Publications by authors named "Guang-Yan Cai"

97 Publications

Relationships among the Dosage of Erythropoiesis-Stimulating Agents, Erythropoietin Resistance Index, and Mortality in Maintenance Hemodialysis Patients.

Blood Purif 2021 Jun 25:1-11. Epub 2021 Jun 25.

The PLA Medical College, Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.

Background: Erythropoiesis-stimulating agents (ESAs) constitute an important treatment option for anemia in hemodialysis (HD) patients. We investigated the relationships among the dosage of ESA, erythropoietin resistance index (ERI) scores, and mortality in Chinese MHD patients.

Methods: This multicenter observational retrospective study included MHD patients from 16 blood purification centers (n = 824) who underwent HD in 2011-2015 and were followed up until December 31, 2016. We collected demographic variables, HD parameters, laboratory values, and ESA dosages. Patients were grouped into quartiles according to ESA dosage to study the effect of ESA dosage on all-cause mortality. The ERI was calculated as follows: ESA (IU/week)/weight (kg)/hemoglobin levels (g/dL). We also compared outcomes among the patients stratified into quartiles according to ERI scores. We used the Cox proportional hazards model to measure the relationships between the ESA dosage, ERI scores, and all-cause mortality. Using propensity score matching, we compared mortality between groups according to ERI scores, classified as either > or ≤12.80.

Results: In total, 824 patients were enrolled in the study; 200 (24.3%) all-cause deaths occurred within the observation period. Kaplan-Meier analyses showed that patients administered high dosages of ESAs had significantly worse survival than those administered low dosages of ESAs. A multivariate Cox regression identified that high dosages of ESAs could significantly predict mortality (ESA dosage >10,000.0 IU/week, HR = 1.59, 95% confidence intervals (CIs) (1.04, 2.42), and p = 0.031). Our analysis also indicated a significant increase in the risk of mortality in patients with high ERI scores. Propensity score matching-analyses confirmed that ERI > 12.80 could significantly predict mortality (HR = 1.56, 95% CI [1.11, 2.18], and p = 0.010).

Conclusions: Our data suggested that ESA dosages >10,000.0 IU/week in the first 3 months constitute an independent predictor of all-cause mortality among Chinese MHD patients. A higher degree of resistance to ESA was related to a higher risk of all-cause mortality.
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http://dx.doi.org/10.1159/000506536DOI Listing
June 2021

Cellular senescence and the senescence-associated secretory phenotype: Potential therapeutic targets for renal fibrosis.

Exp Gerontol 2021 08 11;151:111403. Epub 2021 May 11.

School of Medicine, Nankai University, Tianjin 300071, China; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China. Electronic address:

Renal fibrosis plays a crucial role in the progression of chronic kidney disease and end-stage renal disease. However, because the aetiology of this pathological process is complex and remains unclear, there is still no effective treatment. Cellular senescence and the senescence-associated secretory phenotype (SASP) have been reported to lead to renal fibrosis. This review first discusses the relationships among cellular senescence, the SASP and renal fibrosis. Then, the key role of the SASP in irreversible renal fibrosis, including fibroblast activation and abnormal extracellular matrix accumulation, is discussed, with the results of studies having indicated that inhibiting cellular senescence and the SASP might be a potential preventive and therapeutic strategy for renal fibrosis. Finally, we summarize promising therapeutic strategies revealed by existing research on senescent cells and the SASP, including emerging interventions targeting the SASP, caloric restriction and mimetics, and novel regeneration therapies with stem cells.
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http://dx.doi.org/10.1016/j.exger.2021.111403DOI Listing
August 2021

Efficacy and safety of Shenyankangfu Tablet, a Chinese patent medicine, for primary glomerulonephritis: A multicenter randomized controlled trial.

J Integr Med 2021 Mar 30;19(2):111-119. Epub 2021 Jan 30.

Department of Nephrology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China.

Background: Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease.

Objective: This trial compared the efficacy and safety of SYKFT, for the control of proteinuria in primary glomerulonephritis patients, against the standard drug, losartan potassium.

Design, Setting, Participants And Intervention: This was a multicenter, double-blind, randomized, controlled clinical trial. Primary glomerulonephritis patients, aged 18-70 years, with blood pressure ≤ 140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min per 1.73 m, and 24-hour proteinuria level of 0.5-3.0 g, were recruited in 41 hospitals across 19 provinces in China and were randomly divided into five groups: SYKFT, losartan potassium 50 mg or 100 mg, SYKFT plus losartan potassium 50 mg or 100 mg.

Main Outcome Measures: The primary outcome was change in the 24-hour proteinuria level, after 48 weeks of treatment.

Results: A total of 735 participants were enrolled. The percent decline of urine protein quantification in the SYKFT group after 48 weeks was 8.78% ± 2.56% (P = 0.006) more than that in the losartan 50 mg group, which was 0.51% ± 2.54% (P = 1.000) less than that in the losartan 100 mg group. Compared with the losartan potassium 50 mg group, the SYKFT plus losartan potassium 50 mg group had a 13.39% ± 2.49% (P < 0.001) greater reduction in urine protein level. Compared with the losartan potassium 100 mg group, the SYKFT plus losartan potassium 100 mg group had a 9.77% ± 2.52% (P = 0.001) greater reduction in urine protein. With a superiority threshold of 15%, neither was statistically significant. eGFR, serum creatinine and serum albumin from the baseline did not change statistically significant. The average change in TCM syndrome score between the patients who took SYKFT (-3.00 [-6.00, -2.00]) and who did not take SYKFT (-2.00 [-5.00, 0]) was statistically significant (P = 0.003). No obvious adverse reactions were observed in any group.

Conclusion: SYKFT decreased the proteinuria and improved the TCM syndrome scores of primary glomerulonephritis patients, with no change in the rate of decrease in the eGFR. SYKFT plus losartan potassium therapy decreased proteinuria more than losartan potassium therapy alone.

Trial Registration Number: NCT02063100 on ClinicalTrials.gov.
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http://dx.doi.org/10.1016/j.joim.2021.01.009DOI Listing
March 2021

Identification of Potential Gene and MicroRNA Biomarkers of Acute Kidney Injury.

Biomed Res Int 2021 8;2021:8834578. Epub 2021 Jan 8.

Department of Nephrology, The First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China.

Acute kidney injury (AKI) is a disease that seriously endangers human health. At present, AKI lacks effective treatment methods, so it is particularly important to find effective treatment measures and targets. Bioinformatics analysis has become an important method to identify significant processes of disease occurrence and development. In this study, we analyzed the public expression profile with bioinformatics analysis to identify differentially expressed genes (DEGs) in two types of common AKI models (ischemia-reperfusion injury and cisplatin). DEGs were predicted in four commonly used microRNA databases, and it was found that miR-466 and miR-709 may play important roles in AKI. Then, we found key nodes through protein-protein interaction (PPI) network analysis and subnetwork analysis. Finally, by detecting the expression levels in the renal tissues of the two established AKI models, we found that Myc, Mcm5, E2f1, Oip5, Mdm2, E2f8, miR-466, and miR-709 may be important genes and miRNAs in the process of AKI damage repair. The findings of our study reveal some candidate genes, miRNAs, and pathways potentially involved in the molecular mechanisms of AKI. These data improve the current understanding of AKI and provide new insight for AKI research and treatment.
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http://dx.doi.org/10.1155/2021/8834578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810567PMC
May 2021

Method used to establish a large animal model of drug-induced acute kidney injury.

Exp Biol Med (Maywood) 2021 Apr 19;246(8):986-995. Epub 2021 Jan 19.

Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China.

Acute kidney injury is a serious health hazard disease due to its complex etiology and lack of effective treatments, resulting in high medical costs and high mortality. At present, a large number of basic research studies on acute kidney injury have been carried out. However, acute kidney injury models established in rodents sometimes do not simulate the course of human disease well. Research in large animal models of acute kidney injury is relatively rare, and methods to build a mature model of acute kidney injury have failed. Because its kidney anatomy and morphology are very similar to those in humans, the mini pig is an ideal animal in which to model kidney disease. Nephrotoxic drug-induced acute kidney injury has a high incidence. In this study, we established models of acute kidney injury induced by two drugs (gentamicin and cisplatin). Finally, the model of cisplatin-induced acute kidney injury was developed successfully, but we found the model of gentamycin-induced acute kidney injury was not reproducible. Compared to other models, these models better represent acute kidney injury caused by antibiotics and chemotherapeutic drugs and provide a basis for the study of new treatments for acute kidney injury in a large animal model.
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http://dx.doi.org/10.1177/1535370220981756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024500PMC
April 2021

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

Chin Med J (Engl) 2020 Nov 4;134(2):206-211. Epub 2020 Nov 4.

Department of Nephrology, Chinese People's Liberation Army General Hospital, Chinese People's Liberation Army Institute of Nephrology, State Key Laboratory of Kidney Diseases (2011DAV00088), National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing 100853, China.

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 ± 6.1 g/L vs. 21.5 ± 5.7 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 (β = 178.010, 95% CI: 147.888-208.132, P < 0.001) and renal interstitial edema (β = 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.
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http://dx.doi.org/10.1097/CM9.0000000000001218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817344PMC
November 2020

Therapeutic effect of intravenous sodium thiosulfate for uremic pruritus in hemodialysis patients.

Ren Fail 2020 Nov;42(1):987-993

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.

Objectives: This study aimed to compare the efficacy of intravenous sodium thiosulfate (IV STS) with that of loratadine in the treatment of uremic pruritus in hemodialysis (HD) patients.

Methods: This retrospective study included 44 HD patients with pruritus aged over 18 years between June 2018 and January 2020 at the Aerospace Center Hospital of China. Twenty-four HD patients received 3.2 g IV STS treatment three times per week at the end of each HD session for 8 weeks. Twenty HD patients received loratadine (10 mg/day) for 8 weeks. Pruritus intensity was measured using a visual analog scale (VAS) and the detailed pruritus score (DPS) at three time points. The safety of STS was evaluated according to adverse event symptoms and biological variable changes.

Results: There was no significant difference between the STS and loratadine groups in age, sex, characteristics of pruritus, or other clinical variables before treatment. After 8 weeks of treatment, the VAS score (7.07 ± 2.56 and 2.67 ± 2.01) and DPS (30.72 ± 4.81 and 8.04 ± 2.86) decreased significantly in the STS group ( < 0.05). The mean decrease in VAS score (6.89 ± 1.98 and 6.34 ± 2.35) and DPS (28.90 ± 3.24 and 26.92 ± 2.41) in the loratadine group was not statistically significant ( > 0.05). There were no morbidities or mortalities associated with the use of either drug. All biological variables remained stable after therapy.

Conclusions: STS can improve uremic pruritus in HD patients. However, literature on the subject remains lacking. Close monitoring for adverse effects is advised.
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http://dx.doi.org/10.1080/0886022X.2020.1822867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534216PMC
November 2020

Caloric restriction alleviates aging-related fibrosis of kidney through downregulation of miR-21 in extracellular vesicles.

Aging (Albany NY) 2020 Aug 27;12(18):18052-18072. Epub 2020 Aug 27.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Chinese PLA General Hospital, Beijing 100853, China.

Glomerulosclerosis and renal interstitial fibrosis occur with the aging kidney. In this study, we examined the expression of miR-21, peroxisome proliferator-activated receptor(PPARα), hypoxia-inducible factor(HIF-1α) in the kidney of 3-month-old rats fed ad libitum (YAL), 24-month-old rats fed ad libitum (OAL) and 24-month-old rats subjected to a 70% calorie-restricted diet for 8 months (OCR). We found long-term caloric restriction (CR) ameliorated aging and aging-related fibrosis. CR ameliorated the increment of miR-21 and HIF-1α, as well as the decrement of PPARα in old ad libitum group. Human proximal tubular cells (HPTCs) presented phenotypes of senescence and epithelial to mesenchymal transition (EMT) under high-glucose conditions, in which senescence occurred earlier than EMT. Senescent cells secreted extracellular vesicles (EVs) which contained miR-21 into the recipient cells. Inhibiting miR-21 of donor cells prevented the occurrence of EMT in recipient cells. In addition, miR-21 induced EMT through targeting PPARα protein and consequently enhancing HIF-1α expression, although other pathways cannot be ruled out. These findings demonstrated that miR-21-containing EVs derived from the senescent cells could facilitate EMT of HPTCs via PPARα-HIF-1α signaling pathway. Long-term caloric restriction and caloric restriction mimetics alleviated aging-related-fibrosis of kidney through downregulation of miR-21.
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http://dx.doi.org/10.18632/aging.103591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585074PMC
August 2020

Risk factors for mortality in elderly haemodialysis patients: a systematic review and meta-analysis.

BMC Nephrol 2020 08 31;21(1):377. Epub 2020 Aug 31.

Department of Nephrology, Chinese PLA Generl Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China.

Background: Older haemodialysis patients accompany a high burden of functional impairment, limited life expectancy, and healthcare utilization. This meta-analysis aimed to evaluate how various risk factors influenced the prognosis of haemodialysis patients in late life, which might contribute to decision making by patients and care providers.

Methods: PubMed, Embase, and Cochrane Central were searched systematically for studies evaluating the risk factors for mortality in elderly haemodialysis patients. Twenty-eight studies were included in the present systematic review. The factors included age, cardiovascular disease, diabetes mellitus, type of vascular access, dialysis initiation time, nutritional status and geriatric impairments. Geriatric impairments included frailty, cognitive or functional impairment and falls. Relative risks with 95% confidence intervals were derived.

Results: Functional impairment (OR = 1.45, 95% CI: 1.20-1.75), cognitive impairment (OR = 1.46, 95% CI: 1.32-1.62) and falls (OR = 1.14, 95% CI: 1.06-1.23) were significantly and independently associated with increased mortality in elderly haemodialysis patients. Low body mass index conferred a mortality risk (OR = 1.43, 95% CI: 1.31-1.56) paralleling that of frailty as a marker of early death. The results also confirmed that the older (OR = 1.43, 95% CI: 1.22-1.68) and sicker (in terms of Charlson comorbidity index) (OR = 1.41, 95% CI: 1.35-1.50) elderly haemodialysis patients were, the more likely they were to die. In addition, increased mortality was associated with early-start dialysis (OR = 1.18, 95% CI: 1.01-1.37) and with the use of a central venous catheter (OR = 1.53, 95% CI: 1.44-1.62).

Conclusions: Multiple factors influence the risk of mortality in elderly patients undergoing haemodialysis. Geriatric impairment is related to poor outcome. Functional/cognitive impairment and falls in elderly dialysis patients are strongly and independently associated with mortality.
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http://dx.doi.org/10.1186/s12882-020-02026-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457491PMC
August 2020

GLA missense and promoter variants co-segregating in a Chinese family with Fabry disease.

Ann Transl Med 2020 Jul;8(14):865

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China.

Background: Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder due to mutations in the GLA gene leading to deficiency of lysosomal α-galactosidase A (α-Gal A) and has a wide range of clinical presentations. Over 900 GLA gene mutations are currently known and of those most are thought not to be clinically significant, some with doubtful clinical significance, posing diagnostic and prognostic difficulties for the clinician.

Methods: Whole-exome sequencing (WES) was performed to detect the mutation in family members with Fabry disease. The function of g.1170C>T mutation was confirmed by dual luciferase system.

Results: A total of 1,375 variants were found in a Chinese family with FD. A missense variants c.1025C>T (p.Arg342Gln) which have been previously reported in association with FD and g.1170C>T single-nucleotide polymorphism (SNP) in the GLA gene were found in five patients. The g.1170C>T SNP affects transcription of GLA gene, presumably the transcription start site. Female patients only have hypohidrosis and neuropathic pain, while male patients have severe symptoms with simultaneous renal impairment.

Conclusions: Two simultaneous variants in cis of the GLA gene, c.1025C>T (p.Arg342Gln) and g.1170C>T, were verified in Chinese individuals, and the corresponding clinical symptoms were described. The disease severity in male patients is worse than in female patients. These results may be helpful for genetic counseling, diagnosis and prognosis of patients with FD.
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http://dx.doi.org/10.21037/atm-19-4510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396806PMC
July 2020

Associations of coenzyme Q10 with endothelial function in hemodialysis patients.

Nephrology (Carlton) 2021 Jan 1;26(1):54-61. Epub 2020 Sep 1.

Medical School of Chinese PLA, Beijing, PR China.

Background: Endothelial dysfunction is common in patients undergoing hemodialysis (HD). However, little is known about the relationship between endothelial dysfunction and coenzyme Q10 (CoQ10) levels in HD patients.

Methods: Eligible HD patients were enrolled in this study according to prespecified inclusion and exclusion criteria. Endothelial function was assessed by brachial artery flow-mediated dilation (FMD). Plasma CoQ10, serum malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) levels were measured. The potential confounders identified by univariate analyses (P < 0.15) were selected in a stepwise multiple regression model.

Results: In total, 111 HD patients were enrolled in this study. The mean CoQ10 level was 633.53 ± 168.66 ng/mL, and endothelial dysfunction was prevalent (91.0%) using a cut-off value of 10% FMD. A significant correlation was observed between FMD and plasma CoQ10 level (r = 0.727, P < 0.001). After adjusting for potential parameters, a stepwise multivariate linear regression analysis revealed that CoQ10 level was an independent predictor of FMD (β = 0.018, P < 0.001). When CoQ10 was dichotomized using the median value (639.74 ng/mL), the conclusion remained unchanged (β = 0.584, P < 0.001). Pearson's correlation analyses revealed that plasma CoQ10 level was negatively correlated with MDA (r = -0.48, P < 0.001) and 8-OHdG (r = -0.43, P < 0.001) levels.

Conclusion: Our data demonstrate that impaired brachial artery FMD was common in HD patients. CoQ10 level was independently associated with FMD, and oxidative stress may constitute a link between CoQ10 level and endothelial dysfunction in these patients.
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http://dx.doi.org/10.1111/nep.13766DOI Listing
January 2021

Single-cell RNA sequencing data suggest a role for angiotensin-converting enzyme 2 in kidney impairment in patients infected with 2019-novel coronavirus.

Chin Med J (Engl) 2020 May;133(9):1129-1131

Department of Nephrology, Chinese People's Liberation Army General Hospital, Chinese People's Liberation Army Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing 100039, China.

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http://dx.doi.org/10.1097/CM9.0000000000000783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213623PMC
May 2020

Relationship between serum C3/C4 ratio and prognosis of immunoglobulin A nephropathy based on propensity score matching.

Chin Med J (Engl) 2020 Mar(6):631-637

Department of Nephrology, Chinese People's Liberation Army General Hospital, Chinese People's Liberation Army Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China.

Background: Aberrant activation of the complement system plays an important role in the pathogenesis and development of immunoglobulin A nephropathy (IgAN). The relationship between serum complement and the clinical-histopathological features and outcomes of IgAN is controversial. This retrospective study aimed to examine the relationship between the complement 3/4 (C3/C4) ratio and the clinicopathologic changes and prognosis of patients with IgAN.

Methods: A total of 397 patients with primary IgAN from January 2007 to December 2012 at the Chinese People's Liberation Army General Hospital were included in this study. The correlation test and Chi-square test or one-way analysis of variance test were performed to evaluate the relationship between the C3/C4 ratio and other clinical-pathological factors. Propensity score matching and a multivariate Cox regression model were used to calculate the risk factors of renal outcome.

Results: The median follow-up period was 75 months. During the follow-up period, 62 patients (15.6%) developed into the end-stage renal disease (ESRD). The C3/C4 ratio at baseline was associated with the level of serum creatinine (SCr), 24 h urinary protein excretion (24 h Upre), global glomerular sclerosis, and tubulointerstitial lesion. The level of SCr and 24 h Upre and the degree of chronic kidney injury were statistically different among groups defined by different C3/C4 ratio levels. The survival rates of patients among groups with different C3/C4 ratio levels were different. After propensity score matching, eighty-eight pairs of patients were successfully matched, and the C3/C4 ratio was an influencing factor for the patients' outcome (hazard ratio 0.587, 95% confidence interval 0.329-0.880). Patients with a C3/C4 ratio <3.6 had a poorer outcome compared with the others (P = 0.002).

Conclusions: IgAN patients with decreased C3/C4 ratio displayed significantly more severe clinical symptoms and chronic renal injury than patients with higher ratios. A low C3/C4 ratio could be a risk factor for patients developing to ESRD.
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http://dx.doi.org/10.1097/CM9.0000000000000674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190234PMC
March 2020

Risk Factors For Hyperuricemia In Chinese Centenarians And Near-Centenarians.

Clin Interv Aging 2019 19;14:2239-2247. Epub 2019 Dec 19.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases,Beijing Key Laboratory of Kidney Diseases, Beijing 100853, People's Republic of China.

Purpose: Hyperuricemia is an important potential pathogenic factor for hypertension, cardiovascular disease and stroke. The current study aimed to investigate the prevalence of hyperuricemia and its relationship to lifestyle characteristics and dietary habits in centenarians and near-centenarians.

Patients And Methods: In total, 966 centenarians and 788 near-centenarians were included. Community-based surveys were conducted to collect information about lifestyle. Blood examinations were performed using enzymatic assays. T-tests and χ2 tests were used to investigate significant indicators of hyperuricemia, and multivariate logistic regression was used to analyze the related risk factors. A comprehensive analysis of nineteen modifiable factors, including lifestyle characteristics, dietary habits, general characteristics and blood test indexes, was conducted.

Results: The prevalence of hyperuricemia was 29.02%. The percentage of men, waist circumference (WC), waist-hip ratio, estimated glomerular filtration rate (eGFR), levels of total protein (TP), alanine aminotransferase, aspartate aminotransferase, triglycerides, high-density lipoprotein cholesterol, serum homocysteine, serum uric acid, serum urea and serum creatinine, passive smoking, alcohol consumption, snoring, preference for fried flavors, and meat, seafood and vegetable consumption were significantly different between the hyperuricemia group and the normouricemia group (p<0.05). Multivariate logistic regression analysis showed that WC (OR=1.020), eGFR (OR=0.960), TP level (OR=1.038), serum urea level (OR=1.154), passive smoking (OR=2.589), snoring (OR=2.003), meat consumption (OR=2.506), seafood consumption (OR=1.422) and vegetable consumption (OR=0.521) were significantly associated with the risk of hyperuricemia (p<0.05).

Conclusion: Low eGFR and vegetable consumption, high WC, TP, and serum urea levels, passive smoking, snoring, and high meat and seafood consumption were independent risk factors for hyperuricemia. It is recommended that people at high risk for hyperuricemia should actively limit their intake of fried food, alcohol and purine-rich food, increase their intake of fresh vegetables, actively treat sleep apnea syndrome, avoid passive smoking, maintain a healthy WC and seek to improve their kidney and liver function.
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http://dx.doi.org/10.2147/CIA.S223048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927493PMC
March 2020

Association of the malnutrition-inflammation score with anthropometry and body composition measurements in patients with chronic kidney disease.

Ann Palliat Med 2019 Nov 12;8(5):596-603. Epub 2019 Nov 12.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease, Beijing 100853, China.

Background: The malnutrition-inflammation score (MIS) is a nutritional scoring system that has been validated in chronic kidney disease (CKD) stages III-V, especially in dialysis patients. We aimed to test whether the MIS changed in the early stages of CKD and whether it was associated with anthropometry and body composition measurements (BCMs) in patients with CKD.

Methods: This was a cross-sectional study conducted in the Nephrology Department. A total of 144 patients with CKD were included in the study between May 2017 and December 2017. The MIS was calculated without computing the dialysis vintage in the scoring. Body composition was measured using a portable whole-body bioimpedance spectroscopy device. Anthropometric, laboratory, and other body composition parameters were recorded.

Results: The MIS was increased in patients with CKD. It was negatively correlated with body mass index (BMI), mid-arm muscle circumference (MAMC), handgrip strength, lean tissue index (LTI), fat tissue index (FTI), phase angle (PA), and hemoglobin and albumin concentrations, and it was positively correlated with sex, overhydration, urinary protein excretion and IL-6. A high MIS was significantly correlated with a low LTI (r=-0.274; P=0.001), low FTI (r=-0.179; P=0.032), overhydration (r=0.457; P<0.001) and low PA (r=-0.475; P<0.001). A rather strong correlation was observed between the PA and the MIS. In the multivariate regressions, after adjusting for age, sex, presence of diabetes, handgrip strength, BMI, overhydration, glomerular filtration rate, albumin and IL-6 concentrations, these relationships did not diminish.

Conclusions: The MIS was strongly linked with indicators of nutrition. As a simple and practical tool for assessing nutritional status, the MIS should be calculated in the early stages of CKD.
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http://dx.doi.org/10.21037/apm.2019.10.12DOI Listing
November 2019

Diagnostic efficacy of serum anti-phospholipase A2 receptor antibodies for idiopathic membranous nephropathy in patients with diabetic kidney disease.

Clin Chim Acta 2020 Mar 13;502:222-226. Epub 2019 Nov 13.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China. Electronic address:

Aim: Serum anti-phospholipase A2 receptor (anti-PLA2R) antibodies are highly accurate in diagnosing idiopathic membranous nephropathy (IMN) in populations with kidney disease. However, the diagnostic value of anti-PLA2R antibodies for IMN in diabetic kidney disease (DKD) is unclear. The objective of this study is to determine the diagnostic efficacy and the optimal cut-off value of this marker in populations with DKD.

Methods: This study included 227 patients with type 2 diabetes who were admitted to the Department of Nephrology of the Chinese People's Liberation Army General Hospital from May 2016 to January 2018 and underwent pathological diagnosis by renal biopsy. Anti-PLA2R antibodies were detected by enzyme-linked immunosorbent assay in this population. According to the pathological results, the participants were divided into an IMN group and non-membranous nephropathy (non-MN) group. The clinical characteristics were analyzed, the diagnostic ability of anti-PLA2R antibodies was evaluated, and the receiver operating characteristic (ROC) curve was constructed to obtain the optimal cut-off value.

Results: There were 45 patients in the IMN group, accounting for 19.8% of the study sample. The patients in this group were older at the time of renal biopsy than the non-MN group and presented a shorter duration of diabetes, better glycemic control, lower blood pressure and uric acid, and better renal function; in addition, their clinical symptoms indicated nephrotic syndrome. The optimal cut-off value for anti-PLA2R antibodies for the diagnosis of IMN in DKD was 2.71 Ru/ml, sensitivity was 0.800, specificity was 0.951, positive predictive value was 0.800, negative predictive value was 0.951, accuracy was 0.921, and the Yoden index was 0.750. The area under the ROC curve was 0.87 (95% CI, 0.788-0.952) (p < 0.001).

Conclusions: Patients in the IMN group were older, had better renal function and general condition, and the clinical symptoms indicated nephrotic syndrome. Anti-PLA2R antibodies had a good diagnostic performance for IMN in the population with DKD, and the optimal cut-off value was 2.71.
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http://dx.doi.org/10.1016/j.cca.2019.11.004DOI Listing
March 2020

miRNAs in stem cell-derived extracellular vesicles for acute kidney injury treatment: comprehensive review of preclinical studies.

Stem Cell Res Ther 2019 09 3;10(1):281. Epub 2019 Sep 3.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, 100853, China.

Stem cell therapy has been applied in many fields. Basic and clinical studies on stem cell therapy for acute kidney injury (AKI) have been conducted. Stem cells have been found to exert renal protection through a variety of mechanisms, such as regulating the immune system and secreting growth factors, cytokines, and extracellular vesicles (EVs). Among them, EVs are considered to be important mediators for stem cell protection because they contain various biological components, including microRNAs (miRNAs). miRNAs are a class of small RNAs that function in posttranscriptional gene regulation. A number of studies have confirmed that miRNAs in stem cell-derived EVs can protect from AKI. miRNAs can enter the injured renal tissue through EVs released from stem cells, thereby exerting anti-inflammatory, anti-apoptotic, anti-fibrotic, and pro-angiogenesis effects on AKI. However, the stem cell sources and AKI models used in these studies have differed. This article will summarize the miRNAs that play a role in kidney protection in stem cell EVs and clarifies the treatment characteristics and mechanisms of different miRNAs. This may provide a reference for clinical practice for acute and chronic kidney diseases.
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http://dx.doi.org/10.1186/s13287-019-1371-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724288PMC
September 2019

Predictive Capabilities of Three Widely Used Pathology Classification Systems and a Simplified Classification (Beijing Classification) in Primary IgA Nephropathy.

Kidney Blood Press Res 2019 28;44(5):928-941. Epub 2019 Aug 28.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.

Background/aims: Several pathological classification systems were commonly used in clinical practice to predict the prognosis of IgA nephropathy (IgAN). However, how prognostic value differs between these systems is unclear. The aim of this study was to compare the Lee grade, the Oxford classification, and the Haas classification and to find a simplified classification.

Methods: We retrospectively analyzed IgAN cases diagnosed between January 2002 and December 2007. The endpoints were progression to end-stage renal disease (ESRD) or a ≥50% decline in estimated glomerular filtration rate (eGFR). The predictive capabilities were evaluated by comparing the ability of discrimination (continuous net reclassification) and calibration (Akaike information criterion [AIC]).

Results: A total of 412 IgAN patients were included in the study. The average follow-up period was 80.62 ± 23.63 months. A total of 44 (10.68%) patients progressed to ESRD, and 70 (16.99%) patients showed a ≥50% decline in eGFR. All multivariate Cox regression models had limited power for high AIC values. The prognostic values of the Lee grade and the Oxford classification were higher than those of models containing only established baseline clinical indicators for progression to ESRD or a ≥50% decline in eGFR (Lee grade 0.50, 95% CI 0.21-0.74; Oxford classification 0.48, 95% CI 0.28-0.71). The prognostic value of the Haas classification was lower than that of the other pathological classification systems for progression to ESRD or a ≥50% decline in eGFR (Lee grade 0.53, 95% CI 0.23-0.92; Oxford classification 0.59, 95% CI 0.10-0.74). The prognostic value of hierarchical classification (Beijing classification) using M and T lesion was similar to the Oxford classification.

Conclusions: Both the Lee grade and the Oxford classification showed incremental prognostic values beyond established baseline clinical indicators. The Haas classification was slightly inferior to the Lee grade and the Oxford classification. The hierarchical classification (Beijing classification) using less pathological parameters does not lose predictive efficiency.
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http://dx.doi.org/10.1159/000500459DOI Listing
March 2020

Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis.

N Engl J Med 2019 09 24;381(11):1011-1022. Epub 2019 Jul 24.

From the Department of Nephrology, Institute of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (N.C.), the Division of Nephrology, Huashan Hospital Fudan University (C.H.), and the Department of Nephrology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (G.J.), Shanghai, the Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine (B.-C.L.), the Department of Nephrology, First Affiliated Hospital (Jiangsu Province Hospital), Nanjing Medical University (C.X.), and the National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine (Zhihong Liu), Nanjing, First Affiliated Hospital of Dalian Medical University, Dalian (H.L.), the Department of Nephrology, First Affiliated Hospital of Baotou Medical College of Inner Mongolia University of Science and Technology, Baotou (Caili Wang), the Division of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences (X. Liang) and the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research (Zhengrong Liu), Guangzhou, the Department of Nephrology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital (X. Li), the Department of Nephrology, Peking University People's Hospital (L.Z.), the Renal Division, Department of Medicine, Peking University First Hospital and Institute of Nephrology, Peking University (M.Z.), and the Department of Nephrology, Chinese People's Liberation Army General Hospital, State Key Lab of Kidney Disease, National Clinical Research Center for Kidney Disease (G.-Y.C.), Beijing, the First Affiliated Hospital of Nanchang University, Nanchang (L.L.), the Department of Nephrology, Lanzhou University Second Hospital, Lanzhou (J.W.), and the Department of Nephrology, Second Hospital of Anhui Medical University, Hefei (L.H.) - all in China; and FibroGen, San Francisco (R.L., Chunrong Wang, C.L., T.N., L.S., K.-H.P.Y.).

Background: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed regarding the effectiveness and safety of roxadustat as compared with standard therapy (epoetin alfa) for the treatment of anemia in patients undergoing dialysis.

Methods: In a trial conducted in China, we randomly assigned (in a 2:1 ratio) patients who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with epoetin alfa for at least 6 weeks to receive roxadustat or epoetin alfa three times per week for 26 weeks. Parenteral iron was withheld except as rescue therapy. The primary end point was the mean change in hemoglobin level from baseline to the average level during weeks 23 through 27. Noninferiority of roxadustat would be established if the lower boundary of the two-sided 95% confidence interval for the difference between the values in the roxadustat group and epoetin alfa group was greater than or equal to -1.0 g per deciliter. Patients in each group had doses adjusted to reach a hemoglobin level of 10.0 to 12.0 g per deciliter. Safety was assessed by analysis of adverse events and clinical laboratory values.

Results: A total of 305 patients underwent randomization (204 in the roxadustat group and 101 in the epoetin alfa group), and 256 patients (162 and 94, respectively) completed the 26-week treatment period. The mean baseline hemoglobin level was 10.4 g per deciliter. Roxadustat led to a numerically greater mean (±SD) change in hemoglobin level from baseline to weeks 23 through 27 (0.7±1.1 g per deciliter) than epoetin alfa (0.5±1.0 g per deciliter) and was statistically noninferior (difference, 0.2±1.2 g per deciliter; 95% confidence interval [CI], -0.02 to 0.5). As compared with epoetin alfa, roxadustat increased the transferrin level (difference, 0.43 g per liter; 95% CI, 0.32 to 0.53), maintained the serum iron level (difference, 25 μg per deciliter; 95% CI, 17 to 33), and attenuated decreases in the transferrin saturation (difference, 4.2 percentage points; 95% CI, 1.5 to 6.9). At week 27, the decrease in total cholesterol was greater with roxadustat than with epoetin alfa (difference, -22 mg per deciliter; 95% CI, -29 to -16), as was the decrease in low-density lipoprotein cholesterol (difference, -18 mg per deciliter; 95% CI, -23 to -13). Roxadustat was associated with a mean reduction in hepcidin of 30.2 ng per milliliter (95% CI, -64.8 to -13.6), as compared with 2.3 ng per milliliter (95% CI, -51.6 to 6.2) in the epoetin alfa group. Hyperkalemia and upper respiratory infection occurred at a higher frequency in the roxadustat group, and hypertension occurred at a higher frequency in the epoetin alfa group.

Conclusions: Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia in Chinese patients undergoing dialysis. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652806.).
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http://dx.doi.org/10.1056/NEJMoa1901713DOI Listing
September 2019

Can we predict who will develop postoperative hyperkalaemia after parathyroidectomy in dialysis patients with secondary hyperparathyroidism?

BMC Nephrol 2019 06 20;20(1):225. Epub 2019 Jun 20.

Department of Nephrology, National Clinical Research Center for Kidney Diseases, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China.

Background: Hyperkalaemia occurs frequently in many maintenance haemodialysis (MHD) patients after parathyroidectomy (PTX) with secondary hyperparathyroidism (SHPT). However, the clinical risk factors that predict postoperative hyperkalaemia are uncertain.

Methods: This retrospective cohort study included 90 maintenance haemodialysis patients aged ≥18 years who underwent PTX between April 2011 and April 2016 at Aerospace Center Hospital (Peking University Aerospace School of Clinical Medicine). Pre- and post-PTX surgery venous samples were measured in quadruplicate. We examined univariate associations with demographics, dialysis characteristics, laboratory values and medications. Hyperkalaemia was defined as serum potassium >5.3 mmol/L.

Results: Out of nighty patients, twenty-two (24.4%) developed postoperative hyperkalaemia, of whom sixteen (18.1%) developed hyperkalaemia on postoperative day 3. The univariate analysis showed that weight, dialysis duration, preoperative serum potassium, alkaline phosphate, triglyceride, and postoperative alkaline phosphate were independently associated with hyperkalaemia after parathyroidectomy. The univariate logistic regression model showed that preoperative serum potassium was the only independent factor that could predict hyperkalaemia after parathyroidectomy (odds ratio, 1.59; 95% confidence interval, 1.24-2.05). The optimal cut-off for pre-operative K was 3.9 mmol/L according to the receiver operating characteristic (ROC) curve. A higher incidence of postoperative hyperkalaemia was found in male and younger patients, but the difference was not statistically significant (p>0.05).

Conclusions: Pre-operative serum potassium less than 3.9 mmol/L was associated with less hyperkalaemia post-operatively in end-stage renal disease (ESRD) patients undergoing PTX.
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http://dx.doi.org/10.1186/s12882-019-1416-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585140PMC
June 2019

The prevalence of depression and the association between depression and kidney function and health-related quality of life in elderly patients with chronic kidney disease: a multicenter cross-sectional study.

Clin Interv Aging 2019 15;14:905-913. Epub 2019 May 15.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease, Beijing, People's Republic of China.

The prevalence of depression and the relationship between depression and kidney function and health-related quality of life (HRQOL) are not well understood in elderly patients with predialysis chronic kidney disease (CKD). This study aimed to evaluate the prevalence of depression and the association between depression and kidney function and HRQOL. In this cross-sectional study, 1079 elderly participants with CKD were recruited at 32 clinical centers located within 26 cities throughout 24 provinces in China. Demographic information and laboratory analyses were collected. Symptoms of depression were assessed using the 15-item Geriatric Depression Scale (GDS-15). HRQOL was evaluated using the Kidney Disease Quality of Life-36 (KDQOL-36) instrument. The prevalence of depression was 23.0%. The estimated glomerular filtration rate (eGFR) was negatively correlated with the GDS score whether it was treated as a categorical variable (r=-0.097, =0.001) or as a continuous variable (r=-0.100, =0.001). Marital status, education level, history of CVD and diabetes, CKD stage and proteinuria confirmed to be independent and significant predictors of depression in patients with CKD. Compared with CKD 1-2 patients, we observed an increase of 0.541 and 4.171 in the odds for developing depression in patients CKD 4 (odds ratio [OR] =1.541; =0.031) and CKD 5 (odds ratio [OR] =5.171; <0.001), respectively. We observed negative and significant correlations with the GDS score for the following components: PCS (r=-0.370, <0.001), MCS (r=-0.412, <0.001), burden of kidney disease (r=-0.403, <0.001), symptoms and problems of kidney disease (r=-0.360, <0.001) and effects of kidney disease (r=-0.355, <0.001). Depression was an independent and significant predictor of all the subcomponents of the HRQOL. The prevalence of depression in elderly patients with CKD was high and was negatively correlated with kidney function. Depression had a major negative impact on HRQOL.
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http://dx.doi.org/10.2147/CIA.S203186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526925PMC
September 2019

Methionine restriction delays senescence and suppresses the senescence-associated secretory phenotype in the kidney through endogenous hydrogen sulfide.

Cell Cycle 2019 07 5;18(14):1573-1587. Epub 2019 Jun 5.

a Department of Nephrology, Chinese PLA General Hospital , Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases , Beijing , China.

Aging is a risk factor for various acute and chronic kidney injuries. Kidney aging is accompanied by the secretion of growth factors, proteases, and inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). These factors accelerate the aging process and senescence-associated changes. Delaying kidney senescence may prevent acute and chronic kidney injury. Methionine restriction (MR) was found to be an effective intervention for delaying senescence. However, the mechanism of MR remains unclear. In this study, we investigated the effect of MR on the survival rate and renal aging of C57BL/6 mice and examined the relevant mechanisms. MR increased the survival rate and decreased the levels of senescence markers in the aging kidney. Both in vivo and in vitro, MR upregulated the transsulfuration pathway to increase HS production, downregulated senescence markers and the SASP, and activated AMPK. The ability of MR to delay aging was reduced when AMPK was inhibited. These results suggest that MR may slow animal aging and kidney senescence through HS production and AMPK pathway activation. : DR: diet restriction; MR: methionine restriction; SASP: senescence-associated secretory phenotype; AL: ad libitum; CKD, chronic kidney disease; AKI: acute kidney disease; TSP: transsulfuration pathway; CGL: cystathionine g-lyase; HS: hydrogen sulfide; AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin; IS: indoxyl sulfate; CC: compound C.
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http://dx.doi.org/10.1080/15384101.2019.1618124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619995PMC
July 2019

Urinary angiostatin: a novel biomarker of kidney disease associated with disease severity and progression.

BMC Nephrol 2019 04 3;20(1):118. Epub 2019 Apr 3.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, 100853, China.

Background: This study aimed to evaluate the value of urinary angiostatin levels for assessing disease severity and progression of IgA nephropathy (IgAN).

Methods: Urinary angiostatin was identified as one of the distinct proteins in samples of patients with IgAN analyzed by Raybiotech protein array, and further confirmed by enzyme-linked immunosorbent assay (ELISA).

Results: Urinary angiostatin levels were significantly higher in IgAN patients than that in healthy controls (HC) subjects and lower than in disease controls (DC) patients. The concentrations of angiostatin in urine normalized to urinary creatinine (angiostatin/Cr) were positively associated with proteinuria level. With advancing chronic kidney disease (CKD) stage, urinary angiostatin/Cr levels were gradually increased. Urinary angiostatin/Cr levels in patients with Lee's grade IV-V were significantly higher than those in Lee's grade I-II and III. We further compared urinary angiostatin/Cr levels by using Oxford classification and found the expression in patients with mesangial proliferative score 1(M1) was significantly higher than that in M0 (P < 0.001). In addition, the levels of urinary angiostatin/Cr in patients with tubular atrophy/interstitial fibrosis score 1(T1) and T2 were significantly higher than those in T0 (P < 0.01, P < 0.001, respectively). After follow-up, renal survival was significantly worse in patients with higher levels of urinary angiostatin (P < 0.05).

Conclusions: Urinary angiostatin may be a useful novel noninvasive biomarker to evaluate disease severity and progression of IgAN.
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http://dx.doi.org/10.1186/s12882-019-1305-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446319PMC
April 2019

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF--Induced Angiogenesis.

J Am Soc Nephrol 2019 04 11;30(4):546-562. Epub 2019 Mar 11.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;

Background: Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich -2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-/activin receptor-like kinase 1 (ALK1) signaling. However, LRG1's role in the kidney, particularly in the setting of DKD, has been unclear.

Methods: We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA hybridization. We examined the effects of genetic ablation of on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes.

Results: LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes.

Conclusions: These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.
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http://dx.doi.org/10.1681/ASN.2018060599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442349PMC
April 2019

A non-invasive diagnostic model of immunoglobulin A nephropathy and serological markers for evaluating disease severity.

Chin Med J (Engl) 2019 Mar;132(6):647-652

Department of Nephrology, Chinese People's Liberation Army General Hospital, Chinese People's Liberation Army Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing 100853, China.

Background: Immunoglobulin A nephropathy (IgAN) is the most common pathological type of glomerular disease. Kidney biopsy, the gold standard for IgAN diagnosis, has not been routinely applied in hospitals worldwide due to its invasion nature. Thus, we aim to establish a non-invasive diagnostic model and determine markers to evaluate disease severity by analyzing the serological parameters and pathological stages of patients with IgAN.

Methods: A total of 272 biopsy-diagnosed IgAN inpatients and 518 non-IgA nephropathy inpatients from the Department of Nephrology of Chinese People's Liberation Army General Hospital were recruited for this study. Routine blood examination, blood coagulation testing, immunoglobulin-complement testing, and clinical biochemistry testing were conducted and pathological stages were analyzed according to Lee grading system. The serological parameters and pathological stages were analyzed. The receiver operating characteristic (ROC) analysis was performed to estimate the diagnostic value of the clinical factors. Logistic regression was used to establish the diagnostic model.

Results: There were 15 significantly different serological parameters between the IgAN and non-IgAN groups (all P < 0.05). The ROC analysis was performed to measure the diagnostic value for IgAN of these parameters and the results showed that the area under the ROC curve (AUC) of total protein (TP), total cholesterol (TC), fibrinogen (FIB), D-dimer (D2), immunoglobulin A (IgA), and immunoglobulin G (IgG) were more than 0.70. The AUC of the "TC + FIB + D2 + IgA + age" combination was 0.86, with a sensitivity of 85.98% and a specificity of 73.85%. Pathological grades of I, II, III, IV, and V accounted for 2.21%, 17.65%, 62.50%, 11.76%, and 5.88%, respectively, with grade III being the most prevalent. The levels of urea nitrogen (UN) (13.57 ± 5.95 vs. 6.06 ± 3.63, 5.92 ± 2.97, 5.41 ± 1.73, and 8.41 ± 3.72 mmol/L, respectively) and creatinine (Cr) (292.19 ± 162.21 vs. 80.42 ± 24.75, 103.79 ± 72.72, 96.41 ± 33.79, and 163.04 ± 47.51 μmol/L, respectively) were significantly higher in grade V than in the other grades, and the levels of TP (64.45 ± 7.56, 67.16 ± 6.94, 63.22 ± 8.56, and 61.41 ± 10.86 vs. 37.47 ± 5.6 mg/d, respectively), direct bilirubin (DB) (2.34 ± 1.23, 2.58 ± 1.40, 1.91 ± 0.97, and 1.81 ± 1.44 vs. 0.74 ± 0.57 μmol/L, respectively), and IgA (310.35 ± 103.78, 318.48 ± 107.54, 292.58 ± 81.85, and 323.29 ± 181.67 vs. 227.17 ± 68.12 g/L, respectively) were significantly increased in grades II-V compared with grade I (all P < 0.05).

Conclusions: The established diagnostic model that combined multiple factors (TC, FIB, D2, IgA, and age) might be used for IgAN non-invasive diagnosis. TP, DB, IgA, Cr, and UN have the potential to be used to evaluate IgAN disease severity.
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http://dx.doi.org/10.1097/CM9.0000000000000121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416104PMC
March 2019

Analysis of chronic kidney disease staging with different estimated glomerular filtration rate equations in Chinese centenarians.

Chin Med J (Engl) 2019 Mar;132(5):512-518

Department of Nephrology, Chinese People's Liberation Army General Hospital, Chinese People's Liberation Army Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing 100853, China.

Background: Accurate estimation of the glomerular filtration rate (GFR) and staging of chronic kidney disease (CKD) are important. Currently, there is no research on the differences in several estimated GFR equations for staging CKD in a large sample of centenarians. Thus, this study aimed to investigate the differences in CKD staging with the most commonly used equations and to analyze sources of discrepancy.

Methods: A total of 966 centenarians were enrolled in this study from June 2014 to December 2016 in Hainan province, China. The GFR with the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Berlin Initiative Study 1 (BIS1) equations were estimated. Agreement between these equations was investigated with the κ statistic and Bland-Altman plots. Sources of discrepancy were investigated by partial correlation analysis.

Results: The κ values of the MDRD and CKD-EPI equations, MDRD and BIS1 equations, and CKD-EPI and BIS1 equations were 0.610, 0.253, and 0.381, respectively. Serum creatinine (Scr) explained 10.96%, 41.60% and 17.06% of the variability in these three comparisons, respectively. Serum uric acid (SUA) explained 3.65% and 5.43% of the variability in the first 2 comparisons, respectively. Gender was associated with significant differences in these 3 comparisons (P < 0.001).

Conclusions: The strengths of agreement between the MDRD and CKD-EPI equations were substantial, but those between the MDRD and BIS1 equations and the CKD-EPI and BIS1 equations were fair. The difference in CKD staging of the first 2 comparisons strongly depended on Scr, SUA and gender, and that of CKD-EPI and BIS1 equations strongly depended on Scr and gender. The incidence at various stages of CKD staging was quite different. Thus, a new equation that is more suitable for the elderly needs to be built in the future.
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http://dx.doi.org/10.1097/CM9.0000000000000079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416091PMC
March 2019

Progress of small ubiquitin-related modifiers in kidney diseases.

Chin Med J (Engl) 2019 Feb;132(4):466-473

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing 100853, China.

Objective: Small ubiquitin-related modifiers (SUMOs) are a group of post-translational modification proteins extensively expressed in eukaryotes. Abnormal SUMOylation can lead to the development of various diseases. This article summarizes the progress on research of the role of SUMOs in various types of kidney diseases to further increase the understanding of the regulatory functions of SUMOylation in the pathogenesis of kidney diseases.

Data Sources: This review was based on articles published in the PubMed databases up to January 2018, using the keywords including "SUMOs," "SUMOylation," and "kidney diseases."

Study Selection: Original articles and critical reviews about SUMOs and kidney disease were selected for this review. A total of 50 studies were in English.

Results: SUMO participates in the activation of NF-κB inflammatory signaling pathway, playing a central regulatory role in the inflammation and progression of DN, and the secretion of various chemokines in AKI. SUMO involves in the regulation of TG2 and Nrf2 antioxidant stress, affecting renal tubular injury in AKI. SUMO affects the MAPK/ERK pathway, regulating intracellular signal transduction, modulating the transcription and expression of effector molecules in DN. SUMO contributes to the TGF-β/Smad pathway, leading to fibrosis of the kidney. The conjugate combination of SUMO and p53 regulates cell proliferation and apoptosis, and participates in the regulation of tumorigenesis. In addition, SUMOylation of MITF modulates renal tumors secondary to melanoma, Similarly, SUMOylation of tumor suppressor gene VHL regulates the occurrence of renal cell carcinoma in VHL syndrome.

Conclusions: Tissue injury, inflammatory responses, fibrosis, apoptosis, and tumor proliferation in kidney diseases all involve SUMOs. Further research of the substrate SUMOylation and regulatory mechanisms of SUMO in kidney diseases will improve and develop new treatment measures and strategies targeting kidney diseases.
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http://dx.doi.org/10.1097/CM9.0000000000000094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595721PMC
February 2019

Modulation of Macrophage Polarization by Human Glomerular Mesangial Cells in Response to the Stimuli in Renal Microenvironment.

J Interferon Cytokine Res 2018 12 5;38(12):566-577. Epub 2018 Dec 5.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory for Kidney Diseases, Beijing, China.

Mesangial cell (MC) activation and macrophage infiltration are 2 major events closely related with each other in mesangial proliferative glomerulonephritis. In the anti-Thy 1 nephritis model, macrophages mediate the damage and also the expansion of mesangium through secreting various inflammatory factors; however, in glomerular microenvironment how MCs affect macrophage activity in the presence of various stimuli have not yet been understood. In the present study, we found that resting human MCs (HMCs) constitutively expressed chemokine [C-C motif] ligand 2 (CCL-2) and interleukin (IL)-6 and induced M2 polarization of macrophages in the coculture system. HMC proliferation and migration and expression of IL-6, CCL-2, and macrophage colony-stimulating factor in HMCs were enhanced after platelet-derived growth factor (PDGF)-BB stimulation, among which CCL-2 was responsible for inducing the M2 polarization of macrophages. Furthermore, PDGF-BB-stimulated HMCs alleviated the classical activation of macrophages and drove more intensified M2 polarization of macrophages than resting HMCs did. However, lipopolysaccharide and interferon-γ (IFN-γ) stimulated HMCs maintained the M1 phenotype of cocultured macrophages. In conclusion, MCs actively participated in glomerular inflammation through influencing macrophage polarization. The interplay between MCs and infiltrated macrophages is finely modulated by secretory factors such as PDGF-BB and IFN-γ in response to the renal inflammatory microenvironment.
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http://dx.doi.org/10.1089/jir.2018.0093DOI Listing
December 2018

Clinicopathological Features of Nondiabetic Renal Diseases from Different Age Groups: An Observational Cross-sectional Study.

Chin Med J (Engl) 2018 Dec;131(24):2953-2959

Department of Nephrology, Chinese People's Liberation Army General Hospital, Chinese People's Liberation Army Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing 100853, China.

Background: Diabetes mellitus (DM) has become the leading cause of chronic kidney disease (CKD). Nondiabetic renal diseases (NDRDs) have different clinicopathological features and prognosis from those of diabetic nephropathy. Our study sought to analyze the clinical and pathological features of NDRDs, in different age groups through a cross-sectional study.

Methods: All patients with type 2 DM at our center who underwent renal biopsy between March 1997 and March 2017 were screened and divided into three groups by age: Group 1 (youth group), 18-44 years old; Group 2 (middle-aged group), 45-59 years old; and Group 3 (elderly group), ≥60 years old. We analyzed the clinicopathological data and risk factors by univariate and multivariate logistic regression for NDRD of the patients to identify the features of NDRD in different age groups.

Results: We included 982 patients in the final analysis. Patients with NDRD accounted for 64.4% of all patients. IgA nephropathy (IgAN) was the most common pathological pattern in young patients with NDRD, accounting for 26.3%. In the middle-aged group, the two most common pathological patterns were IgAN and membranous nephropathy. Membranous nephropathy was the most common pathological pattern in elderly patients with NDRD, accounting for 29.3%. Consistent with pathological features, glomerular hematuria is a risk factor for NDRD in Group 1 (odds ratio [OR], 26.514; 95% confidence interval [CI], 2.503-280.910; P = 0.006). On the other hand, rapidly increasing proteinuria or nephrotic syndrome is a risk factor for NDRD in Group 2 (OR, 5.921; 95% CI, 2.061-17.013; P = 0.001) and Group 3 (OR, 90.409; 95% CI, 6.198-1318.826; P = 0.001).

Conclusions: This single-center study showed that the proportion and composition of NDRD differ among different age groups. Consistent with pathological features, some clinical indices such as hematuria and proteinuria showed different features among different age groups.
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http://dx.doi.org/10.4103/0366-6999.247197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302642PMC
December 2018

Identification of key genes and pathways in diabetic nephropathy by bioinformatics analysis.

J Diabetes Investig 2019 Jul 21;10(4):972-984. Epub 2019 Jan 21.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA Medical School, Beijing, China.

Aims/introduction: The aim of the present study was to identify candidate differentially expressed genes (DEGs) and pathways using bioinformatics analysis, and to improve our understanding of the cause and potential molecular events of diabetic nephropathy.

Materials And Methods: Two cohort profile datasets (GSE30528 and GSE33744) were integrated and used for deep analysis. We sorted DEGs and analyzed differential pathway enrichment. DEG-associated ingenuity pathway analysis was carried out. The screened gene expression feature was verified in the db/db mouse kidney cortex. Then, rat mesangial cells cultured with high-concentration glucose were used for verification. The target genes of transcriptional factor E26 transformation-specific-1 (ETS1) were predicted with online tools and validated using chromatin immunoprecipitation assay quantitative polymerase chain reaction.

Results: The two GSE datasets identified 89 shared DEGs; 51 were upregulated; and 38 were downregulated. Most of the DEGs were significantly enriched in cell adhesion, the plasma membrane, the extracellular matrix and the extracellular region. Quantitative reverse transcription polymerase chain reaction analysis validated the upregulated expression of Itgb2, Cd44, Sell, Fn1, Tgfbi and Il7r, and the downregulated expression of Igfbp2 and Cd55 in the db/db mouse kidney cortex. Chromatin immunoprecipitation assay quantitative polymerase chain reaction showed that Itgb2 was the target gene of transcription factor Ets1. ETS1 knockdown in rat mesangial cells decreased integrin subunit beta 2 expression.

Conclusion: We found that EST1 functioned as an important transcription factor in diabetic nephropathy development through the promotion of integrin subunit beta 2 expression. EST1 might be a drug target for diabetic nephropathy treatment.
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http://dx.doi.org/10.1111/jdi.12986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626994PMC
July 2019
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