Association of trimethylamine N-Oxide with cardiovascular and all-cause mortality in hemodialysis patients.

BACKGROUND: Trimethylamine-N-Oxide (TMAO) is a proatherogenic and prothrombotic metabolite. Our study examined the association of plasma TMAO level with cardiovascular and all-cause mortality in hemodialysis (HD) patients. METHODS: Patients who were at least 18 years-old and received HD for at least 6 months were enrolled within 6 months. Patients with coronary heart disease, congestive heart failure, arrhythmia, or stroke within 3 months before study onset were excluded. The primary endpoints were cardiovascular and all-cause death, and the secondary endpoint was cerebrovascular death. RESULTS: We recruited 252 patients and divided them into a high-TMAO group (>4.73 µg/mL) and a low-TMAO group (≤4.73 µg/mL). The median follow-up time was 73.4 months (interquartile range: 42.9, 108). A total of 123 patients died, 39 from cardiovascular disease, 19 from cerebrovascular disease, and 65 from other causes. Kaplan-Meier analysis indicated that the high-TMAO group had a greater incidence of cardiovascular death (Log-Rank: p = 0.006) and all-cause death (Log-Rank: p < 0.001). Cox regression analysis showed that high TMAO level was significantly associated with cardiovascular and all-cause mortality. After adjustment for confounding, this association remained significant for cardiovascular mortality (TMAO as a continuous variable: HR: 1.18, 95%CI: 1.07, 1.294, p < 0.001; TMAO as a dichotomous variable: HR: 3.44, 95%CI: 1.68, 7.08, p < 0.001) and all-cause mortality (TMAO as a continuous variable: HR: 1.14, 95%CI: 1.08, 1.21, p < 0.001; TMAO as a dichotomous variable: HR: 2.54, 95%CI: 1.71, 3.76, p < 0.001). CONCLUSIONS: High plasma TMAO level is significantly and independently associated with cardiovascular and all-cause mortality in HD patients.

Delayed ischaemic preconditioning in the presence of galectin-9 protects against renal ischaemic injury through a regulatory T-cell dependent mechanism.

AIM: Renal ischaemia/reperfusion injury (IRI) is a complication of major surgeries. Regulatory T cells (Tregs) can suppress immunologic damage in the renal IR. Previous studies indicated that delayed ischaemic preconditioning (IPC) partially attenuates IR by inducing Treg expansion. Galectin-9 also attenuates inflammation-related organ injury by expanding Tregs, but it was not used in renal IR yet. Our aim was to test whether IPC combined with galectin-9 has an increased renoprotective effect. METHODS: Mice were divided into five treatment groups (n = 6 per group): (i) IR group: renal ischaemia/reperfusion group; (ii) IPC-IR group: IPC followed by renal IR; (iii) IPC-Gal9-IR group: Gal-9 injections during the time between IPC and IR; (iv) IPC-Gal9-PC61-IR group: anti-CD25 antibody administration apart from IPC, Gal-9 and IR; (v) sham-sham group. We assessed the renal function, histopathological scores, and percentages of Tregs and interferon-γ (IFN-γ) cells in peripheral bood, spleen, and kidney and compared these values among the different groups. RESULTS: Serum creatinine measured was significantly lower after IPC and even lower in combination with Gal-9 injection. The histopathological scores for tubulo-interstitial injury were decreased following IPC and markedly lower after the addition of Gal-9. The number of kidney infiltrating neutrophils and IFN-γ secreting CD4+ T cells was diminished in the IPC/Gal9 combination group, while the percentage of Treg cells in the peripheral blood, spleen, and kidney of animals from the IPC-Gal9-IR group was also markedly increased. CONCLUSION: The renoprotective effect of delayed IPC combined with galectin-9 was superior to IPC alone, through a mechanism related to expansion of regulatory T cells.

Lymphocyte depletion and subset alteration correlate to renal function in chronic kidney disease patients.

BACKGROUND: It is widely accepted that chronic renal failure is associated with severe alterations of immune system. However, few studies looked into the immune alteration in earlier stage of chronic kidney disease (CKD) patients. To characterize immune defect in CKD patients, we performed lymphocyte subset analysis and explored its relationship to renal function in this population. METHODS: 472 CKD patients were enrolled in this study. Lymphocyte subsets (CD19(+), CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD56(+)CD16(+)) were determined by flow cytometry. Clinical and laboratory data were collected. Patterns of immune cells in different stages of CKD were compared. Multivariate linear regression was used to evaluate the relationship between lymphocyte subset group and renal function. Correlation analysis was used to assess the relationship between lymphocyte subset and other clinical and laboratory data. RESULTS: Decreased lymphocyte counts occurred long before the end stage of renal disease. Increased NK cell percentage was negatively related to estimated glomerular filtration rate (eGFR) (r = -0.259, p < 0.001) while B cell percentage was positively related to eGFR (r = 0.249, p < 0.001). Further multivariate linear regression showed increased B cell percentage (ß = 16.470, 95%CI [1.018-31.922], p = 0.037) and decreased NK cell percentage (ß = -10.659, 95%CI [-20.063 to -1.254], p = 0.026) were independently correlated with higher eGFR, respectively. Patients with lower NK cell percentage and higher B cell percentage tended to have the best renal function. CONCLUSIONS: Lymphocyte depletion and subset alteration occurred during the progress of CKD. Further studies are needed to clarify the role of immune system in CKD and to expand our knowledge about the effect of uremia on the structure and function of immune system.

[The risk factors and prognosis of acute kidney injury after cardiac surgery: a prospective cohort study of 4007 cases].

OBJECTIVE: To investigate the risk factors and prognosis influential factors of acute kidney injury (AKI) after cardiac surgery. METHODS: The clinical data of patients who were hospitalized and underwent cardiac surgery from April 2009 to May 2011 were collected prospectively. Demographic characteristics, types of surgeries, preoperative renal function, pre- and intra-operative conditions and clinical outcomes, etc were recorded. RESULTS: A total of 4007 patients underwent cardiac surgery were recruited. The overall incidence of AKI was 31.2% (1250/4007). The incidence of AKI requiring renal replacement treatment (AKI-RRT) was 2.6% (104/4007). The overall hospital mortality was 1.9% (77/4007), and was significantly higher in AKI group than in non-AKI group (5.4% vs 0.3%, P < 0.01). The hospital mortality of AKI-RRT group was 36.5% (38/104). Grouped by type of surgery, cardiac transplantation had the highest AKI incidence (73.0%) and highest in-hospital mortality (18.9%), followed by coronary artery bypass grafting (CABG) combined with valve surgery (AKI incidence 57.8%, in-hospital mortality 6.1%) and aneurysm surgery (AKI incidence 52.0%, in-hospital mortality 5.5%). Multivariate logistic regression analysis showed that man, age, BMI, hypertension, chronic heart failure, pre-operative serum creatinine (SCr) > 106.0 µmol/L, intra-operative cardiopulmonary bypass time, intra-operative hypotension and aneurysm surgery were the risk factors of AKI after cardiac surgery. Multivariate logistic regression analysis showed that pre-operative SCr > 106.0 µmol/L and intra-operative hypotension were independent risk factors of renal recovery after cardiac surgery while recovery of urine output was the favorable factor. CONCLUSIONS: Cardiac surgery usually induces high AKI incidence and poor prognosis, which closely associated with many risk factors in peri-operative stage. The incidence of AKI is related to a number of perioperative risk factors. Heart transplantation, aneurysm surgery, CABG combined valve surgery are high risk surgeries.

[Effects of hypoxic preconditioning on the migration of bone marrow derived mesenchymal stem cells].

OBJECTIVE: To explore the effects and probable mechanism of CoCl2-induced hypoxic preconditioning on the migration of bone marrow derived mesenchymal stem cells (BMSC). METHODS: BMSC were cultured by whole bone marrow adherence and identified by surface markers (CD29, CD90 and CD45) with flow cytometry (FCM). The methods of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and FCM were applied to establish the model of CoCl2-induced hypoxic preconditioning. The migratory capacity of BMSC with hypoxic preconditioning was analyzed by the assays of scratch wound healing and transwell migration. The protein and mRNA expressions of HIF-1α and CXCR4 of BMSC were detected by Western blot and real-time polymerase chain reaction (PCR). After silencing HIF-1α by siRNA technique and blocking CXCR4 by its antagonist AMD3100, the changes of migratory capacity of BMSC were also tested. RESULTS: Cultured BMSC were uniformly positive for CD29 and CD90 and negative for CD 45. According to the results of MTT and FCM, 200 µmol/L CoCl2 and 24 h culture time was the ideal hypoxic preconditioning model of BMSC. The migratory capacity of BMSC in hypoxic preconditioning group was higher than the one in control group (scratch wound healing assay: (0.396 ± 0.018) mm vs (0.200 ± 0.011) mm, transwell migration assay: 21.0 ± 4.5 vs 8.5 ± 1.7, both P < 0.05). The protein and mRNA levels of HIF-1α and CXCR4 of BMSC in hypoxic preconditioning group were significantly higher than in control group. After silencing HIF-1α or blocking CXCR4 by AMD3100, the migratory capacity of BMSC in hypoxic preconditioning group decreased and had no difference with the control group. CONCLUSIONS: Hypoxic preconditioning may enhance the migratory capacity of BMSC in vitro. And it is partially attributable to the up-regulation of HIF-1α/CXCR4 axis after preconditioning.

[Goal-directed renal replacement therapy for acute kidney injury after cardiac surgery].

OBJECTIVE: To compare the efficacy and safety of goal-directed renal replacement therapy(GDRRT) and daily high volume hemofiltration (dHVHF) in the treatment of acute kidney injury (AKI) after cardiac surgery. METHODS: Clinical data from 128 patients received either GDRRT (n = 64) or dHVHF (n = 64) for AKI after cardiac surgery were analyzed retrospectively. parameters examined included: urea nitrogen, serum creatinine (SCr, before and after treatment), heart rate, mean artery pressure (MAp, recorded within 72 hours after the initiation of renal replacement therapy). The hospital mortality, day-28 mortality, renal function recovery rate, and the incidence of adverse events in the two groups were also compared. RESULTS: The hospital mortality was 43.75% for both GDRRT and dHVHF treated patients (group). The day-28 mortality in GDRRT group were slightly lower, but the difference was not significant (43.75% vs. 57.81%, P = 0.055). Also no significant difference was found between the two groups in hospital stay. The patients received dHVHF had longer intensive care unit (ICU) stay (hours) and duration of mechanical ventilation (days) as compared to the patients received GDRRT [356.5 (176.3, 554.6) vs. 238.3 (119.6, 440.9), P = 0.023; 8.0 (5.0, 16.0) vs. 6.0 (3.0, 13.5), P = 0.042]. The logistic regression analyses showed that complete renal function recovery rate in GDRRT group was significantly higher (39.1% vs. 18.8%, P < 0.01). The partial renal function recovery rate in GDRRT group was slightly lower but not statistically different from dHVHF group (3.1% vs. 9.4%, P > 0.05). In dHVHF group, the maximum SCr during the treatment, and the SCr before discharge were both significantly higher than GDRRT group (µmol/L: SCr maximum 559.0 ± 236.0 vs. 440.4 ± 192.0, SCr before discharge 381.4 ± 267.0 vs. 271.2 ± 164.4, both P < 0.01). No significant difference was found between the two groups in incidence of hypotension (35.9% vs. 37.5%) and MAP (mm Hg, 1 mm Hg=0.133 kPa, 82 ± 13 vs. 81 ± 15) 72 hours into the therapy (both P > 0.05). The incidence of tachycardia, and incidence of blood coagulation were both higher in dHVHF group (78.1% vs. 59.4%, 35.9% vs. 20.3%, both P < 0.05). However, the hospitalization expense (thousand yuan) was significantly higher for dHVHF group (15.00 ± 2.80 vs. 9.85 ± 3.00, P < 0.01). CONCLUSION: For patients with post-cardiac surgery AKI, GDRRT and dHVHF are very similar in terms of short-term survival rate and safety. But GDRRT is superior for renal function recovery and cost saving.

Epidemiology of Takayasu arteritis in Shanghai: A hospital-based study and systematic review.

BACKGROUND: Takayasu arteritis (TAK) is a rare large vessel vasculitis, and epidemiological data on TAK are lacking in China. Thus, we designed this study to estimate the TAK prevalence and incidence in residential Shanghai, China. METHODS: Data on diagnosed TAK cases aged over 16 years were retrieved from 22 tertiary hospitals in Shanghai through hospital electronic medical record systems between January 1, 2015 and December 31, 2017 to estimate the prevalence and incidence. A systematic literature review based on searches in PubMed, Ovid-Medline, Excerpta Medica Database (EMBASE), Web of Science, and China National Knowledge Infrastructure (CNKI) was performed to summarize TAK distribution across the world. RESULTS: In total 102 TAK patients, with 64% female, were identified. The point prevalence (2015-2017) was 7.01 (95% CI 5.65-8.37) cases per million, and the mean annual incidence was 2.33 (1.97-3.21) cases per million. The average age of TAK patients was 44 ± 16 years, with the highest prevalence (11.59 [9.23-19.50] cases per million) and incidence (3.55 [0.72 3.74] cases per million) in the 16 to 34 years population. Seventeen reports were included in the system review, showing that the epidemiology of TAK varied greatly across the world. The incidence and prevalence were both relatively higher in Asian countries, with the prevalence ranging 3.3-40 cases per million and annual incidence ranging 0.34-2.4 cases per million. CONCLUSIONS: The prevalence and incidence of TAK in Shanghai was at moderate to high levels among the previous reports. The disease burden varied globally among racial populations.

[A multi-center survey of hypertension and its treatment in patients with maintenance hemodialysis in Shanghai].

OBJECTIVE: To study the prevalence, treatment policy and control of hypertension in patients with maintenance hemodialysis, and to analyze the influencing factors of hypertension control. METHODS: We studied the current status of 1382 patients with maintenance hemodialysis in 11 dialysis centers in Shanghai, among them 809 were male, and 573 were female. Hypertension was defined as systolic blood pressure (SBP)≥140 and/or diastolic blood pressure (DBP)≥90 mm Hg (1 mm Hg=0.133 kPa). Those who had a history of hypertension and requiring antihypertensive therapy were also diagnosed as hypertension though their blood pressure was within normal range during the survey. Hypertension control was defined as blood pressure<140/90 mm Hg before each dialysis session. RESULTS: The prevalence of hypertension in the hemodialysis patients was 86.3%. The treatment rate and control rate in those patients were 96.8% and 25.5% respectively. More than half (50.4%) of patients were treated with only one kind of anti-hypertensive drug, and 34.4% with 2 kinds, 14.2% with 3 kinds, 1.0% with 4 kinds or more. Calcium channel blocker (CCB) was the most frequently prescribed drug (61.0%), followed by angiotensin II receptor blockers (56.4%), centrally acting anti-hypertensive agent (26.4%), beta blockers and alpha, beta-blockers (14.0%). The control rate of hypertension in those hemodialysis people was aggravated by the existence of coronary artery disease. The patients who need more kinds of antihypertensive agents have a poorer control rate of hypertension. The hypertension control rate elevated significantly with the adequate hemodialysis. CONCLUSIONS: There is a very high prevalence of hypertension in maintenance hemodialysis patients. Although the treatment rate is high, the control rate is unsatisfactory. So the control of hypertension in hemodialysis patient is still a clinical challenge. Appropriate dialysis adequacy, reasonable use of erythropoietin, treatment of heart disease and judicious use of antihypertensive drugs may be helpful to improve the clinical outcome.

Endoplasmic reticulum stress associated apoptosis as a novel mechanism in indoxyl sulfate­induced cardiomyocyte toxicity.

Indoxyl sulfate (IS), a typical uremic toxin, is of great importance in the development of chronic kidney disease. In addition to its nephrotoxicity, previous studies have provided increasing evidence for its cardiovascular toxicity. The mechanism underlying IS­induced cardiovascular toxicity has been elusive to date. The present study aimed to evaluate whether IS treatment could induce apoptosis of H9C2 cells, and used the endoplasmic reticulum (ER) stress­modulator 4­phenylbutyric acid (4­PBA) to evaluate whether IS­induced apoptosis is indeed associated with ERS. To evaluate whether IS induces apoptosis in H9C2 cardiomyocytes, cells were exposed to increasing concentrations of IS (500, 1,000, and 2,000 µM) for 24 h, and apoptosis was detected by flow cytometry. To determine whether IS­induced apoptosis is associated with ERS, cells were divided into 4 groups: control group, PBA group, IS group and PBA+IS group. IS dose­dependently induced apoptosis, and increased the expression of ER chaperones in H9C2 cells. Additionally, 4­PBA treatment decreased IS­induced apoptosis, and reduced ERS­associated protein expression induced by IS. Therefore, the mechanism may be associated with the CCAAT­enhancer­binding protein homologous protein and c­Jun N­terminal kinase signaling pathways.

Inappropriately elevated endothelin-1 plays a role in the pathogenesis of intradialytic hypertension.

The aim of this study is to investigate the effects of endogenous vasoactive substances on the occurrence of intradialytic hypertension (IDH) in patients during maintenance hemodialysis. Thirty-four maintenance hemodialysis patients were enrolled in this trial, and 17 of them were diagnosed with IDH (defined as an increase in blood pressure of at least 10 mmHg during or immediately after a hemodialysis session), while 17 age-matched and sex-matched controls without IDH were selected for a retrospective comparison. We collected patients' blood samples before and after a dialysis session and measured the plasma levels of N-terminal fragment brain natriuretic peptide, renin, angiotensin-II, aldosterone (ALD), angiotensin-converting enzyme (ACE), endothelin-1 (ET-1), nitric oxide (NO), norepinephrine (NOR), and adrenomedullin. The post-dialysis serum ET-1 concentrations were significantly higher (4.09 ± 2.06 vs. 2.75 ± 1.34 pg/mL, P < 0.05), while the post-dialysis ratio of NO to ET-1 was lower (17.79 ± 5.65 vs. 24.78 ± 12.04, P < 0.05) in IDH patients compared with the control group. Post-dialysis ALD and NOR values were significantly lower (P < 0.01) and ACE levels were significantly higher (P < 0.01) than the pre-dialysis concentrations only in the control and not in the IDH group. All other measured factors did not differ significantly between the groups and between pre-dialysis and post-dialysis determinations. Compared with blood angiotensin-II, ALD, ACE, NOR, adrenomedullin, N-terminal fragment brain natriuretic peptide, and NO status, inappropriately elevated ET-1 plasma concentrations may play a predominant role in the pathogenesis of IDH.