Evaluation of safety, effectiveness and treatment patterns of sodium zirconium cyclosilicate in management of hyperkalaemia in China: a real-world study protocol.

INTRODUCTION: Hyperkalaemia (HK) is a potentially life-threatening electrolyte imbalance associated with several adverse clinical outcomes. The efficacy and negative effects of currently existing treatment options have made HK management questionable. Sodium zirconium cyclosilicate (SZC), a novel highly selective potassium binder, is approved for the treatment of HK. The present study will be aimed to assess the safety, effectiveness and treatment patterns of SZC in Chinese patients with HK in a real-world clinical setting as it is required by China's drug review and approval process. METHODS AND ANALYSIS: This is a multicentre, prospective cohort study which plans to enrol 1000 patients taking SZC or willing to take SZC from approximately 40 sites in China. Patients ≥18 years of age at the time of signing the written informed consent and with documented serum potassium levels ≥5.0 mmol/L within 1 year before study enrolment day will be included. Eligible patients will receive SZC treatment and will be followed up for 6 months from enrolment day. The primary objective will be to evaluate the safety of SZC for the management of HK in Chinese patients in terms of adverse events (AEs), serious AEs as well as discontinuation of SZC. The secondary objectives will include understanding the SZC dosage information in terms of its effectiveness and treatment patterns under real-world clinical practice and assessing effectiveness of SZC during the observational period. ETHICS AND DISSEMINATION: This study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Dalian Medical University (approval number: YJ-JG-YW-2020). All the participating sites have received the ethics approval. Results will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05271266.

Efficacy and Mechanism of Roxadustat plus Oral Iron in the Treatment of Elderly Chronic Kidney Disease with Anemia.

Objective: For investigating the efficacy and mechanism of Roxadustat + oral iron in the treatment of elderly chronic kidney disease (CKD) complicated with anemia. Methods: A total of 100 elderly patients with CKD and anemia admitted to our hospital between April 2020 and December 2021 were enrolled as research subjects, and the patients were assigned to control group (Con group, n = 50) or experimental group (Exp group, n = 50). The patients in the Con group were given oral iron, and those in the Exp group were given Roxadustat capsule based on the Con group. Both groups were given subcutaneous injection of recombinant human erythropoietin. The clinical efficacy, anemia indexes, iron metabolism indexes, inflammatory indexes, and adverse reactions were compared between the two groups. Results: The Exp group showed a notably higher treatment effective rate than the Con group (P < 0.05). After treatment, the anemia indexes, iron metabolism indexes, and inflammatory indexes in the Exp group were notably better than those in the Con group (P < 0.05). The Exp group showed a notably lower incidence of adverse reactions during treatment than the Con group (P < 0.05). Conclusion: Roxadustat plus oral iron yields a pronounced clinical efficacy in the therapy of elderly patients with CKD and anemia.

Surfactant protein A deficiency exacerbates renal interstitial fibrosis following obstructive injury in mice.

Renal interstitial fibrosis is an inevitable consequence of virtually every type of chronic kidney disease. The underlying mechanisms, however, are not completely understood. In the present study, we identified surfactant protein A (SP-A) as a novel protein factor involved in the renal fibrosis induced by unilateral ureter obstruction (UUO). UUO induced SP-A expression in mouse kidney epithelium, likely due to the increased acidic stress and inflammation. Interestingly, SP-A deficiency aggravated UUO-prompted kidney structural damage, macrophage accumulation, and tubulointerstitial fibrosis. SP-A deficiency appeared to worsen the fibrosis by enhancing interstitial myofibroblast accumulation. Moreover, SP-A deficiency increased the expression of TGF-ß1, the major regulator of kidney fibrosis, particularly in the interstitial cells. Mechanistically, SP-A deficiency increased the expression and release of high mobility group box 1 (HMGB1), a factor regulating TGF-ß expression/signaling and implicated in renal fibrosis. SP-A also blocked HMGB1 activities in inducing TGF-ß1 expression and myofibroblast transdifferentiation from kidney fibroblasts, demonstrating that SP-A protected kidney by impeding both the expression and fibrogenic function of HMGB1. Since SP-A physically interacted with HMGB1 both in vitro and in kidney tissue in vivo, SP-A may exert its protective role by binding to HMGB1 and thus titrating its activity during UUO-induced renal fibrosis.

Macrophage polarization in kidney diseases.

Macrophage accumulation associates closely with the degree of renal structural injury and renal dysfunction in human kidney diseases. Depletion of macrophages reduces while adoptive transfer of macrophages worsens inflammation in animal models of the renal injury. However, emerging evidence support that macrophage polarization plays a critical role in the progression of a number of kidney diseases including obstructive nephropathy, ischemia-reperfusion injury, glomerulonephritis, diabetic nephropathy, and other kidney diseases. In this mini-review, we briefly summarize the macrophage infiltration and polarization in these inflammatory and fibrotic kidney diseases, discussing the results mostly from studies in animal models. In view of the critical role of macrophage in the progression of these diseases, manipulating macrophage phenotype may be a potential effective strategy to treat various kidney diseases.

HMGB1 exacerbates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury.

Previous studies have indicated that macrophage phenotype diversity is involved in the progression of renal fibrosis. However, the factors facilitating M1 or M2 phenotypes and the function of these polarized macrophages in kidney injury and fibrosis remain largely unknown. In the present study, we found that macrophages accumulated in the kidney interstitium exhibited mainly as the M1 phenotype at the early stage of unilateral ureter obstruction (UUO). High-mobility group box 1 (HMGB1) protein expressed and released from tubular epithelial cells and interstitial macrophages was essential for the M1 macrophage transition. HMGB1 significantly induced the expression of the M1 marker inducible nitric oxide synthase while decreasing the M2 marker IL-10 in macrophages. Moreover, a glycyrrhizic acid derivative, a blocker of HMGB1 release, reduced UUO-mediated kidney injury and ameliorated UUO-induced renal fibrosis. Interestingly and importantly, UUO caused a low pH value in the urine accumulated in the obstructed ureter, and the acidified urine induced HMGB1 release from tubular epithelial cells and macrophages in vitro. Our data demonstrate that HMGB1 is an essential contributor in facilitating M1 polarization at the early stage of UUO. Inhibition of HMGB1 release may alter macrophage phenotype and contribute to the protection of kidney tissue from injury and fibrosis.

Propyl gallate plays a nephroprotective role in early stage of diabetic nephropathy associated with suppression of glomerular endothelial cell proliferation and angiogenesis.

There is growing evidence suggesting that glomerular endothelial cell proliferation and angiogenesis may be responsible for the pathophysiological events in the early stage of diabetic nephropathy. This study was designed to investigate the factors related to glomerular endothelial cell proliferation and glomerular angiogenesis and assess the effect of propyl gallate on preventing these disorders in diabetic rats. We found that glomerular hypertrophy, glomerular mesangial matrix expansion, and albuminuria were significantly increased in DN rats. CD31+ endothelial cells significantly increased in glomerulus of diabetic rats. Double immunofluorescence staining showed some structurally defective vasculus tubes in glomerulus. Real-time PCR and western blot demonstrated the glomerular eNOS expression remained at the same level, while remarkable decreased NO productions and suppressed eNOS activities were observed in diabetic rats. Treatment with propyl gallate improved glomerular pathological changes, reduced endothelial cell proliferation, decreased albuminuria, and restored eNOS activity, but did not alter eNOS expression. These data suggest that endothelial cell proliferation and immature angiogenesis may be the contributors to progression of DN. Propyl gallate is a potential novel therapeutic agent on prevention of diabetic nephropathy.

Imbalance of glomerular VEGF-NO axis in diabetic rats: prevention by chronic therapy with propyl gallate.

BACKGROUND: The uncoupling of the vascular endothelial growth factor-nitric oxide (VEGF-NO) axis may play a vital role in inducing glomerular endothelial dysfunction. We investigate the factors that contribute to the imbalance of the VEGF-NO axis and evaluate the effect of propyl gallate on preventing endothelial dysfunction. METHODS: Streptozotocin (STZ, 60 mg/kg) was administrated to rats to establish an animal diabetic nephropathy model. The diabetic rats were randomly divided into a diabetic model group and a propyl gallate-treated group. Animals were sacrificed 8 weeks after the model was established. Periodic acid-Schiff staining was conducted to observe pathological changes, and reverse transcriptase polymerase chain reaction and Western blot were employed to analyze endothelial nitric oxide synthase (eNOS) and VEGF expressions. Commercial kits were used to detect glomerular eNOS activity and NO production, as well as oxidative stress. RESULTS: Compared with that in the normal control group, glomerular eNOS activity significantly decreased in diabetic rats, but eNOS expression remained at the same level. The expression of VEGF increased at this stage. Levels of glomerular oxidative stress also increased in diabetic rats and were inversely correlated with eNOS activity. Treatment with propyl gallate restored eNOS activity, ameliorated oxidative stress and improved glomerular pathological changes, but did not alter eNOS and VEGF expressions. CONCLUSION: The imbalance of the VEGF-NO axis in the glomeruli of diabetic rats may have resulted from eNOS inactivation, but not from the decrement in eNOS expressions at the early stage of rat diabetic nephropathy. Propyl gallate improved glomerular pathological changes in diabetic rats, possibly through oxidative stress reduction and VEGF-NO axis recovery.

Tubulointerstitial macrophage accumulation is regulated by sequentially expressed osteopontin and macrophage colony-stimulating factor: implication for the role of atorvastatin.

Infiltration and local proliferation are known factors that contribute to tubulointerstitial macrophage accumulation. This study explored the time course of these two contributors' roles as tubulointerstitial inflammation and fibrosis progressing, and evaluated the mechanisms of the protective effect of atorvastatin. Unilateral ureteral obstructive (UUO) rats were treated with atorvastatin (10 mg/Kg) or vehicle. Expression of osteopontin (OPN) and macrophage colony-stimulating factor (M-CSF) was evaluated by RT-PCR and immunohistochemistry. Immunohistochemistry staining of ED1 was used to assess macrophage accumulation in interstitium. Histological evaluation was performed to semiquantify tubulointerstitial fibrosis. The results showed that on day 3 after UUO operation, OPN expression significantly increased and positively correlated with the number of the interstitial ED1(+) cells, while on day 10, M-CSF expression upregulated and correlated with interstitial ED1(+) cells. In atorvastatin treatment group, the increments of these two factors were attenuated significantly at the two time points, respectively. ED1(+) cell accumulation and fibrosis also ameliorated in the treatment group. For all the samples of UUO and treatment group on day 10, ED1(+) cells also correlated with interstitial fibrosis scores. The results suggest that OPN may induce the early macrophage/monocyte infiltration and M-CSF may play an important role in regulating macrophage accumulation in later stage of UUO nephropathy. Statin treatment decreases interstitial inflammation and fibrosis, and this renoprotective effect may be mediated by downregulating the expression of OPN and M-CSF.