jak-STAT components is important in cell fate determination in many cell types, including bone marrow-derived cells, which are important contributors in renal interstitial fibrosis. In this study, we tested the effect of a new STAT3 inhibitor, BP-1-102, on monocyte-to-fibrocyte transition and the progression of renal interstitial fibrosis. We tested the effect of BP-1-102 in a mouse model of unilateral ureteral obstruction in vivo and IL-33-treated bone marrow-derived monocytes in vitro. BP-1-102 treatment alleviated renal interstitial fibrosis, reduced collagen deposition and extracellular matrix protein production, inhibited inflammatory cell infiltration, suppressed the percentage of CD45+ PDGFRß+, CD45+ CD34- Col I+ and CD45+ CD11b+ Col I+ cells within the obstructed kidney and reduced the mRNA levels of the proinflammatory and profibrotic cytokines IL-1ß, TGF-ß, TNF-α, ICAM-1, and CXCL16. In vitro, BP-1-102 inhibited the IL-33-induced phenotypic transition into fibroblast precursors in bone marrow-derived monocytes, marked by reduced CD45+ CD34- Col I+ and CD45+ CD11b+ Col I+ cell percentage. Our results indicate a potential mechanism by which the STAT3 inhibitor BP-1-102 inhibits bone marrow-derived monocyte transition into fibroblast precursors in an IL-33/STAT3-dependent manner and thereby alleviates renal interstitial fibrosis.

Short-term high salt intake impairs hepatic mitochondrial bioenergetics and biosynthesis in SIRT3 knockout mice.

High salt intake (HS) is an important factor in the development of many metabolic diseases. The liver is the metabolic center in the body. However, the effect of short-term HS on the liver mitochondria and its mechanism are still unclear. In this study, we investigated the effects of short-term HS on liver mitochondrial function. We found that HS reduced Sirtuin3 (SIRT3) protein level, increasing protein carbonylation in mice liver. HS intake decreased ATP production, mitochondrial transcription factor A (TFAM), and complex I level. SIRT3 knockout (SKO) mice exhibited similar results with HS-treated wild-type mice but with a less extent of carbonylation and ATP reduction. Our study shows that short-term HS led to increased hepatic oxidative state, impaired mitochondrial biosynthesis, and bioenergetics. HS-treated mice could still maintain hepatic glucose homeostasis by compensatory activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK). However, in HS-treated SKO mice, AMPK was not activated, instead, the glycogen synthase activity increased, which caused an exceptionally increased glycogen accumulation. This study provides evidence that short-term HS intake could cause the early hepatic metabolic changes, highlighting the importance of controlling salt intake especially in those patients with defects in SIRT3. Highlights High salt intake down-regulates SIRT3 protein level and increases oxidation. High salt intake activates AMPK via AMP-dependent pathway. High salt intake impairs energy metabolism. High salt combined with SIRT3 knockout results in glycogen accumulation.

B lymphocytes in renal interstitial fibrosis.

Fibrosis is defined as an excessive deposition of extracellular matrix (ECM), which leads to the destruction of organ structure and impairment of organ function. Fibrosis occurs not only in kidney but also in lung, liver, heart, and skin. Common pathways of fibrosis are thought to exist. Renal interstitial fibrosis is a complex process that involves multiple molecular signaling and multiple cellular components, in which B cells appear to be one of the emerging important players. B cells may affect fibrosis through cytokine production and through interaction with other cells including fibroblasts, macrophages and T cells. This review summarizes recent research findings of B cells in fibrosis and provides an insight of how the future therapeutics of fibrosis could be developed from a B-cell point of view.

Chronic lithium treatment diminishes the female advantage in lifespan in Drosophila melanogaster.

Two studies have concluded that lithium exposure extends the lifespan of Caenorhabditis elegans. However, the effect of lithium on another widely used model organism, Drosophila melanogaster, remains unclear. Here, we demonstrate that chronic treatment with a low to moderate dose of lithium chloride does not extend lifespan in D. melanogaster and that the drug abolishes the female lifespan advantage in flies.