Pegmolesatide for the treatment of anemia in patients undergoing dialysis: a randomized clinical trial.

Background: Pegmolesatide, a synthetic peptide-based erythropoietin (EPO) receptor agonist, is being evaluated as an alternative to epoetin alfa for treating anemia of chronic kidney disease (CKD) in Chinese dialysis patients. There is a critical need for a long-acting, cost-effective erythropoiesis-stimulating agent that does not produce EPO antibodies. Methods: A randomized, open-label, active-comparator, non-inferiority phase three trial was conducted at 43 dialysis centers in China between May 17th, 2019, and March 28th, 2022. Eligible patients aged 18-70 years were randomly assigned (2:1) to receive pegmolesatide once every four weeks or epoetin alfa one to three times per week, with doses adjusted to maintain a hemoglobin level between 10.0 and 12.0 g/dL. The primary efficacy endpoint was the mean change in hemoglobin level from baseline to the efficacy evaluation period in the per-protocol set (PPS) population. Non-inferiority of pegmolesatide to epoetin alfa was established if the lower limit of the two-sided 95% confidence interval for the between-group difference was ≥ -1.0 g/dL. Safety assessment included adverse events and potential anaphylaxis reactions. This trial is registered at ClinicalTrials.gov, NCT03902691. Findings: Three hundreds and seventy-two patients were randomly assigned to the pegmolesatide group (248 patients) or the epoetin alfa group (124 patients). A total of 347 patients (233 in the pegmolesatide group and 114 in the epoetin alfa group) were included in the PPS population. In the PPS, the mean change (standard deviation, SD) in hemoglobin level from baseline to the efficacy evaluation period was 0.07 (0.92) g/dL in the pegmolesatide group and -0.22 (0.97) g/dL in the epoetin alfa group. The between-group difference was 0.29 g/dL (95% confidence interval: 0.11-0.47), verifying non-inferiority of pegmolesatide to epoetin alfa. Adverse events occurred in 231 (94%) participants in the pegmolesatide group and in 110 (89%) in the epoetin alfa group. Hypertension was the most common treatment-related adverse event. No fatal cases of anaphylaxis or hypotension were reported. Interpretation: Monthly subcutaneously injection of pegmolesatide was as effective and safe as conventional epoetin alfa administrated one to three times a week in treating anemia in Chinese dialysis patients. Funding: The study was supported by Hansoh Medical Development Group.

Normal-weight central obesity: implications for diabetes mellitus.

Background: Current guidelines for obesity prevention and control focus on body mass index (BMI) and rarely address central obesity. Few studies have been conducted on the association between normal-weight central obesity and the risk of diabetes mellitus (DM). Methods: 26,825 participants from the National Health and Nutrition Examination Survey (NHANES) were included in our study. A weighted multivariate logistic regression model was used to analyze the relationship between different obesity patterns and the risk of DM. Results: Our results suggest that normal-weight central obesity is associated with an increased risk of DM (OR: 2.37, 95% CI: 1.75-3.23) compared with normal-weight participants without central obesity. When stratified by sex, men with normal-weight central obesity, obesity and central obesity were found to have a similar risk of DM (OR: 3.83, 95% CI: 2.10-5.97; OR: 4.20, 95% CI: 3.48-5.08, respectively) and a higher risk than all other types of obesity, including men who were overweight with no central obesity (OR: 1.21, 95% CI: 0.96-1.51) and obese with no central obesity (OR: 0.53, 95% CI: 0.30-0.91). Conclusion: Our results highlight the need for more attention in people with central obesity, even if they have a normal BMI.

Akkermansia muciniphila ameliorates chronic kidney disease interstitial fibrosis via the gut-renal axis.

CONTEXT: Chronic kidney disease (CKD) affects approximately 10% of the global population. The abundance of Akkermansia muciniphila (AKK) is significantly reduced in CKD patients. OBJECTIVE: This study investigated the effects of AKK bacteria on kidney damage and the renal interstitium in rats with CKD. MATERIALS AND METHODS: CKD model 5/6 nephrectomy rats were used. CKD rats were supplemented with AKK (2 × 108 cfu/0.2 mL) for 8 weeks. RESULTS: AKK administration significantly suppressed epithelial-mesenchymal transition (EMT), and high-throughput 16S rRNA pyrosequencing showed that AKK supplementation restored the disordered intestinal microecology in CKD rats. AKK also enhanced the intestinal mucosal barrier function. AKK may regulate the intestinal microecology and reduce renal interstitial fibrosis by enhancing the abundance of probiotics and reducing damage to the intestinal mucosal barrier. CONCLUSION: The results suggest that AKK administration could be a novel therapeutic strategy for treating renal fibrosis and CKD.

Different pregnancy outcomes in patients with systemic lupus erythematosus treated with belimumab.

OBJECTIVES: Systemic lupus erythematosus (SLE) predominantly occurs in women of child-bearing age. Selecting drugs for pregnant SLE patients has always been a difficult choice. Although there have been several reports of safety of belimumab in SLE patients during pregnancy, the data are far from sufficient. METHODS: We report on 4 cases of belimumab exposure in pregnant SLE patients. We also summarized 6 case reports and case series which were previously published. Further, we compared the different outcomes among SLE patients and their babies who continued with belimumab during pregnancy with those who discontinued belimumab in early pregnancy. RESULTS: Two cases discontinued belimumab in the early pregnancy, while the other two received belimumab until the late pregnancy. All the four women tolerated belimumab. Newborns have all developed normally and continue without complications during 1 year of follow-up. CONCLUSION: In this small case series, we found that belimumab was well tolerated in pregnant SLE patients. There were no safety signals for the mothers or their babies.

Comparison between outcomes of IgA nephropathy with nephrotic-range proteinuria and nephrotic syndrome: do podocytes play a role?

BACKGROUND: Nephrotic syndrome (NS) and nephrotic-range proteinuria (NRP) are uncommon in IgA nephropathy (IgAN), and their clinicopathology and prognosis have not been discussed. Podocytes may play an important role in both clinical phenotypes. METHODS: We investigated 119 biopsy-proven IgAN patients with proteinuria over 2 g/d. The patients were divided into three groups according to proteinuria level: the overt proteinuria (OP) group, NS group, and NRP group. In addition, according to the severity of foot process effacement (FPE), the patients were divided into three groups: the segmental FPE (SFPE) group, moderate FPE (MFPE) group, and diffuse FPE (DFPE) group. The outcome was survival from a combined event defined by a doubling of the baseline serum creatinine and a 50% reduction in eGFR or ESRD. RESULTS: Compared with the NRP group, patients in the NS group had more severe microscopic hematuria, presented with more severe endocapillary hypercellularity and had a higher percentage of DFPE. The Kaplan-Meier curve showed that MFPE patients had a better outcome in the NRP group <50% of tubular atrophy/interstitial fibrosis. In the multivariate model, the NRP group (HR = 17.098, 95% CI = 3.835-76.224) was associated with an increased risk of the combined event, while MFPE (HR = 0.260, 95% CI = 0.078-0.864; p = 0.028) was associated with a reduced risk of the combined event. After the addition of renin-angiotensin system inhibitors (RASi), the incidence of the combined event in the MFPE group (HR = 0.179, 95% CI = 0.047-0.689; p = 0.012) was further reduced. CONCLUSIONS: NS presented more active lesions and more severe FPE in IgAN. NRP was an independent risk factor for progression to the renal endpoint, while MFPE indicated a better prognosis in NRP without obvious chronic renal lesions, which may benefit from RASi.

Auricular Acupressure for Hemodialysis Patients with Insomnia: A Multicenter Double-Blind Randomized Sham-Controlled Trial.

Background and objectives: The effect of auricular acupressure (AA) for maintenance hemodialysis (MHD) patients with insomnia has been controversial. This study assessed the efficacy and safety of AA for MHD patients with chronic insomnia. Design, setting, participants, and measurements: This was a multicenter, double-blind (participant and assessor), randomized sham-controlled trial. A total of 133 subjects were randomized to receive AA on active points (AA group, n = 64) or on sham auricular acupressure (SAA) points (SAA group, n = 69) for 8 weeks and followed up for 12 weeks. AA was provided by assigned qualified nurses who were not involved in assessment. The primary outcome was the clinical response rate, which was defined as the percentage of participants who reached a reduction of Pittsburgh Sleep Quality Index (PSQI) global score ≥3 in each group. Secondary outcomes included changes in PSQI scores over time, PSQI scores and hypnotics use at each visit, and changes in the weekly dose of hypnotics for drug-dependent subjects. Results: At week 8, the AA group yielded a higher clinical response rate than the SAA group (AA: 55% vs. SAA: 36%, odds ratio: 1.5, 95% confidence interval: 1.0-2.2, p = 0.033). Both groups showed a reduction in PSQI global scores during treatment and follow-up, compared with the baseline, respectively. A significant change of PSQI global score was observed over time (F = 28.387, p < 0.001). PSQI global score of the AA group was relatively lower than that of the SAA group at each visit (p < 0.05 at week 16 and 20). For those depending on hypnotics, AA reduced their consumption of hypnotics. The intervention was safe, and its adherence was satisfactory. Conclusion: AA could serve as a complementary or alternative therapy for MHD patients with insomnia by improving their sleep quality and reducing their use of hypnotics. Clinical trial registration: Clinicaltrials.gov, Identifier: NCT03015766.

JMJD1A/NR4A1 Signaling Regulates the Procession of Renal Tubular Epithelial Interstitial Fibrosis Induced by AGEs in HK-2.

Diabetic kidney disease (DKD) is one of the most serious complications of diabetic patients. Advanced glycation end products (AGEs) induce epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells (HK-2), resulting in renal tubulointerstitial fibrosis. However, the underlying epigenetic mechanisms remain to be further investigated. In this work, we investigated the functional role of JMJD1A involved in DKD progression. The molecular mechanism study was performed in AGEs-induced HK-2 cells by gene expression analysis, RNA sequencing (RNA-seq), and JMJD1A lentiviral knockdown and overexpression particle transfection. The results showed that AGEs could upregulate JMJD1A, and the expressions of related fibrotic factor were also increased. At the same time, in the DKD animal model induced by unilateral nephrectomy plus streptozotocin (STZ), IHC immunohistochemical staining showed that compared with the control group, the expressions of JMJD1A, FN, and COL1 in the model group were all increased, masson staining results also show that the model group has typical fibrotic changes. This is consistent with the results of our in vitro experiments. In order to determine the downstream pathway, we screened out JMJD1A downstream transcription factors by RNA-seq. Further analysis showed that JMJD1A overexpression could accelerate the progression of AGEs-induced renal fibrosis by reducing the expression of NR4A1 in HK-2 cells. Meanwhile, NR4A1 inhibitor can promote the expression of fibrosis-related factors such as VIM, a-SMA in HK-2 cells, and aggravate the process of fibrosis. Taken together, JMJD1A/NR4A1 signaling can regulate the procession of renal tubular epithelial interstitial fibrosis induced by AGEs in HK-2.

Rhubarb Enema Improved Colon Mucosal Barrier Injury in 5/6 Nephrectomy Rats May Associate With Gut Microbiota Modification.

Chronic kidney disease (CKD) is often accompanied with colon mucosal barrier damage and gut microbiota disturbance, which strongly associate with up-regulated inflammation and kidney tubulointerstitial fibrosis. However, few interventions could protect the damaged barrier effectively. Rheum palmatum L or rhubarb is a common herbal medicine which is widely used to protect the colon mucosal barrier. In previous studies, we found that rhubarb intervention may reduce renal inflammation and tubulointerstitial fibrosis, via gut microbiota modification. However, whether intestinal barrier function could be improved by rhubarb intervention and the relationship with intestinal flora are still unknown. Therefore, we investigated the effects of rhubarb enema on intestinal barrier, and further analyzed the relationship with gut microbiota in 5/6 nephrectomy rats. Results indicated that rhubarb enema improved the intestinal barrier, regulated gut microbiota dysbiosis, suppressed systemic inflammation, and alleviated renal fibrosis. More specifically, rhubarb enema treatment inhibited the overgrowth of conditional pathogenic gut bacteria, including Akkermansia, Methanosphaera, and Clostridiaceae in CKD. The modification of gut microbiota with rhubarb intervention displayed significant correlation to intestinal barrier markers, TLR4-MyD88-NF-κB inflammatory response, and systemic inflammation. These results revealed that rhubarb enema could restore intestinal barrier by modifying several functional enteric bacteria, which may further explain the renal protection mechanism of the rhubarb enema.

Bupi Yishen Formula Versus Losartan for Non-Diabetic Stage 4 Chronic Kidney Disease: A Randomized Controlled Trial.

Chinese herbal medicine (CHM) might have benefits in patients with non-diabetic chronic kidney disease (CKD), but there is a lack of high-quality evidence, especially in CKD4. This study aimed to assess the efficacy and safety of Bupi Yishen Formula (BYF) vs. losartan in patients with non-diabetic CKD4. This trial was a multicenter, double-blind, double-dummy, randomized controlled trial that was carried out from 11-08-2011 to 07-20-2015. Patients were assigned (1:1) to receive either BYF or losartan for 48 weeks. The primary outcome was the change in the slope of the estimated glomerular filtration rate (eGFR) over 48 weeks. The secondary outcomes were the composite of end-stage kidney disease, death, doubling of serum creatinine, stroke, and cardiovascular events. A total of 567 patients were randomized to BYF (n = 283) or losartan (n = 284); of these, 549 (97%) patients were included in the final analysis. The BYF group had a slower renal function decline particularly prior to 12 weeks over the 48-week duration (between-group mean difference of eGFR slopes: -2.25 ml/min/1.73 m2/year, 95% confidence interval [CI]: -4.03,-0.47), and a lower risk of composite outcome of death from any cause, doubling of serum creatinine level, end-stage kidney disease (ESKD), stroke, or cardiovascular events (adjusted hazard ratio = 0.61, 95%CI: 0.44,0.85). No significant between-group differences were observed in the incidence of adverse events. We conclude that BYF might have renoprotective effects among non-diabetic patients with CKD4 in the first 12 weeks and over 48 weeks, but longer follow-up is required to evaluate the long-term effects. Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR-TRC-10001518.

p53 induces miR-199a-3p to suppress mechanistic target of rapamycin activation in cisplatin-induced acute kidney injury.

How p53 participates in acute kidney injury (AKI) progress and what are the underlying mechanisms remain illusive. For this issue, it is important to probe into the role of p53 in cisplatin-induced AKI. We find that p53 was upregulated in cisplatin-induced AKI, yet, pifithrin-α inhibites the p53 expression to attenuated renal injury and cell apoptosis both in vivo cisplatin-induced AKI mice and in vitro HK-2 human renal tubular epithelial cells. To knock down p53 by siRNA significantly decreased the miRNA, miR-199a-3p, expression in HK-2 cells. Blockade of miR-199a-3p significantly reduced cisplatin-induced cell apoptosis and inhibited caspase-3 activity. Mechanistically, we identified that miR-199a-3p directly bound to mechanistic target of rapamycin (mTOR) 3'-untranslated region and overexpressed miR-199a-3p reduce the expression and phosphorylation of mTOR. Furthermore, we demonstrated that p53 inhibited mTOR activation through activating miR-199a-3p. In conclusion, our findings reveal that p53, upregulating the expression of miR-199a-3p affects the progress of cisplatin-induced AKI, which might provide a promising therapeutic target of AKI.

Auricular acupressure for insomnia in hemodialysis patients: study protocol for a randomized controlled trial.

BACKGROUND: Patients on maintenance hemodialysis (MHD) frequently complain of insomnia. Poor sleep quality impairs their quality of life and adversely affects long-term outcome. Previously we applied auricular acupressure therapy (AAT) for MHD patients with insomnia and yielded favorable results. AAT probably improves sleep quality by stimulating the vagus nerve and inhibiting sympathetic overactivity. However, the efficacy of AAT for insomnia in this population is still lacking. The proposed randomized controlled trial (RCT) will evaluate the efficacy and safety of AAT for improvement of sleep quality in MHD patients with insomnia. METHODS/DESIGN: The proposed study is a multi-center, double-blind (participants and assessors), parallel-group RCT. A total of 112 participants with insomnia will be recruited from six hemodialysis centers in Guangzhou, China, and randomly allocated in a 1:1 ratio to receive auricular acupressure on either active points (AA group) or control points (points irrelevant to insomnia management, SAA group). The treatment will last for 8 weeks prior to a follow-up period of 12 weeks. Evaluation by blinded assessors at baseline, at 8 weeks (end of treatment) as well as at 4-week, 8-week and 12-week follow-ups (after intervention) will include Pittsburgh Sleep Quality Index (PSQI) scores and average weekly dose of hypnotics. The primary endpoint is clinical response rate (percentage of participants who reach a reduction of PSQI global score ≥ 3 in each group) at 8 weeks from baseline. Secondary endpoints include the changes in PSQI scores over time from baseline, as well as the changes in weekly dose of hypnotics. DISCUSSION: This paper describes the rationale and design of a double-blind RCT that aims to determine the efficacy and safety of AAT for insomnia of hemodialysis patients. If successful, this project will provide evidence of the efficacy and safety of AAT for insomnia of hemodialysis patients. TRIAL REGISTRATION: ClinicalTrials.gov , Identifier: NCT03015766 . Registered on 22 December 2016.