Association of physical performance with cognitive impairment in middle-aged to older haemodialysis patients: a multicentre cross-sectional observational study.

OBJECTIVE: To determine the prevalence of cognitive impairment (CI) among middle-aged to older patients receiving maintenance haemodialysis (MHD) and to investigate the potential association between CI and physical performance. METHODS: This cross-sectional observational study enrolled participants aged 55-85 years who received MHD. Cognitive status was assessed using the Mini Mental State Examination (MMSE). Physical performance was measured by hand grip strength, the Timed Up and Go Test (TUGT) and the 4-m walking speed. Sociodemographic, clinical and laboratory parameters were recorded for each patient. RESULTS: The study included 592 patients (363 males); and of these, 126 (21.3%) were diagnosed with CI. Compared with patients with normal cognitive function, those with CI were significantly older and had significantly longer dialysis duration, lower educational level, higher Malnutrition Inflammation Score, higher depression and higher Charlson Comorbidity Index score. After adjustment for covariates, multiple regression analysis suggested that grip strength (odds ratio [OR] = 0.959, 95% confidence interval [CI] = 0.924, 0.996) and 4-m walking speed (OR = 0.161, 95% CI = 0.070, 0.368) were protective factors. TUGT (OR = 1.037, 95%CI = 1.003, 1.071) was a risk factor. CONCLUSION: Physical performance was correlated with CI and might be a significant indicator for the early identification of CI in middle-aged to older MHD patients.

Association between hearing loss and physical performance in patients on maintenance hemodialysis.

BACKGROUND: The correlation between hearing loss (HL) and physical performance in patients receiving maintenance hemodialysis (MHD) remains poorly investigated. This study explored the association between HL and physical performance in patients on MHD. METHODS: This multicenter cross-sectional study was conducted between July 2020 and April 2021 in seven hemodialysis centers in Shanghai and Suzhou, China. The hearing assessment was performed using pure-tone average (PTA). Physical performance was assessed using the Timed Up and Go Test (TUGT), handgrip strength, and gait speed. RESULTS: Finally, 838 adult patients (male, 516 [61.6%]; 61.2 ± 2.6 years) were enrolled. Among them, 423 (50.5%) had mild to profound HL (male, 48.6% and female, 53.4%). Patients with HL had poorer physical performance than patients without HL (p < 0.001). TUGT was positively correlated with PTA (r = 0.265, p < 0.001), while handgrip strength and gait speed were negatively correlated with PTA (r = -0.356, p < 0.001 and r = -0.342, p < 0.001, respectively). Physical performance in patients aged <60 years showed significant dose-response relationships with HL. After adjusting for confounders, the odds ratios (95% confidence intervals) for HL across the TUGT quartiles (lowest to highest) were 1.00 (reference), 1.15 (0.73-1.81), 1.69 (1.07-2.70), and 2.87 (1.69-4.88) (p for trend = 0.005). CONCLUSION: Lower prevalence of HL was associated with a faster TUGT and a stronger handgrip strength in patients on MHD.

Plasma Aß42:Aß40 ratio as a biomarker for cognitive impairment in haemodialysis patients: a multicentre study.

Background: Mild cognitive impairment (MCI) and dementia are more prevalent in patients undergoing haemodialysis (HD). Although the cerebrospinal fluid amyloid beta (Aß) and tau (τ) have proven to be valid biomarkers for the diagnosis of Alzheimer's disease (AD) in the general population, the roles of plasma Aß and τ for the diagnosis of cognitive impairment in HD patients remain unknown. Methods: We conducted a cross-sectional study including patients receiving HD in three hospitals in Shanghai. All patients completed the Montreal Cognitive Assessment-Basic (MoCA-B). To validate the effectiveness of the MoCA-B score for screening MCI, a subset group underwent neuropsychological batteries. Serum proteomes were compared in HD patients with normal cognitive function and dementia. Plasma Aß42, Aß40 and total τ were measured using a single molecule array. Results: A total of 311 HD patients were enrolled (mean age 63 years, 55% male). The best cut-off score of MoCA-B for differentiating MCI and normal cognition was 24, with an area under the curve of 0.94. Serum proteomics revealed that neurodegenerative pathways related to AD were enriched in HD patients with dementia. The plasma Aß42:Aß40 ratio was significantly reduced in patients with MCI and dementia and was independently associated with cognitive function after adjusting for age, sex and education levels. Conclusions: We validated the MoCA-B as an optimal cognitive function screening instrument for MCI in HD patients. The plasma Aß42:Aß40 ratio was a potential biomarker in distinguishing normal cognition, MCI and dementia in HD populations.

Prevalence and predisposing factors of depressive symptoms in continuous ambulatory peritoneal dialysis patients: a cross-sectional single center study.

BACKGROUND: The aim of this study was to identify the prevalence of the depressive symptoms and the factors associated with the depressive symptoms in peritoneal dialysis patients. METHODS: A cross-sectional study was carried out to evaluate the prevalence and associated factors of depression in 132 continuous ambulatory peritoneal dialysis patients. Depression was evaluated using Zung Self-Rating Depression Scale. Sociodemographic and clinical characteristic were also investigated. Univariate analysis and multivariate logistic regression analysis were performed to select factors associated with depressive symptoms. RESULTS: Their median age was 57.5 years, and 58.3% were male. The rate of depressive symptoms in peritoneal dialysis patients was 78.0%. The rate of moderate/severe depressive symptoms was 64.4%. Multivariable logistic regression analysis showed that lower serum hemoglobin was significantly associated with increased risks of depression (OR = 0.989, 95CI%=0.979-0.998, p = 0.023). CONCLUSION: Depression was highly prevalent in the peritoneal dialysis patients. Serum hemoglobin was independent risk factor for depressive symptoms in peritoneal dialysis patients.

Association of Sleep Duration with Physical Performance in Hemodialysis Patients: A Multicenter Cross-Sectional Study.

BACKGROUND: Hemodialysis (HD) patients have decreased physical function. Getting enough sleep is important for maintaining physical function. However, the relationship between sleep duration and physical performance in HD patients is unclear. METHODS: We conducted a multicenter cross-sectional study at seven HD centers in Shanghai and Suzhou, China. 880 HD patients were enrolled between July 2020 and April 2021. Clinical Characteristics, laboratory indicator, sleep assessment data were collected. Physical performance included balance function, muscle strength, and mobility, which were measured by timed up and go test (TUGT), handgrip, and 4-m walk test, respectively. We divided sleep duration into four groups <7 h, 7-8 h, >8-9 h, ≥9 h. RESULTS: A total of 840 patients had completed data (men 525, women 315, mean age 61.24 years). TUGT in group <7 h and ≥9 h was higher than mid-range sleep duration. Handgrip strength in group ≥9 h was lower than group <7 h and 7-8 h. Gait speed in group <7 h and ≥9 h was lower than group 7-8 h. Adjusting for the covariates, short and long sleep duration were associated with slower gait speed. CONCLUSION: HD patients with abnormal sleep duration had poorer physical performance. Short and long sleep duration were significantly associated with gait speed.

Development and validation of a diagnostic nomogram for sarcopenia in Chinese hemodialysis patients.

BACKGROUND: Sarcopenia is a clinical condition that is common in patients with chronic kidney disease (CKD), especially in those on dialysis. However, the relatively complicated diagnostic procedure limits its use in clinical situations. In this study we aimed to establish a simplified tool for the diagnosis of sarcopenia in patients on hemodialysis (HD). METHODS: Overall, 757 eligible patients from seven HD centers in Shanghai and Suzhou, China, were recruited from 2020 to 2021. The cross-sectional data were analyzed. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 criteria. Among them, 511 consecutive patients (77 with and 434 without sarcopenia) from five centers were included in the training set for the establishment of a diagnostic nomogram. Ten investigative parameters including clinical characteristics, body measurements and physical performance were used to derive the diagnostic nomogram. A total of 246 consecutive patients (47 with and 199 without sarcopenia) were included for validation of the diagnostic model. RESULTS: The average age of the enrolled patients was 60.4 ± 12.1 years, 59.8% were males and 90.5% received dialysis using an arteriovenous fistula. Overall, the sarcopenia rate was 16.4%. The training and validation sets showed no significant differences in sarcopenia rate (15.1% and 19.1%, respectively; P = .160). The nomogram derived from the training set for sarcopenia, which was based on only four features-age, sex, body weight and grip strength-achieved high C-indexes of 0.929 [95% confidence interval (CI) 0.904-0.953] and 0.955 (95% CI 0.931-0.979) in the training and external sets, respectively, and had a well-fitted calibration curve. The cut-off value was 0.725, with a sensitivity of 0.909 and a specificity of 0.816. The nomogram accurately diagnosed sarcopenia with fewer variables and more simplified diagnostic procedures. CONCLUSIONS: The nomogram had a good diagnostic capability for sarcopenia in patients on HD and may be a convenient tool for clinical use.

Relationship Between Serum Indirect Bilirubin Levels and Cardiovascular Events and All-Cause Mortality in Maintenance Hemodialysis Patients.

Purpose: Unconjugated bilirubin is one of the most endogenous antioxidant substances. Mildly elevated total bilirubin concentrations may protect against cardiovascular disease and total death. However, most studies only focused on the association between serum total bilirubin and the risk of cardiovascular disease and total death. This study aimed to investigate the relationship between serum indirect bilirubin (IBIL) and the cardiovascular events in maintenance hemodialysis patients. Patients and Methods : This retrospective cohort study included 284 maintenance hemodialysis patients. Patients were divided into two groups according to the median IBIL level: high IBIL group (IBIL ≥3.0 µmol/L) and low IBIL group (IBIL <3.0 µmol/L). All demographic and laboratory data were recorded at baseline. The endpoint was cardiovascular events and all-cause mortality. Results: During the median follow-up time of 62 months, 96 patients developed cardiovascular disease. There were 134 deaths. In Kaplan-Meier analysis curves, the risk of cardiovascular events in the low IBIL group was significantly higher than high IBIL group (P < 0.001). In multivariate Cox regression analysis, the risk of cardiovascular events in high IBIL group was 0.484 times (95% CI 0.278-0.844, P = 0.010) the risk in low IBIL group. However, there was no significant association between serum IBIL level and all-cause mortality (P = 0.269). Conclusion: Our findings suggest that lower circulating IBIL levels were associated with the increased risk of cardiovascular events in maintenance hemodialysis patients.

Comparison of three nutritional screening tools for detecting sarcopenia in patients with maintenance hemodialysis.

Background: Malnutrition, dynapenia, and sarcopenia are prevalent conditions among patients with maintenance hemodialysis (MHD). They are related to numerous adverse health outcomes. The aim of this study was to compare the effect of three nutritional screening tools on predicting the risk of dynapenia and sarcopenia in patients with MHD. Methods: From July 2020 to April 2021, a total of 849 patients with MHD were enrolled at seven different healthcare facilities in Shanghai, China in this multi-center cross-sectional study. Geriatric nutritional risk index (GNRI), malnutrition inflammation score (MIS), and creatinine (Cr) index were used for nutritional assessment. The cutoff values of muscle mass and strength to define dynapenia, pre-sarcopenia, and sarcopenia were based on the consensus by the Asia Working Group of Sarcopenia in 2019. Results: Among 849, almost 60% were malnourished with the majority suffering from dynapenia (27.7%), followed by sarcopenia (22.7%), and pre-sarcopenia (6.2%).The area under the receiver-operating characteristic curve for GNRI was 0.722 [95% confidence interval (CI) = 0.684-0.760] and 0.723 (95% CI = 0.663-0.783) in predicting sarcopenia and pre-sarcopenia. The GNRI [odds ratio (OR) =6.28, 95% CI: 4.05-9.73], MIS (OR =1.91, 95% CI: 1.31-2.78), and the Cr index (OR =2.73, 95% CI: 1.71-4.34) were all significantly associated with the risk of sarcopenia. More importantly, the sarcopenia predictability of the GNRI appears greater than the MIS and Cr index, while MIS was similar to the Cr index. Similarly, the superiority of GNRI prediction was also found in pre-sarcopenia, but not in dynapenia. Conclusion: All the three nutritional screening tools were significantly associated with an increased risk of sarcopenia. The sarcopenia predictability of the GNRI was greater than the MIS and Cr index.

Relationship between physical performance and mild cognitive impairment in elderly hemodialysis patients is modified by the presence of diabetes: A multicenter cross-sectional study.

Objective: The purpose of this study was to observe the relationship between physical performance and mild cognitive impairment (MCI) in the presence or absence of type 2 diabetes in elderly hemodialysis patients. Methods: In this multicenter cross-sectional study, 396 clinically stable and aged ≥60 years hemodialysis patients (255 men; mean age: 68.3 ± 5.9 years) were included from seven dialysis units in Shanghai, China. The Chinese version of the Modified Mini-Mental State Examination (MMSE) and the Instrumental Activities of Daily Living (IADL) scale were utilized to assess MCI. The performance-based assessments consisted of three physical tests, grip strength (GS), Timed Up and Go Test (TUGT), and 4-m walking test, which respectively represent muscle strength, mobility, and walking speed (WS). Logistic regression and multivariate linear regression were used for analysis. Results: Hemodialysis patients with diabetes had a high prevalence of MCI (20.6%). The odds ratio (OR) of MCI for the interacted items [(TUGT) * (diabetes) and (WS) * (diabetes)] was significant (p < 0.05). In diabetes patients, TUGT was positively associated with MCI, and WS was negatively associated with MCI after adjusting covariates [OR = 0.129; 95% confidence interval (CI) = 0.028-0.704, p = 0.021]. However, no significant association was found between physical performance and MCI in the non-diabetes hemodialysis patients (p > 0.05). Further analysis showed that TUGT was negatively associated with attention and calculation and language. WS was positively associated with recall and language in diabetic hemodialysis patients. Conclusions: Physical performance was associated with MCI in diabetic hemodialysis patients rather than the non-diabetes group. Whether increasing mobility or WS can positively influence MCI in individuals with type 2 diabetes requires further study.

Different stages of chronic kidney disease are associated with physical performance in adults over 60 years.

Objective: The purpose of this study was to determine the association between different stages of chronic kidney disease (CKD) and sarcopenia and its components in the Chinese older population. Methods: The study comprised of 2,213 participants aged ≥ 60 years (1,025 men; mean age: 70.7 years) recruited from Shanghai who were invited to participate in a comprehensive geriatric assessment. Sarcopenia was defined according to the AWGS 2019 consensus update on sarcopenia diagnosis criteria. The glomerular filtration rate (GFR) was estimated using the equation that originated from the CKD-EPI equation, the stages of CKD are classified according to the Kidney Disease-Improving Global Outcomes (KDIGO). Results: The overall prevalence of sarcopenia was 19.0%, which increased with the severity of CKD. The prevalence of sarcopenia in patients with CKD 3-4 and kidney failure was significantly higher than that in normal and CKD 1-2 (p < 0.05). In logistic regression analysis model, compared with normal and CKD 1 patients, kidney failure was significantly associated with the increased risk of sarcopenia and low grip strength (p < 0.05); CKD 2, CKD 3-4 and kidney failure groups were significantly associated with an increased risk of low walking speed (p < 0.05), respectively; while the association between CKD and muscle mass was not shown. Conclusions: In our study, only decreased physical performance, as represented by walking speed, was significantly associated with increased CKD severity. This may improve the evidence for the prevention and intervention of sarcopenia in patients with CKD.

Angiotensin 1-7 and its analogue decrease blood pressure but aggravate renal damage in preeclamptic mice.

Preeclampsia (PE) is a multisystem disease that affects the health of both the pregnant women and the fetus during pregnancy. Agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) play a significant role in the pathogenesis of PE. This study aimed to determine the effects of Angiotensin 1-7 (Ang 1-7) and its analogue AVE0991 on AT1-AA-induced PE model. Pregnant mice were divided into five groups: the normal pregnant group, AT1-AA-induced preeclampsia group, and AT1-AA-induced preeclampsia group treated with Losartan, Ang 1-7, and AVE0991, respectively. AT1-AA-induced PE model was established on gestational day 13 by tail intravenous injection of purified AT1-AA polyclonal antibody from serum of guinea pigs. Blood urea nitrogen (BUN), urine albumin and urinary creatinine were measured on day 18 of pregnancy. The systolic blood pressure (SBP) was measured from gestational day 13 to day 18. Renal structure changes were observed via light and electron microscopy. Compared with the normal pregnant group (NP group), AT1-AA-induced preeclampsia group (PE group) exhibited elevated blood pressure and proteinuria, consistent with the characteristics of PE. Ang 1-7 or AVE0991 treatment decreased blood pressure without showing renoprotective effects. The findings indicated that Ang 1-7 and its analogue reduced blood pressure but aggravated renal damage in AT1-AA-induced PE mice.

Efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection for the treatment of renal anemia in Chinese hemodialysis patients: A randomized, open-label, parallel-group, noninferiority phase III trial.

Background: This study was to explore the clinical efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection (recombinant human erythropoietin injection, rHuEPO) for the treatment of anemia associated with chronic kidney failure in Chinese patients undergoing hemodialysis. Method: This study was a multicenter, randomized, open-label, intergroup parallel control phase III noninferiority trial from April 19, 2013 to September 9, 2014 at 25 sites. In this study, the members of the darbepoetin alfa group underwent intravenous administration once per week or once every two weeks. The members of the control drug epoetin alfa group underwent intravenous administration two or three times per week. All subjects underwent epoetin alfa administration during the 8-week baseline period. After that, subjects were randomly assigned to the darbepoetin alfa group or epoetin alfa group. The noninferiority in the changes of the average Hb concentrations from the baseline to the end of the evaluation period (noninferiority threshold: -1.0 g/dl) was tested between the two treatments. The time-dependent hemoglobin (Hb) concentration and the maintenance rate of the target Hb concentration (the proportion of subjects with Hb concentrations between 10.0 and 12.0 g/dl) were also evaluated. Iron metabolism, including changes in the serum iron, total iron-binding capacity, ferritin, transferrin saturation, and comparisons of the dose adjustments between the two groups during the treatment period were analyzed further. Adverse events (AEs) were also observed and compared, and the safety was analyzed between the two treatment groups. The conversion rate switching from epoetin alfa to darbepoetin alfa was also discussed. SAS® software version 9.2 was used to perform all statistical analyses. Descriptive statistics were used for all efficacy, safety, and demographic variable analyses, including for the primary efficacy indicators. Results: Four hundred and sixty-six patients were enrolled in this study, and ultimately 384 cases were analyzed for safety, including 267 cases in the darbepoetin alfa group and 117 cases in the epoetin alfa group. There were 211 cases in the per-protocol set, including 152 cases in the darbepoetin alfa group and 59 cases in the epoetin alfa group. The changes in the average Hb concentrations from the baseline to the end of the evaluation period were -0.07 and -0.15 g/dl in the darbepoetin alfa group and epoetin alfa group respectively. The difference between the two groups was 0.08 g/dl (95% confidence interval [CI]: -0.22 to 0.39), and the lower limit of the 95% CI was -0.22 > -1.0 g/dl. The average Hb concentrations of the two groups were 10.88-11.43 g/dl (darbepoetin alfa) and 10.91-11.38 g/dl (epoetin alfa) during the study period of Weeks 0-28, with the maintenance rates of the target Hb concentration ranging within 71%-87% and 78%-95% in the darbepoetin alfa group and epoetin alfa group respectively. During the period of comparison between the two groups, the incidence of AEs in the darbepoetin alfa group was 61.42%, while in the epoetin alfa group it was 56.41%. All of the adverse events and reactions in the study were those commonly associated with hemodialysis. Conclusion: The overall efficacy and safety of darbepoetin alfa for the treatment of Chinese renal anemia patients undergoing hemodialysis are consistent with those of epoetin alfa.

Darbepoetin alfa injection versus epoetin alfa injection for treating anemia of Chinese hemodialysis patients with chronic kidney failure: A randomized, open-label, parallel-group, non-inferiority Phase III trail.

Background: Erythropoietin is a glycoprotein that mainly regulates erythropoiesis. In patients with chronic renal failure with anemia, darbepoetin alfa can stimulate erythropoiesis, correct anemia, and maintain hemoglobin levels. This study was designed to demonstrate the efficacy and safety of darbepoetin alfa injections as being not inferior to epoetin alfa injections (Recombinant Human Erythropoietin injection, rHuEPO) when maintaining hemoglobin (Hb) levels within the target range (10.0-12.0 g/dL) for the treatment of renal anemia. Methods: Ninety-five patients were enrolled in this study from April 15, 2013 to April 10, 2014 at 25 sites. In this study, patients (n = 95) aged 18-70 years were randomized into a once per week intravenous darbepoetin alfa group (n = 56) and a twice or three times per week intravenous epoetin alfa group (n = 39) for 28 weeks, who had anemia with hemoglobin levels between 6 g/dL and 10 g/dL due to chronic kidney disease (CKD) and were undergoing hemodialysis or hemofiltration with ESA-naive (erythropoiesis stimulating agent-naive). The primary efficacy profile was the mean Hb level (the non-inferiority margin was -1.0 g/dL, week 21-28); the secondary efficacy profiles were the Hb increase rate (week 0-4), the target Hb achievement cumulative rate and time, the change trends of the Hb levels, and the target Hb maintenance ratio. Adverse events (AEs) were observed and compared, and the efficacy and safety were analyzed between the two treatment groups. Additionally, the frequencies of dose adjustments between the darbepoetin alfa and epoetin alfa groups were compared during the treatment period. SAS® software version 9.2 was used to perform all statistical analyses. Descriptive statistics were used for all efficacy, safety, and demographic variable analyses, including for the primary efficacy indicators. Results: The mean Hb level was 11.3 g/dL in the darbepoetin alfa group and 10.7 g/dL in the epoetin alfa group, respectively; the difference of the lower limits of the 95% confidence intervals (CI) between the two groups was 0.1 g/dL (>-1.0 g/dL), and non-inferiority was proven; the Hb levels started to increase in the first four weeks at a similar increase rate; no obvious differences were observed between the groups in the target Hb achievement cumulative rates, and the Hb levels as well as the target Hb level maintenance rate changed over time. The incidence of AEs was 62.5% in the darbepoetin alfa group and 76.9% in the epoetin alfa group. All the adverse events observed in the study were those commonly associated with hemodialysis. Conclusion: Darbepoetin alfa intravenously once per week can effectively increase Hb levels and maintain the target Hb levels well, which makes it not inferior to epoetin alfa intravenously twice or three times per week. Darbepoetin alfa shows an efficacy and safety comparable to epoetin alfa for the treatment of renal anemia.

Empagliflozin Ameliorates Preeclampsia and Reduces Postpartum Susceptibility to Adriamycin in a Mouse Model Induced by Angiotensin Receptor Agonistic Autoantibodies.

Preeclampsia (PE) is the leading cause of maternal and perinatal morbidity and mortality and also is a risk factor for cardiovascular and kidney disease later in life. PE is associated with oversecretion of autoantibodies against angiotensin II type 1 receptor (AT1-AA) by the placenta into the maternal circulation. Here, we sought to determine the therapeutic value of the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin (EMPA) in mice with AT1-AA-induced preeclampsia. Pregnant mice were injected with AT1-AA at gestation day (GD) 13 and treated daily with EMPA until GD 19, at which point some of the maternal mice were sacrificed and assessed. The other maternal mice were labored on time and challenged with adriamycin (ADR) at 12 weeks postpartum; their offspring were assessed for fetal outcomes. We showed that EMPA treatment significantly relieved high systolic blood pressure and proteinuria and ameliorated kidney injury in PE mice without affecting fetal outcomes. EMPA also ameliorated podocyte injury and oxidative stress, reduced the expression of SGLT2 and activated the AMPK/SIRT1 signaling pathway in vivo and in vitro. Remarkably, EMPA treatment during pregnancy reduced ADR-induced kidney and podocyte injury postpartum. These findings suggest that EMPA could be a potential pharmacological agent for PE.

Klotho/FGF23 and Wnt in SHPT associated with CKD via regulating miR-29a.

OBJECTIVE: Recently, the interaction between Klotho/fibroblast growth factor 23 (FGF-23) axis and Wnt signaling has been recognized to be responsible for chronic kidney disease (CKD)-associated comorbidities, including secondary hyperparathyroidism (SHPT). This study aimed to investigate the molecular mechanism of the interaction between Klotho/FGF23 axis and Wnt. METHODS: A SHPT model was successfully established with a high-phosphorus diet plus 5/6 nephrectomy. Cell counting Kit-8 (CCK-8) assay and calcium deposit experiment were applied to detect the proliferation and calcium levels. Quantitative real-time PCR (qRT-PCR), Western blotting and immunofluorescence (IF) were used to determine the expression or location of FGF23, calcification-related factors and ß-catenin after lentivirus-mediated Klotho overexpression. Luciferase reporter assay was performed to further validate the transcriptional regulation between microRNA-29a (miR-29a) and Dickkopf-1 (DDK1). RESULTS: We found increased serum biochemical factors including parathyroid hormone (PTH), phosphorus, calcium, enhanced parathyroid calcification, and decreased expressions of Klotho in a rat model of secondary hyperparathyroidism. Moreover, genetic-induced upregulation of Klotho inhibited the proliferation, reduced the calcification and the alkaline phosphatase (ALP) activity, and downregulated Wnt/ß-catenin signaling in parathyroid cells. CONCLUSIONS: Mechanistically, Klotho suppressed miR-29a expression, led to upregulated expression of Wnt/ß-catenin signaling inhibitor DKK1, and finally downregulated the activity of Wnt/ß-catenin signaling. These findings suggest a novel molecular mechanism in the pathogenesis of CKD-associated SHPT, which provides a potential therapeutic target in the future.

Heparanase promotes endothelial-to-mesenchymal transition in diabetic glomerular endothelial cells through mediating ERK signaling.

Glomerular endothelial cells (GEnCs) dysfunction occurs at the early stage of diabetic nephropathy (DN). One of its characteristics is endothelial-to-mesenchymal transition (EndMT). Heparanase (HPSE) is the only known mammalian endoglycosidase capable of degrading heparin sulfates and has a prominent role in DN pathogenesis. However, whether HPSE induces EndMT of GEnCs remains unknown. This study aimed to determine the effect and potential mechanism of HPSE on GEnCs phenotype under high-glucose conditions. In the early development of streptozotocin (STZ)-induced diabetic mice, HPSE overexpression was positively correlated with renal injury and the number of GEnCs undergoing EndMT, which was characterized by loss of endothelial marker CD31 and gain of mesenchymal markers including α-SMA and Snail1/2 by double immunofluorescence staining. Bioinformatics analysis revealed a positive correlation between HPSE and ERK. The counts of double positive staining of CD31 and p-ERK1/2 was significantly increased in the glomeruli of STZ-induced diabetic mice compared with sham mice. In cultured GEnCs, high glucose dramatically upregulated the expressions of HPSE and p-ERK1/2, both of which were markedly blocked by HPSE siRNA. Furthermore, recombinant mouse HPSE (rmHPSE) promoted the expressions of mesenchymal markers and p-ERK1/2 in a dosage- and time-dependent manner. U0126, a specific MEK/ERK inhibitor, significantly inhibited either high glucose or rmHPSE-induced EndMT of GEnCs. These data indicate that high glucose induces EndMT of GEnCs at least partially through upregulating HPSE and that HPSE promotes EndMT of GEnCs via activating ERK signaling. This study improves understanding the crucial role of HPSE in DN development and progression.

Undernutrition when young and the risk of poor renal function in adulthood in women with diabetes in Shanghai, China.

OBJECTIVE: To evaluate the effect of undernutrition when young on the risk of poor renal function in adulthood in women with diabetes mellitus. METHODS: We studied diabetic women born between 1921 and 1958 who were exposed to the 1959-to-1962 Chinese famine when they were 0 to 37 years old. Exposure age was classified as young adulthood (18 to 37 years), adolescence (10 to 17 years), or childhood (0 to 9 years). The Adolescence group, which was provided with the largest amount of food during the famine, was used as the control group, and variance and binary logistic regression analyses were performed. RESULTS: The prevalences of low estimated glomerular filtration rate (eGFR) in the Childhood, Adolescence, and Young adulthood groups were 5.26%, 22.39%, and 79.24%, respectively. The risk of low eGFR for the Young adulthood group (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.10, 2.48), but not for the Childhood group (OR 1.10, 95% CI 0.68, 1.78), was higher than that for the Adolescence group after adjustment for potential confounders. CONCLUSIONS: Undernutrition during young adulthood significantly increases the risk of renal dysfunction in adult women with diabetes. Therefore, the nutrition of less affluent young women should be improved.

Bioinformatic investigation for candidate genes and molecular mechanism in the pathogenesis of membranous nephropathy.

AIM: We aimed to explore the detailed molecular mechanism of immune-associated genes in membranous nephropathy (MN). METHODS: A microarray data set (GSE133288) was retrieved from the Gene Expression Omnibus database. Differentially expressed mRNAs (DEMs) in MN vs control groups were identified, and MN-related DEMs (MN-DEMs) were further verified and screened using the comparative toxicogenomics database (CTD) database. The publicly available database, InnateDB was used to investigate immune genes, and the overlapped genes between MN-DEMs and the immune genes were considered as MN-related immune genes (iDEMs). A protein-protein interaction network (PPI) was constructed based on these iDEMs, followed by function and pathway enrichment analysis. Finally, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) associated with iDEMs were predicted, followed by a lncRNA-miRNA-mRNA (competing endogenous RNAs, ceRNA) network construction. RESULTS: A total of 327 DEMs and 48 iDEMs were revealed; a PPI network was constructed with 100 PPI pairs and 37 iDEMs. iDEMs including JUN and FOS were mainly enriched in pathways such as osteoclast differentiation and function including response to immobilization stress, respectively. Based on mRNA-associated miRNA and lncRNA prediction, 30 ceRNA interactions including KCNQ1OT1-miR-204-5p-SRY-Box Transcription Factor 4 (SOX4) were explored. CONCLUSION: mRNAs including FOS and JUN might participate in MN development via response to immobilization stress function and the osteoclast differentiation pathway. The mRNA SOX4 might contribute to MN progression via sponging KCNQ1OT1-miR-204-5p interaction.